Use Of Angiotensin System Inhibitors Research Articles

The Impact of Renin–Angiotensin System Inhibitor Use on Clinical Outcomes by GRACE Score in ST-elevation MI Patients Undergoing Successful Percutaneous Coronary Intervention with Drug-eluting Stents

The Impact of Renin–Angiotensin System Inhibitor Use on Clinical Outcomes by GRACE Score in ST-elevation MI Patients Undergoing Successful Percutaneous Coronary Intervention with Drug-eluting Stents

Understanding Prescribing Practices and Patient Experiences with Renin Angiotensin System Inhibitors Use in Chronic Kidney Disease: A Qualitative Study

Introduction: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) improve outcomes but are underutilized in patients with chronic kidney disease (CKD). Little is known about reasons for discontinuation and lack of reinitiating these medications. We aimed to explore clinicians’ and patients’ experiences and perceptions of ACEI/ARB use in CKD. Methods: A multi-profession sample of health care clinicians and patients with documented ACEI/ARB-associated side effects in the past 6 months. Participants were recruited from 2 Veterans Affairs healthcare systems in Texas and Tennessee. A total of 15 clinicians and 10 patients completed interviews. We used inductive and deductive qualitative data analysis approaches to identify themes related to clinician and patient experiences with ACEI/ARB. Thematic analysis focused on prescribing decisions and practices, clinical guidelines, and perception of side effects. Data were analyzed as they amassed, and recruitment was stopped at the point of thematic saturation. Results: Clinicians prescribe ACEI/ARB for blood pressure control and kidney protection and underscored the importance of these medications in patients with diabetes. While clinicians described providing comprehensive patient education about ACEI/ARB in CKD, patient interviews revealed significant knowledge gaps about CKD and ACEI/ARB use. Many patients were unaware of their CKD status, and some did not know why they were prescribed ACEI/ARB. Clinicians’ drug management strategies varied widely, as did their understanding of prescribing guidelines. They identified structural and patient-level barriers to prescribing and many endorsed the development of a decision support tool to facilitate ACEI/ARB prescribing and management. Discussion/Conclusion: Our qualitative study of clinicians and providers identified key target areas for improvement to increase ACEI/ARB utilization in patients with CKD with the goal to improve long-term outcomes in high-risk patients. These findings will also inform the development of a decision support tool to assist with prescribing ACEI/ARBs for patients with CKD.

Does Heterogeneity Exist in Treatment Associations With Renin–Angiotensin–System Inhibitors or Beta-blockers According to Phenotype Clusters in Heart Failure with Preserved Ejection Fraction?

BackgroundWe explored the association between use of renin–angiotensin system inhibitors and beta-blockers, with mortality/morbidity in 5 previously identified clusters of patients with heart failure with preserved ejection fraction (HFpEF). Methods and ResultsWe analyzed 20,980 patients with HFpEF from the Swedish HF registry, phenotyped into young–low comorbidity burden (12%), atrial fibrillation–hypertensive (32%), older–atrial fibrillation (24%), obese–diabetic (15%), and a cardiorenal cluster (17%). In Cox proportional hazard models with inverse probability weighting, there was no heterogeneity in the association between renin–angiotensin system inhibitor use and cluster membership for any of the outcomes: cardiovascular (CV) mortality, all-cause mortality, HF hospitalisation, CV hospitalisation, or non-CV hospitalisation. In contrast, we found a statistical interaction between beta-blocker use and cluster membership for all-cause mortality (P = .03) and non-CV hospitalisation (P = .001). In the young–low comorbidity burden and atrial fibrillation–hypertensive cluster, beta-blocker use was associated with statistically significant lower all-cause mortality and non-CV hospitalisation and in the obese–diabetic cluster beta-blocker use was only associated with a statistically significant lower non-CV hospitalisation. The interaction between beta-blocker use and cluster membership for all-cause mortality could potentially be driven by patients with improved EF. However, patient numbers were diminished when excluding those with improved EF and the direction of the associations remained similar. ConclusionsIn patients with HFpEF, the association with all-cause mortality and non-CV hospitalisation was heterogeneous across clusters for beta-blockers. It remains to be elucidated how heterogeneity in HFpEF could influence personalized medicine and future clinical trial design.

The use of angiotensin system inhibitors correlates with longer survival in resected pancreatic adenocarcinoma patients

BackgroundActivities and inhibition of the Renin-Angiotensin-Aldosterone System (RAAS) may affect the survival of resected pancreatic ductal adenocarcinoma (PDAC) patients MethodA single-institution retrospective analysis of resected PDAC patients between 2010 and 2019. To estimate the effect of angiotensin system inhibitors (ASIs) on patient survival, we performed Kaplan Meier analysis, Cox Proportional Hazards model, Propensity Score Matching (PSM), and inverse probability weighting (IPW) analysis. Results742 patients were included in the analysis. The average age was 67.0 years, with a median follow-up of 24.1 months. The use of ASI was associated with significantly longer overall survival in univariate (p = 0.004) and multivariable (HR = 0.70 [0.56–0.88],p = 0.003) adjusted analysis. In a propensity score-matched cohort of 400 patients, ASI use was again associated with longer overall survival (p = 0.039). Lastly, inverse probability weighting (IPW) analysis suggested that the use of ASI was associated with an average treatment effect on the treated (ATT) of HR = 0.68 [0.53–0.86],p = 0.002) for overall survival. ConclusionIn this single-institution retrospective study focusing on resected PDAC patients, the use of ASI was associated with longer overall survival in multiple statistical models. Prospective clinical trials are needed before routine clinical implementation of ASI as an adjuvant to existing therapy can be recommended.

The Association Between Beta-blocker and Renin–Angiotensin System Inhibitor Use After Heart Failure With Reduced Ejection Fraction Hospitalization and Outcomes in Older Patients

IntroductionBeta-blockers (BB) and renin–angiotensin system inhibitors (RASi) are foundational for the treatment of heart failure with reduced ejection fraction (HFrEF). However, given the increased risk of side effects in older patients, uncertainty remains as to whether, on net, older patients benefit as much as the younger patients studied in trials. Methods and ResultsUsing the Get With The Guidelines–Heart Failure registry linked with Medicare data, overlap propensity weighted Cox proportional hazard models were used to examine the association between BB and RASi use at hospital discharge and 30-day and 1-year outcomes among patients with HFrEF. Among the 48,711 patients (aged ≥65 years) hospitalized with HFrEF, there were significant associations between BB and/or RASi use at discharge and lower rates of 30-day and 1-year mortality, including those over age 85 (30-day hazard ratio 0.56, 95% confidence interval 0.45–0.70; 1-year hazard ratio 0.69, 95% confidence interval 0.61–0.78). In addition, the magnitude of benefit associated with BB and/or RASi use after discharge did not decrease with advancing age. Even among the oldest patients, those over age 85, with hypotension, renal insufficiency or frailty, BB and/or RASi use at discharge was still associated with lower 1-year mortality or readmission. ConclusionsAmong older patients hospitalized with HFrEF, BB and/or RASi use at discharge is associated with lower rates of 30-day and 1-year mortality across all age groups and the magnitude of this benefit does not seem to decrease with advancing age. These data suggest that, absent a clinical contraindication, BB and RASi should be considered in all patients hospitalized with HFrEF before or at hospital discharge, regardless of age.

PD33-03 IS ANGIOTENSIN SYSTEM INHIBITOR USE ASSOCIATED WITH IMPROVED OUTCOMES IN PATIENTS WITH LOCALIZED CLEAR CELL RCC?

You have accessJournal of UrologyCME1 May 2022PD33-03 IS ANGIOTENSIN SYSTEM INHIBITOR USE ASSOCIATED WITH IMPROVED OUTCOMES IN PATIENTS WITH LOCALIZED CLEAR CELL RCC? Paige Nichols, Andrew Zganjar, Christine Lohse, Sounak Gupta, John Cheville, Cameron Britton, Aaron Potretzke, Stephen Boorjian, Houston Thompson, Bradley Leibovich, and Vidit Sharma Paige NicholsPaige Nichols More articles by this author , Andrew ZganjarAndrew Zganjar More articles by this author , Christine LohseChristine Lohse More articles by this author , Sounak GuptaSounak Gupta More articles by this author , John ChevilleJohn Cheville More articles by this author , Cameron BrittonCameron Britton More articles by this author , Aaron PotretzkeAaron Potretzke More articles by this author , Stephen BoorjianStephen Boorjian More articles by this author , Houston ThompsonHouston Thompson More articles by this author , Bradley LeibovichBradley Leibovich More articles by this author , and Vidit SharmaVidit Sharma More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002584.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Preclinical studies demonstrate VEGF expression is regulated by angiotensin II. Increased angiotensin II receptor expression in clear cell renal cell carcinoma (ccRCC) may be associated with higher tumor grade and poorer survival. It is unknown if angiotensin system inhibitors, in the form of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), are associated with improved outcomes for hypertensive patients with ccRCC. METHODS: A large nephrectomy registry was queried to identify adults treated with radical or partial nephrectomy for localized ccRCC from 2005-2012. Patients were divided into three groups: (1) patients without HTN, (2) patients with HTN but not treated with ACEIs or ARBs, and (3) patients with HTN treated with ACEIs or ARBs. The primary outcome of disease progression-free survival (PFS) and secondary outcomes of cancer-specific survival and CKD stage PFS were estimated using the Kaplan-Meier method. Associations with disease progression, death from RCC, and CKD stage progression were evaluated using multivariable Cox models. We adjusted for a disease progression score and a death from RCC score in the multivariable models for disease progression and death from RCC, respectively. RESULTS: Among 1,203 patients, there were 432 (36%), 359 (30%), and 412 (34%) in groups 1, 2, and 3, respectively, with a median follow-up of 10.1 (IQR 7.9-12.5) years. Disease PFS for the three groups is shown in Figure 1. On multivariable analysis, group 3 was associated with improved disease PFS compared to group 2 (HR 0.76, 95% CI 0.57-1.00, p=0.05) but not group 1 (HR 0.89, 95% CI 0.68-1.17, p=0.40). A subset multivariable analysis of group 3 treated with ACEIs alone relative to group 2 demonstrated improved disease PFS (HR 0.68, 95% CI 0.49-0.93, p=0.02). There were no significant differences between groups for either cancer specific survival or CKD stage PFS on multivariable analysis. CONCLUSIONS: The use of ACEIs or ARBs is associated with improved disease PFS in patients with HTN and localized ccRCC after radical or partial nephrectomy. No appreciable differences in cancer specific survival or CKD stage PFS were identified. Further studies are warranted to validate this finding and elucidate underlying mechanisms of angiotensin blockade in ccRCC patients. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e553 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Paige Nichols More articles by this author Andrew Zganjar More articles by this author Christine Lohse More articles by this author Sounak Gupta More articles by this author John Cheville More articles by this author Cameron Britton More articles by this author Aaron Potretzke More articles by this author Stephen Boorjian More articles by this author Houston Thompson More articles by this author Bradley Leibovich More articles by this author Vidit Sharma More articles by this author Expand All Advertisement PDF DownloadLoading ...

Rates of Spironolactone Initiation and Subsequent Hyperkalemia Hospitalizations in Patients with Heart Failure with Preserved Ejection Fraction Following the TOPCAT trial: A Cohort Study of Medicare Beneficiaries

BackgroundThe impact of the TOPCAT trial publication on spironolactone initiation and subsequent hospitalizations for hyperkalemia among patients with heart failure with preserved ejection fraction (HFpEF) has not been evaluated empirically. Methods and ResultsWe designed a cohort study using US Medicare fee-for-service data. Annual cohorts of patients with HFpEF from 2013 to 2018 were identified based on a validated claims-based phenotyping model. We determined spironolactone initiation in each annual cohort overall and within subgroups with hyperkalemia risk factors of baseline renin–angiotensin system inhibitors use, chronic kidney disease, and diabetes. We reported incidence rates of hospitalization for hyperkalemia within 6 months of treatment initiation. A total of 621,171 patients with HFpEF (mean age 80 ± 8 years, 62.9% female) were included. We identified 40,241 initiations of spironolactone with initiation rate/100 person-years of 16.8 (95% confidence interval [CI] 16.4–17.1) in 2013 and increasing to 19.9 (95% CI 19.4–20.5) in 2018. Among initiators, we identified a total of 164 hyperkalemia hospitalization with stable incidence rates per 1000 person-years between 2013 (12.0, 95% CI 8.8–16.1) and 2018 (10.6, 95% CI 6.2–17.0). These results were consistent for all subgroups. ConclusionsAfter the dissemination of TOPCAT findings, we noted a steady increase in the initiation of spironolactone, but not in hyperkalemia hospitalizations.

Inhibition of Renin-angiotensin System and Clinical Outcomes of COVID-19

Background and Aim: COVID-19 is an acute respiratory illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A few studies with conflicting results have been performed to evaluate the relationship between the use of angiotensin system inhibitors and COVID-19 outcomes. Therefore, this study was performed to compare the clinical and paraclinical characteristics of patients with COVID-19 in two groups of patients treated with angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) and the control group (no history of ACEIs/ARBs) in Kamkar and Shahid Beheshti hospitals in Qom City, Iran from March 14, 2019, to the end of September 21, 2020. Materials and Methods: This retrospective descriptive study was performed by reviewing the medical record of 359 patients with COVID-19, which was confirmed by a physician via lung scan or reverse transcription polymerase chain reaction (RT-PCR). We used the independent t test to compare quantitative variables and the Chi-square test to analyze qualitative variables. Results: The common clinical symptoms, number of hospitalization days, oxygen saturation, and lung involvement were not significantly different between the two groups. Weakness, nausea, and sweating were significantly reduced in the control group compared to the ACEIs/ARBs group (P<0.05). Regarding the biochemical study, the patients’ hemoglobin levels and lymphocyte count on the first day of hospitalization in the ACEIs/ARBs group were significantly lower than the control (P<0.05) Conclusion: These findings do not provide evidence of adverse or beneficial effects of angiotensin system inhibitors, so we require more detailed studies with a larger sample size.

Inhaled Beta2-Agonists Increase In-Hospital Mortality in ICU Patients with Heart Failure.

The impact of beta2-agonists (B2As) on heart failure (HF) remains controversial. This study aimed to investigate whether inhaled B2As increased in-hospital mortality in ICU patients with HF.The Multiparameter Intelligent Monitoring in Intensive Care III database was initially searched to identify adult patients (≥ 18 years old) with HF in ICU. Then, patients using or not using inhaled B2As were matched using propensity score matching on a 1:1 basis to control for baseline confounders. In-hospital mortality was compared between the two groups, and logistic regression analysis was performed to assess the association between B2As and in-hospital mortality.The initial search retrieved 2345 eligible patients with HF from the database. After propensity score matching, 705 pairs of patients were included in the final analysis. Patients using B2As had markedly higher in-hospital mortality than those not using B2As (4.68% versus 2.27%; P = 0.013). In the multivariate logistic regression analysis, B2A use (odd ratios (OR), 2.471; 95% confidence interval (CI), 1.289-4.734; P = 0.006), stroke (OR, 4.581; 95% CI, 1.621-12.948; P = 0.004), and simplified acute physiology score II (SAPS-II) scores (OR, 1.090; 95% CI, 1.064-1.116; P < 0.001) were significantly associated with increased risk of in-hospital mortality, whereas renin angiotensin system inhibitor use (OR, 0.396; 95% CI, 0.202-0.778; P = 0.007) was significantly associated with decreased risk of in-hospital mortality. Subgroup analysis further indicated that the association between B2A use and mortality was significant only in patients with HF without chronic pulmonary disease (OR, 2.427; 95% CI, 1.351-4.362; P = 0.003), but not in those with chronic pulmonary disease (OR, 2.094; 95% CI, 0.582-7.537; P = 0.258).In ICU patients with HF but without chronic pulmonary disease, the use of inhaled B2As is associated with increased in-hospital mortality.

Angiotensin system inhibitor use is associated with longer survival in resected pancreatic cancer

Presenter: Hao Liu MD, PhD | University of Pittsburgh Medical Center Background: The renin-angiotensin system (RAS) has been correlated with pancreatic adenocarcinoma (PDAC) tumorigenesis and progression. Activities and inhibition of RAS may affect the response to systemic therapy and may correlate with clinical outcomes. Previous observational studies suggested that angiotensin system inhibitor (ASI) use is associated with prolonged survival in a subset of PDAC patients. Our present study focused on resected PDAC patients and further explored the protective effect of ASI. Methods: We conducted a single-institution retrospective analysis of resected PDAC patients between 2010-2019. Clinicopathological characteristics of all cases meeting inclusion criteria were reviewed. The effect of ASI on patient survivals was measured by Kaplan Meier analysis, Cox Proportional Hazards model, Propensity Score Matching (PSM), and inverse propensity score weight (IPW) analysis. The propensity score of ASI treatment was calculated, accounting for comorbidities and treatments received, including the use of beta-blockers, diuretics, metformin, and statins. Results: A total of 813 patients were included in the analysis. The average age was 67.0 (34 – 91) years with a median follow up of 20.2 (1.8 – 117.5) months. On average, ASI users were older (69.1 vs. 65.1y, p<0.001) and has higher Charlson comorbidity index (4.6 vs 5.4, p<0.001). However, the use of ASI was significantly associated with longer overall survival in univariate (HR = 0.78 [95%CI: 0.65-0.92], p = 0.004) and multivariate (HR = 0.73 [0.58-0.91], p = 0.005) adjusted analysis. In the propensity score-matched cohort of 637 patients, ASI use confirmed the association with longer overall survival (HR = 0.75 [0.59-0.94], p = 0.013) as well as longer disease-free progression in the liver (HR = 0.66 [0.45-0.95}, p = 0.026) and peritoneum (HR = 0.60 [0.36-0.98] p = 0.041) but not local recurrence-free survival (HR = 0.92 [0.62-1.34], p = 0.653). Lastly, IPW analysis on the whole cohort of 813 patients demonstrated ASI use to be associated with an average treatment effect on the treated (ATT) of HR = 0.67 [0.53-0.85] (p<0.001) for overall survival. Conclusion: In this single institute retrospective study focusing on resected PDAC patients, the use of ASI was associated with longer overall survival after adjusting for multiple clinicopathological parameters. Propensity score matching and inverse propensity score weighted analysis also showed that ASI use was associated with longer overall and progression-free survival. Further prospective trials on the impact of ASI on PDAC are needed.

Impact of angiotensin system inhibitors on esophageal cancer survival

IntroductionAngiotensin system inhibitors are associated with improved prognosis in patients with gastrointestinal and hepatobiliary cancers. Data suggest that renin–angiotensin system signaling stimulates the tumor's immune microenvironment to impact overall survival. The goal of this study is to investigate the role of angiotensin system inhibitor use on the overall survival and disease-free survival of esophageal cancer patients. MethodsRetrospective review of esophagectomy patients with esophageal adenocarcinoma and squamous cell cancer at a single institution tertiary care center from 2007 to 2018 was performed. Outcomes include overall survival and disease-free survival. Patient characteristics were compared with t test and χ2 test. Survival was analyzed with Kaplan–Meier and Cox proportional-hazards regression. ResultsOne hundred seventy-one patients were identified and 123 underwent esophagectomy for cancer. No significant differences in patient demographics were found between angiotensin system inhibitor users and non–angiotensin system inhibitor users except for the rates of hypertension (40% vs 94%, P < .01) and diabetes (16% vs 47%, P < .01). Distributions of tumor neoadjuvant therapy, adjuvant therapy, pathology, staging, margins, and surgical approach were similar. Postoperatively, there was no difference in major adverse cardiovascular events or infection rates. This study did not find any differences in overall survival and disease-free survival between angiotensin system inhibitor users and non–angiotensin system inhibitor users. ConclusionAngiotensin system inhibitors have been shown to improve survival and decrease relative risk for several types of cancers; however, our data do not support the same effect on esophageal cancer patients undergoing curative intent surgery. Further research is needed to investigate potential nuances in angiotensin system inhibitor dose, chronicity of use, esophageal pathology, and applicability to nonsurgical candidates.

Association between Use of Angiotensin-converting Enzyme Inhibitors or Angiotensin Receptor Blockers and Postoperative Delirium.

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers improve cognitive function. The authors therefore tested the primary hypothesis that preoperative use of angiotensin inhibitors is associated with less delirium in critical care patients. Post hoc, the association between postoperative use of angiotensin system inhibitors and delirium was assessed. The authors conducted a single-site cohort study of adults admitted to Cleveland Clinic critical care units after noncardiac procedures between 2013 and 2018 who had at least one Confusion Assessment Method delirium assessment. Patients with preexisting dementia, Alzheimer's disease or other cognitive decline, and patients who had neurosurgical procedures were excluded. For the primary analysis, the confounder-adjusted association between preoperative angiotensin inhibitor use and the incidence of postoperative delirium was assessed. Post hoc, the confounder-adjusted association between postoperative angiotensin system inhibitor use and the incidence of delirium was assessed. The incidence of delirium was 39% (551 of 1,396) among patients who were treated preoperatively with angiotensin system inhibitors and 39% (1,344 of 3,468) in patients who were not. The adjusted odds ratio of experiencing delirium during critical care was 0.98 (95% CI, 0.86 to 1.10; P = 0.700) for preoperative use of angiotensin system inhibitors versus control. Delirium was observed in 23% (100 of 440) of patients who used angiotensin system inhibitors postoperatively before intensive care discharge, and in 41% (1,795 of 4,424) of patients who did not (unadjusted P < 0.001). The confounder-adjusted odds ratio for experiencing delirium in patients who used angiotensin system inhibitors postoperatively was 0.55 (95% CI, 0.43 to 0.72; P < 0.001). Preoperative use of angiotensin system inhibitors is not associated with reduced postoperative delirium. In contrast, treatment during intensive care was associated with lower odds of delirium. Randomized trials of postoperative angiotensin-converting enzymes inhibitors and angiotensin receptor blockers seem justified.

Abstract A18: Angiotensin receptor blockers normalize the pancreatic ductal adenocarcinoma stroma by reprogramming carcinoma-associated fibroblasts

Abstract The resistance to therapy in pancreatic ductal adenocarcinoma (PDAC) is due in part to carcinoma-associated fibroblasts (CAFs) that produce a highly desmoplastic and proinflammatory tumor microenvironment (TME). Our laboratory has shown that the angiotensin receptor blocker (ARB) losartan reduces the CAF-density and desmoplasia, and improves vascular perfusion, and the uptake and efficacy of drugs in animal models of PDAC (Diop-Frimpong et al., PNAS 2011; Chauhan et al., Nature Comm 2013). These preclinical findings led to a phase II trial at Massachusetts General Hospital in locally advanced PDAC patients, which showed that losartan combined with neoadjuvant-FOLFIRINOX chemotherapy followed by chemoradiation more than doubled the resection rate (Murphy et al., JAMA Oncology 2019). Moreover, in a retrospective analysis, we found that the chronic use of angiotensin system inhibitors was independently associated with longer overall survival in nonmetastatic PDAC patients (Liu et al., Clin Cancer Res 2017). However, how ARBs affect CAFs and desmoplasia in human PDAC remains unknown. Here we performed immunohistochemistry in formalin-fixed, paraffin-embedded sections to examine the effect of chronic use of ARB on CAF phenotypes and the extracellular matrix (ECM) in resected PDAC samples from untreated patients and patients treated with ARBs to control their hypertension. We found that the chronic use of ARBs did not reduce the density of CAFs expressing the fibroblast activation protein (FAP), α-smooth muscle actin (α-SMA), or platelet-derived growth factor receptor-beta alone. However, ARBs increased the fraction of CAFs expressing both the angiotensin receptor 1 (AT1) and α-SMA and decreased the fraction of CAFs expressing both AT1 and FAP. ARBs also reduced the intratumoral levels of hyaluronan, suggesting that ARBs reduce desmoplasia in human PDAC. To reveal the underlying mechanisms, we performed a transcriptomic analysis of the bulk tumor as well as α-SMA+ cells isolated from mice bearing orthotopic PDAC tumors and treated with losartan. Gene expression profiling revealed that in both the tumor bulk and α-SMA+ cells, losartan “normalized” the ECM/cytoskeleton interaction, glycosaminoglycan metabolism and platelet-derived growth factor gene sets, and significantly reduced gene transcripts ofS100A8 and S100A9 . Gene products of S100A8 and S100A9 are S100 proteins that stimulate the development of myeloid-derived suppressor cells. In α-SMA+ cells—but not in tumor bulk—losartan reduced cell cycle and muscle contraction gene sets. These results suggest that ARBs can reprogram α-SMA+ cells and normalize the TME in PDAC. Citation Format: Hao Liu, William W. Ho, Kamila Naxerova, Jelena Grahovac, Hadi Nia, Ivy Chen, Jessica M. Posada, Daniel H. Schanne, Matthias Pinter, Jonathan Crain, Xialong Qi, Jeffrey W. Clark, Theodore S. Hong, David P. Ryan, Peigen Huang, Keith D. Lillemoe, Carlos Fernández-Del Castillo, Cristina R Ferrone, Michael Downes, Ronald M. Evans, Vikram Deshpande, Yves Boucher, Rakesh K. Jain. Angiotensin receptor blockers normalize the pancreatic ductal adenocarcinoma stroma by reprogramming carcinoma-associated fibroblasts [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A18.

Abstract SY33-01: Improving immunotherapy of cancer by normalizing tumor vessels

Abstract SY33-01: Improving immunotherapy of cancer by normalizing tumor vessels

Abstract A115: Use of angiotensin system inhibitors is associated with immune activation and longer survival in pancreatic ductal adenocarcinoma patients

Abstract Purpose: Angiotensin system inhibitors (ASIs) can improve prognosis in multiple cancer types, including pancreatic ductal adenocarcinoma (PDAC). However, no study has examined the effect of ASIs alone or combined with adjuvant chemotherapy in resected PDAC patients. Experimental Design: We performed an analysis of the records of ASI users and non-user patients with PDAC seen at Massachusetts General Hospital between January 2006 and December 2010. To identify mechanisms of ASIs in PDAC, we performed RNA-Seq of resected primary lesions. In a prospective trial (NCT01821729), we investigated circulating biomarkers of losartan activity. Results: 794 consecutive patients were included. In 299 resected patients, ASI-users experienced longer overall survival (OS) in both univariate (median OS: 36.3 vs. 19.3 months, p=0.011) and adjusted multivariate (HR, 0.505; 95%CI, 0.339 - 0.750; p=0.001) analyses. Propensity score adjusted analysis also showed a longer median OS for chronic ASI users. In unresected patients, the beneficial effect of ASIs was significant in patients with locally advanced disease, but not in metastatic patients. RNA-Seq analysis revealed in tumors of ASI-users (lisinopril) a normalized extracellular matrix, a reduced expression of genes involved in PDAC progression (e.g., WNT and Notch signaling) and an increased expression of genes linked with the activity of T-cells and antigen-presenting cells. Finally, chronic use of ASI was associated with a gene expression signature that is predictive of survival in independent validation cohorts. Circulating biomarker data will be presented at the meeting. Conclusions: In patients with non-metastatic PDAC, chronic ASI use is associated with longer OS independently of chemotherapy. Our RNA-Seq analysis suggests that ASI reduce the malignant potential of cancer cells and stimulate the immune microenvironment in primary PDAC. Citation Format: Nilesh P. Talele, Hao Liu, Kamila Naxerova, Matthias Pinter, Joao Incio, Hang Lee, Kohei Shigeta, William W. Ho, Theodoros Michelakos, Theodore S. Hong, Jeffrey W. Clark, Janet E. Murphy, David P. Ryan, Vikram Deshpande, Kieth D. Lillemoe, Carlos Fernandez-del Castillo, Michael Downes, Ronald M. Evans, James Michaelson, Dan G. Duda, Cristina R. Ferrone, Yves Bouches, Rakesh Jain. Use of angiotensin system inhibitors is associated with immune activation and longer survival in pancreatic ductal adenocarcinoma patients [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A115.

Association between renin–angiotensin system inhibitor use and mortality/morbidity in elderly patients with heart failure with reduced ejection fraction: a prospective propensity score-matched cohort study

In heart failure with reduced ejection fraction (HFrEF), renin-angiotensin system inhibitors (RASi) improve morbidity and mortality. However, patients aged >80 years constituted a small minority in trials. We assessed the association between RASi use and mortality/morbidity in HFrEF patients aged >80 years. We included patients with ejection fraction <40% and age >80 years from the Swedish Heart Failure Registry. Propensity scores for RASi use were calculated from 37 variables. Cox regression models for RASi vs. non-RASi with all-cause mortality and all-cause mortality/heart failure (HF) hospitalization as outcomes were fitted in a 1:1 propensity-score-matched cohort. To assess consistency, the same analyses were performed in a 'positive control' cohort aged ≤80 years. Of 6710 patients [median age (interquartile range) 85 (82-87) years; 38% women], 5384 (80%) received RASi. Propensity-score matching yielded 2416 patients, [age 86 (83-91) years]. RASi use was associated with hazard ratio (HR) (95% confidence interval) 0.78 (0.72-0.86) for all-cause mortality and 0.86 (0.79-0.94) for all-cause mortality/HF hospitalization. In positive control patients aged ≤80 years (17 842 patients in the overall cohort, 2126 after matching), HR for all-cause mortality was 0.81 (0.71-0.91), whereas it was 0.85 (0.76-0.94) for all-cause mortality/HF hospitalization. In HFrEF patients with age >80 years, RASi were relatively underused compared with in younger patients, despite similar association with reduced morbidity and mortality and no apparent association with risk of syncope-related hospitalization. These results may be interpreted as hypothesis generating for randomized clinical trials on RASi in this elderly HFrEF subpopulation.

Use of Angiotensin System Inhibitors Is Associated with Immune Activation and Longer Survival in Nonmetastatic Pancreatic Ductal Adenocarcinoma.

Purpose: Angiotensin system inhibitors (ASI) can improve prognosis in multiple cancer types, including pancreatic ductal adenocarcinoma (PDAC). However, no study has examined the effect of ASIs alone or combined with adjuvant chemotherapy in resected PDAC patients.Experimental Design: We performed an analysis of the records of ASI users and nonuser patients with PDAC seen at Massachusetts General Hospital (Boston, MA) between January 2006 and December 2010. To identify mechanisms of ASIs in PDAC, we performed RNA sequencing (RNA-Seq) of resected primary lesions.Results: A total of 794 consecutive patients were included. In 299 resected patients, ASI users experienced longer overall survival (OS) in both univariate (median OS, 36.3 vs. 19.3 months, P = 0.011) and adjusted multivariate [HR, 0.505; 95% confidence interval (CI), 0.339-0.750; P = 0.001] analyses. Propensity score-adjusted analysis also showed a longer median OS for chronic ASI users. In unresected patients, the beneficial effect of ASIs was significant in patients with locally advanced disease, but not in metastatic patients. RNA-Seq analysis revealed in tumors of ASI users (lisinopril) a normalized extracellular matrix, a reduced expression of genes involved in PDAC progression (e.g., WNT and Notch signaling), and an increased expression of genes linked with the activity of T cells and antigen-presenting cells. Finally, chronic use of ASI was associated with a gene expression signature that is predictive of survival in independent validation cohorts.Conclusions: In patients with nonmetastatic PDAC, chronic ASI use is associated with longer OS independently of chemotherapy. Our RNA-Seq analysis suggests that ASIs reduce the malignant potential of cancer cells and stimulate the immune microenvironment in primary PDAC. Clin Cancer Res; 23(19); 5959-69. ©2017 AACR.

Abstract 957: Use of angiotensin system inhibitors is associated with longer overall survival in pancreatic ductal adenocarcinoma patients who underwent pancreatectomy

Abstract Introduction: Angiotensin system inhibitors (ASI) are widely used to manage hypertension. Laboratory and retrospective clinical data suggests that ASIs can improve cancer prognosis. The aim of this study is to investigate the effect of ASIs on overall survival in pancreatic ductal adenocarcinoma (PDAC) patients. Methods: We performed a retrospective review of the clinicopathologic records of patients with PDAC seen at the Massachusetts General Hospital (MGH) between 1/2006 - 12/2010. Patients on angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) were included as ASI users. We performed RNAseq and Gene Set Enrichment Analysis (GSEA) of primary tumor samples from patients with or without chronic ASI use. We also identified a surrogate signature of differentially expressed genes and we measured the extent of angiotensin inhibition in GEO and TCGA datasets. The extent of inhibition was used to correlate with survival. Statistical analysis was performed using Kaplan-Meier estimator and Cox proportional hazards ratio model. Results: A total of 794 consecutive PDAC patients were included, of whom 297 (37.4%) were on ASIs and 183 (23.0%) were on non-ASI antihypertensive drug therapy. In resected patients, ASI users had a significantly longer overall survival on univariate (median OS: 36.3 vs. 19.3 months, p=0.011) and multivariate analysis (HR, 0.49; 95%CI, 0.333-0.734; p&amp;lt;0.001). In our sub-group analysis of resected hypertensive patients treated with chemotherapy, chronic ASI users had a significantly longer overall survival than ASI-naïve patients (p=0.048) (28.7 vs 12.3 months, p&amp;lt; 0.05). Gene Set Enrichment Analysis revealed that the ASI lisinopril down-regulated genes which stimulate the mitotic cell cycle, WNT and Notch signaling and the interaction between integrins and the extracellular matrix. Lisinopril also enhanced gene sets linked with oxidative phosphorylation, antigen processing and presentation and the cytotoxic activity of T cells. In unresected patients, the effect of ASI was only significant in patients with locally advanced disease in multivariate analysis (HR, 0.572; 95%CI, 0.386-0.847; p=0.005), but not in metastatic patients. The low expression of genes down-regulated by ACEi was also significantly associated with longer survival in the TCGA and GSE71729 datasets. Conclusion: In patients with PDAC, ASI use is associated with longer overall survival in resected patients and may benefit patients with locally advanced disease. These findings suggest the need for a prospective study to determine the efficacy of ASI in PDAC patients. Citation Format: Hao Liu, Matthias Pinter, Joao Incio, Hang Lee, William Ho, Jonathan Crain, Kamila Naxerova, Mengyang Di, Alex Jacobson, Daniella Dias Santos, Andrea Zanconato, Vikram Deshpande, Keith Lillemoe, Carlos Fernandez del Castillos, Michael Downes, Ronald Evans, James Michaelson, Cristina Ferrone, Yves Boucher, Jain K. Rakesh. Use of angiotensin system inhibitors is associated with longer overall survival in pancreatic ductal adenocarcinoma patients who underwent pancreatectomy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 957. doi:10.1158/1538-7445.AM2017-957

Comprehensive Analysis of Survival Outcomes in Non-Clear Cell Renal Cell Carcinoma Patients Treated in Clinical Trials.

Clinical data from patients with non-clear cell renal cell carcinoma (nccRCC) receiving targeted therapy are limited, and many clinical trials have excluded these patients from study entry. We sought to investigate the outcomes of patients with nccRCC treated in clinical trials in the modern era compared with the outcomes of patients with clear cell RCC (ccRCC). We conducted a retrospective study of patients with metastatic RCC who had received targeted therapy in Pfizer-sponsored phase II and III clinical trials from 2003 to 2013. Associations between the histologic type and treatment outcome (overall survival [OS] and progression-free survival [PFS]) were assessed using the log-rank test on univariate analysis or the Wald χ2 test from Cox regression on multivariable analysis, adjusted for baseline characteristics, including age, sex, Eastern Cooperative Oncology Group performance status, body mass index, International Metastatic RCC Database Consortium risk factors, previous nephrectomy, previous therapy, metastatic sites, angiotensin system inhibitor use, and statin use. We identified 4527 patients with metastatic RCC: 4235 with ccRCC and 337 with nccRCC. Overall, the median OS was shorter for those with nccRCC than for those with ccRCC (15.7 vs. 20.2 months; hazard ratio [HR], 1.41; 95% confidence interval 1.22-1.63; P< .001). When stratified by the International Metastatic RCC Database Consortium risk group, the median OS was inferior for the intermediate- and poor-risk patients with nccRCC than for those with ccRCC. However, no differences were found in the favorable risk group for nccRCC versus ccRCC. The patients with nccRCC who had received vascular endothelial growth factor-targeted therapy had shorter PFS compared with that of ccRCC patients (median, 6.1 vs. 8.5 months; HR, 1.49; P< .001) but similar PFS when treated with mammalian target of rapamycin inhibitors (median, 4.3 vs. 4.4 months; HR, 0.92; P= .63). Our findings have confirmed that patients with nccRCC are underrepresented in clinical trials and highlight the need for further prospective studies exploring current and novel agents for this patient population.

Angiotensin Inhibitors as Treatment of Sunitinib/Pazopanib-induced Hypertension inMetastatic Renal Cell Carcinoma.

Research suggests that baseline use of angiotensin system inhibitors (ASIs) improves outcome in patients with metastatic renal cell carcinoma (mRCC), but it remains unknown whether the type of antihypertensive medication used to initiate management at onset of treatment-induced hypertension (HTN) is associated with outcome. We evaluated the association of ASIs and outcome among patients with mRCC treated with first-line tyrosine kinase inhibitors (TKIs). We identified 303 consecutive patients with mRCC who were treated with sunitinib or pazopanib in a single university hospital cancer center. Statistical analyses were performed using the Kaplan-Meier method and Cox regression adjusted for known risk factors. Progression-free survival (PFS) and overall survival (OS) were similar among patients with baseline HTN (n= 197; 65%) versus patients with no baseline HTN (n= 106; 35%) (PFS; P= .72) (OS; P= .54). There was a significant difference between patients with treatment-induced HTN (n= 110) versus patients with no treatment-induced HTN (n= 193) for PFS (15.6 vs. 6.4 months, respectively; P< .001) and OS (34.9 vs. 13.9 months, respectively; P< .001). Use of ASIs at baseline (n=126; 41.6%) had no impact on outcome as compared with patients receiving other antihypertensive medication (n= 71; 23.4%) or with patients with no baseline antihypertensive medication (n= 106; 35.0%). Among patients with TKI-induced HTN (n= 110), however, ASI users (n= 91) demonstrated improved OS (37.5 vs. 18.1 months; P= .001) and PFS (17.1 vs. 7.2 months; P= .004) versus ASI nonusers (n= 19), respectively. Our results demonstrate survival benefit for ASI users among patients with TKI-induced HTN. These results, however, require further validation in a prospective setting.