Angiotensin-converting Enzyme Inhibitor Therapy Research Articles

Age- and Genotype-Specific Effects of the Angiotensin-Converting Enzyme Inhibitor Lisinopril on Mitochondrial and Metabolic Parameters in Drosophila melanogaster.

The angiotensin-converting enzyme (ACE) is a peptidase that is involved in the synthesis of Angiotensin II, the bioactive component of the renin-angiotensin system. A growing body of literature argues for a beneficial impact of ACE inhibitors (ACEi) on age-associated metabolic disorders, mediated by cellular changes in reactive oxygen species (ROS) that improve mitochondrial function. Yet, our understanding of the relationship between ACEi therapy and metabolic parameters is limited. Here, we used three genetically diverse strains of Drosophila melanogaster to show that Lisinopril treatment reduces thoracic ROS levels and mitochondrial respiration in young flies, and increases mitochondrial content in middle-aged flies. Using untargeted metabolomics analysis, we also showed that Lisinopril perturbs the thoracic metabolic network structure by affecting metabolic pathways involved in glycogen degradation, glycolysis, and mevalonate metabolism. The Lisinopril-induced effects on mitochondrial and metabolic parameters, however, are genotype-specific and likely reflect the drug’s impact on nutrient-dependent fitness traits. Accordingly, we found that Lisinopril negatively affects survival under nutrient starvation, an effect that can be blunted by genotype and age in a manner that partially mirrors the drug-induced changes in mitochondrial respiration. In conclusion, our results provide novel and important insights into the role of ACEi in cellular metabolism.

Angiotensin-Converting Enzyme Inhibitors or Angiotensin Receptor Blocker use During Stereotactic Body Radiation Therapy Associated with Decreased Pneumonitis: A Multi-center Analysis

Radiation pneumonitis (RP) is a serious adverse effect associated with lung radiation therapy (RT). The use of angiotensin-converting enzyme inhibitors (ACEI) is associated with a lower risk of RP in the setting of conventional lung RT. However, whether ACEI use during stereotactic body radiation therapy (SBRT) has protective properties against RP is unknown. Similarly, the effect of angiotensin receptor blockers (ARB) use on the incidence of RP is not known. The purpose of this study is to examine the impact of ACEI and ARB use during lung SBRT treatment on the development of RP. Under an Institutional Review Board-approved protocol, the records of 252 consecutive patients from 2009 – 2015 at 4 related academic institutions with lung cancer treated with SBRT were reviewed. Presence of RP was determined using all available records, including follow-up data from radiation oncology, pulmonology, medical oncology, and hospitalizations, and graded using the Common Terminology Criteria for Adverse Events Version 4.0. Univariate and multivariate analysis was performed to identify factors associated with clinical outcomes. Kaplan-Meier methods were used to determine OS. A total of 208 patients were used for the analysis with a median follow-up time of 23 months. Median age was 71 years old. Median tumor size was 2.1cm, and 63% of the tumors were peripheral in location. 68% of the tumors were T1, 48% were T2, 7% were T3, and 2% were T4, 8% were node positive. 77 patients (37%) received either ACEI (26%) or ARB (11%) therapy during SBRT. 25 patients developed grade 1 pneumonitis (12%), 20 patients developed grade 2 pneumonitis (10%), 14 patients developed grade 3 pneumonitis (7%), 5 patients developed grade 4 pneumonitis (2%), and 2 patients developed grade 5 pneumonitis (1%). In total 32% of patients developed pneumonitis of any grade. Significantly fewer patients developed any grade of RP if ACEI or ARB were taken during SBRT compared to those who did not - 16.6% vs. 38.4% at 1 year, and 25.6% vs. 39.6% at 2 years (p<=0.005). ACEI or ARB use was associated with higher 5-year overall survival rates, 44.5% vs. 28.5% (HR 0.60, p=0.042). On subset univariate analysis in patients receiving either 3, 4 or 5 fraction SBRT, 5 fraction SBRT was associated with higher rates of any grade RP compared to those treated with 3 or 4 fraction SBRT (HR 2.15, p=0.029). On subset multivariable analysis ACEI/ARB use was significant for lower rates of any grade RP (HR 0.41, p=0.003), and; 5 fraction SBRT and age >65 years were associated with higher rates of any grade RP (HR 2.5, p=0.01, HR 1.92, p=0.049 respectively). ACEI or ARB use during SBRT was associated with significantly greater freedom from any grade RP, and higher likelihood of 5-year survival. ACEI or ARB use during SBRT should be prospectively evaluated.

Serum concentration of renin-angiotensin system components in association with ACE I/D polymorphism among hypertensive subjects in response to ACE inhibitor therapy

ABSTRACTBackground: Renin-angiotensin system (RAS) is a complex network of enzymes and peptides with the essential role in blood pressure control. The relationships between RAS components, RAS-related genetic polymorphisms and therapy response in essential hypertension (EH) were widely explored but the results were inconclusive.Aim: The aim of this study was to explore the functional role of ACE insertion/deletion (I/D) polymorphism on the systemic quantity of angiotensin-converting enzyme (ACE), its homolog - ACE2, chymase and angiotensin II in EH patients with respect to achieved therapeutic blood pressure control.Results: Genotyping of ACE I/D polymorphism was performed among 140 patients with EH from Bulgaria. The serological analyses reveal the significant elevation of the serum quantity of all investigated enzymes in EH than normotensive controls. In addition, serum ACE2 (183.57 pg/ml; vs. 151.78 pg/ml; p = 0.02) and chymase (68.5 pg/ml; vs. 23.66 pg/ml; p = 0.034) were significantly higher in patients with uncontrolled EH than controlled EH in response to ACE-inhibitory therapy. Also, ACE I/D polymorphism showed a significant impact on the serum ACE and chymase levels. ACE quantity was the highest among carriers of DD-genotype, followed by ID and II-genotype. Contrary, chymase was in the highest quantity in II-genotype compared to ID-genotype (p = 0.025) and DD-genotype (p = 0.044).Conclusions: Our results suggest that insufficient blood pressure control by ACE-inhibitory therapy could be associated with elevation of serum ACE2 and chymase levels. Also, it appears that ACE I/D polymorphism may influence the circulating quantity of chymase in addition to ACE.

ACE in the Hole: Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema as a Cause of Recurrent Abdominal Pain

As one of the most prescribed medications in the United States, angiotensin-converting-enzyme inhibitors (ACEI) have a 0.1-0.7% risk of angioedema. Oropharyngeal angioedema is well known and rarer is angioedema of the GI tract, which can present with nonspecific signs of abdominal pain, nausea, or vomiting. We report a case of angioedema of the small bowel in a patient with recurrent abdominal pain and small bowel segmental thickening of the jejunum. A 58-year-old African American woman with a history of hypertension on lisinopril presented with recurrent abdominal pain in the mid-abdomen associated with vomiting and diarrhea. Symptoms would resolve with supportive treatment and she had several admissions for the same complaint over the past year. On exam she was afebrile with normal vitals and a mildly tender but soft abdomen. Laboratory data was remarkable for mild leukocytosis (12.4 WBC/mm3) with normal eosinophils. Infectious workup was negative and she had a normal C-reactive protein level. CT imaging showed segmental thickening of the proximal jejunum with trace ascites. A push enteroscopy was performed that revealed slightly edematous mucosa with erosions. Pathology from the biopsies showed focal areas of eosinophils. Autoimmune antibodies including ANCA, anti-transglutaminase antibodies, and c1-esterase inhibitor testing were negative. Lisinopril was discontinued with resolution of her symptoms and a diagnosis of ACEI small bowel angioedema was made. ACEI small bowel angioedema is a rare side effect of ACEI therapy and can occur at any time during therapy with an ACEI. The diagnosis is made when other more likely causes are ruled out and symptoms resolve on cessation of the drug. Eosinophilic gastritis is an important differential diagnosis but ACEI small bowel angioedema will not present with systemic eosinophilia. Risk factors for ACEI angioedema include female gender, age 40-70, and African American race. C1-esterase inhibitor levels are normal and the jejunum is most commonly affected with associated ascites. The biochemical increase in bradykinin by inhibition of the angiotensin-converting-enzyme is thought to be responsible for the angioedema. Given how common ACEI therapy is prescribed, clinicians should be aware of this potential side effect in a patient taking an ACEI with unexplained recurrent abdominal pain and segmental small bowel wall thickening.2542_A Figure 1. Abdominal CT imaging showing segmental thickening and edema of the jejunum and trace ascites.2542_B Figure 2. Push enteroscopy showing a mildly edematous jejunum.2542_C Figure 3. Jejunal biopsies showing no granulomas and focal areas of eosinophils.

A11374 RAAS Triple A-Testing

Objectives: RAAS Triple-A testing is a novel mass spectrometry based approach providing a comprehensive biochemical evaluation of the circulating renin-angiotensin-system (RAS) on the basis of equilibrium angiotensin levels and circulating aldosterone levels. Methods: RAS-Equilibrium-Analysis combines the robustness and accuracy of LC-MS/MS based quantification with the versatility of serum sampling to generate a highly accurate readout containing multiple layers of information regarding the biochemical features of the circulating RAAS. Equilibrium Angiotensin I (Ang I), Angiotensin II (Ang II) and Aldosterone were simultaneously quantified in 500 μl of standard collected serum samples from healthy volunteers or hypertensive patients receiving different anti-hypertensive first-line therapies. Results: ACE inhibitor therapy resulted in a significant reduction of the Ang II-to-Ang I-Ratio in equilibrium analysis, which was accompanied by an up-regulation of renin. Surprisingly, PRA showed a high correlation with the sum of equilibrium Ang I and Ang II, which was independent of ACE inhibitor treatment. While the ARR was strongly suppressed in the presence of ACE inhibitor treatment, the Aldosterone-to-Angiotensin II-Ratio (AA2-Ratio) was not affected, suggesting superior applicability in screening for primary aldosteronism (PA). Conclusion: RAAS Triple-A testing is a mass spectrometry based multiplex assay combining Ang I, Ang II and Aldosterone to novel angiotensin based surrogate markers for renin and ACE activity drawing a comprehensive picture of a patient's “RAAS Status” while further delivering a novel ACE independent screening test for PA, the AA2-Ratio, which might pave the way for patient screening hypertensive patients without the need of withdrawing anti-hypertensive therapies.

Abstract P251: Angiotensin Based Biomarkers for Molecular Profiling and Drug Efficacy Monitoring in Hypertension

RAAS Triple-A testing is a novel mass spectrometry based approach providing a comprehensive biochemical evaluation of the circulating renin-angiotensin-system (RAS) on the basis of equilibrium angiotensin levels and circulating aldosterone levels. In contrast to previous technologies involving complex sampling procedures, RAS-Equilibrium-Analysis combines the robustness and accuracy of LC-MS/MS based quantification with the versatility of serum sampling to generate a highly accurate readout containing multiple layers of information regarding the biochemical features of the circulating RAAS. Equilibrium Angiotensin I (Ang I), Angiotensin II (Ang II) and Aldosterone were simultaneously quantified in 500μl of standard collected serum samples from healthy volunteers or hypertensive patients receiving different anti-hypertensive first-line therapies. Stable-isotope labeled internal standards were used to control for analyte recovery. Following analyte extraction, samples were subjected to UPLC-MS/MS analysis and diagnostic ratios were calculated. ACE inhibitor therapy resulted in a significant reduction of the Ang II-to-Ang I-Ratio in equilibrium analysis, which was accompanied by an up-regulation of renin, as expected. Surprisingly, PRA showed a high correlation with the sum of equilibrium Ang I and Ang II, which was independent of ACE inhibitor treatment. While the ARR was strongly suppressed in the presence of ACE inhibitor treatment, the Aldosterone-to-Angiotensin II-Ratio (AA2-Ratio) was not affected, suggesting superior applicability in screening for primary aldosteronism (PA). RAAS Triple-A testing is a mass spectrometry based multiplex assay combining Ang I, Ang II and Aldosterone to diagnostic values that draw a comprehensive picture of a patient’s "RAAS Status". While the sum of Ang I and Ang II serves as a strong PRA surrogate marker, ACE activity and ACE inhibitor therapy efficacy can be monitored using the Ang II/Ang I-Ratio. On top, the AA2-Ratio serves as an advanced diagnostic marker for PA that might pave the way for patient screening without the need of withdrawing anti-hypertensive therapies.

Angiotensin-Converting Enzyme Inhibitors Provide Better Long-Term Survival Benefits to Patients With AMI Than Angiotensin II Receptor Blockers After Survival Hospital Discharge.

Renin-angiotensin-aldosterone system inhibitors (RASIs) are widely used in high-risk cardiovascular (CV) diseases, including acute myocardial infarction (AMI). However, it is not yet clear which class of RASIs provides specific benefits to patients with AMI. The present study aimed to evaluate whether angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs) had any different effects on long-term CV and all-cause mortality in patients with AMI who received either agent from admission and were discharged alive from the hospital. We analyzed data of patients with AMI from the Korea Acute Myocardial Infarction Registry-National Institutes of Health registry. Cardiovascular and all-cause mortality at 12 months after AMI were assessed. Among 12 481 patients with AMI who were discharged alive, RASI treatment was as follows: ACEIs (n = 5910), ARBs (n = 4009), and no RASI (n = 2562). After adjustment for multiple factors, compared with no RASI therapy, ACEI therapy was associated with lower hazard ratios (HRs) for 1-year CV and total mortality rates, whereas ARB therapy was not. In a direct comparison, compared with ARB treatment, ACEI treatment was associated with lower HRs (95% confidence interval) for CV and total mortality: 0.562 (0.420-0.753) and 0.567 (0.451-0.713), respectively. The superiority of ACEI to ARB was also observed across several subgroups. The mortality differences between the 2 treatment groups were reproduced in a propensity-score matched analysis (n = 2855 each). Our study of a recent AMI registry data revealed that ACEI therapy in patients with AMI was associated with better long-term survival benefits than ARB therapy.

Effect of PF-04634817, an Oral CCR2/5 Chemokine Receptor Antagonist, on Albuminuria in Adults with Overt Diabetic Nephropathy

IntroductionInflammatory cell recruitment, which is potentially mediated by the monocyte chemoattractant protein 1/C-C chemokine receptor type 2 (CCR2) system and by C-C chemokine receptor type 5 (CCR5) activity, may play a role in the development and progression of diabetic nephropathy. PF-04634817 is a dual chemokine CCR2/5 receptor antagonist that is being developed for the treatment of diabetic nephropathy.MethodsWe evaluated the efficacy of PF-04634817 compared with matching placebo for reduction of albuminuria after 12 weeks of treatment in subjects with type 2 diabetes who received standard of care (SOC; angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy), in a randomized, double-blind, placebo-controlled, parallel-group phase 2 study.ResultsA total of 226 subjects who received SOC with baseline estimated glomerular filtration rates between 20 and 75 ml/min per 1.73 m2 and a baseline urinary albumin-to-creatinine ratio (UACR) of ≥300 mg/g were randomly assigned 3:1 to receive PF-04634817 (150 or 200 mg orally, once daily) or placebo. The primary analysis was Bayesian, with an informative prior for placebo response (equivalent to including an additional 80 subjects in the placebo arm). We observed a placebo-adjusted reduction in UACR of 8.2% (ratio 0.918; 95% credible interval: 0.75–1.09) at week 12 in the PF-04634817 arm. PF-04634817 appeared to be safe and well-tolerated.ConclusionDespite the good safety profile shown by PF-04634817, clinical development for this indication was discontinued in light of the modest efficacy observed.

Reduction of Sympathetic Innervation Following Transition to Sacubitril/Valsartan in the Remodel (Reverse Remodeling Effects of Entresto) Study

Background Increased sympathetic nervous system activity is commonly observed in heart failure with reduced ejection fraction and is one cause of pathological structural remodeling of the left ventricle. Sacubitril/valsartan reduces mortality and heart failure hospitalizations, but its effect on sympathetic nervous system activity is unknown. Methods Patients enrolled in the prospective, longitudinal REMODEL study underwent 123-meta-iodobenzylguanidine scintigraphy prior to and three months following conversion from angiotensin converting enzyme inhibitor or angiotensin receptor blocker therapy to sacubitril/valsartan. The early heart-to-mediastinum (H/M) ratio, late H/M ratio and washout rate were calculated. Baseline and on-therapy values were compared using a paired t-test analysis. Results 40 patients were enrolled in this study. The mean age was 55 ± 12 years, 25 (63%) were male, and 30 (75%) had a non-ischemic heart failure etiology. Following transition to sacubitril/valsartan therapy, the late H/M ratio increased from 1.39 ± 0.19 to 1.52 ± 0.19 (p Conclusions Addition of sacubitril/valsartan to baseline heart failure therapy resulted in a decrease in cardiac sympathetic activity, as shown by a decrease in both the early and late H/M ratio and an increase in the washout rate on MIBG imaging. The decrease in sympathetic nervous system activity may underlie the improvement in survival seen with sacubitril/valsartan and can serve as a good measure of medication response.

Angiotensin Receptor Neprilysin Inhibitor Therapy Improves Ejection Fraction in Patients with Systolic Heart Failure

Introduction The PARADIGM-HF study showed that angiotensin receptor-neprilysin inhibitor (ARNI) therapy with sacubitril/valsartan significantly reduced cardiovascular mortality, heart failure hospitalization, and all-cause mortality compared to ace inhibitor therapy with enalapril in patients with heart failure with reduced ejection fraction (HFrEF). Since being fast tracked for HFrEF treatment in 2015, ARNI has been studied in various aspects related to efficacy and long-term effects. However, the effect of ARNI specifically on ejection fraction (EF) in patients with HFrEF on guideline directed medical therapy (GDMT) remains unknown. Hypothesis Given preliminary data, our hypothesis is that patients with heart failure on GDMT will show significant recovery and improvement in EF after initiating ARNI therapy. Methods A retrospective chart review was conducted to identify all patients treated with ARNI at a dedicated heart failure clinic in the past 12 months meeting the following criteria: (i) age ≥ 18 years, (ii) NYHA class II-III symptoms, (iii) on GDMT (beta blocker, ace inhibitor/angiotensin receptor blocker, and aldosterone antagonist) prior to ARNI initiation, (iv) EF ≤35% at time of ARNI initiation, (v) HFrEF on echo for ≥6 months prior to ARNI initiation, and (vi) follow up echo >3-6 months after ARNI initiation. Interval changes in EF since starting ARNI were compared changes in EF prior to starting ARNI. Results Patients started on ARNI showed significant recovery and improvement in EF at an average follow up of 6 months compared to EF at time of ARNI initiation (32.7% vs 22.6%, respectively, p = 0.0013). Conclusions ARNI therapy shows significant improvement and recovery of EF in patients with HFrEF on GDMT. These findings suggest that ARNI therapy could potentially reduce or delay the necessity for defibrillators and other costly procedures, while also contributing to decreased rates of hospitalizations and overall morbidity and mortality of patients with systolic heart failure.

Prospective Randomized Evaluation of Preoperative Angiotensin-Converting Enzyme Inhibition (PREOP-ACEI).

Intraoperative hypotension is associated with an increased risk of end organ damage and death. The transient preoperative interruption of angiotensinconverting enzyme inhibitor (ACEI) therapy prior to cardiac and vascular surgeries decreases the occurrence of intraoperative hypotension. We sought to compare the effect of two protocols for preoperative ACEI management on the risk of intraoperative hypotension among patients undergoing noncardiac, nonvascular surgeries. Prospective, randomized study. Midwestern urban 489-bed academic medical center. Patients taking an ACEI for at least six weeks preoperatively were considered for inclusion. Randomization of the final preoperative ACEI dose to omission (n = 137) or continuation (n = 138). The primary outcome was intraoperative hypotension, which was defined as any systolic blood pressure (SBP) < 80 mm Hg. Postoperative hypotensive (SBP < 90 mm Hg) and hypertensive (SBP >> 180 mm Hg) episodes were also recorded. Outcomes were compared using Fisher's exact test. Intraoperative hypotension occurred less frequently in the omission group (76 of 137 [55%]) than in the continuation group (95 of 138 [69%]) (RR: 0.81, 95% CI: 0.67 to 0.97, P = .03, NNH 7.5). Postoperative hypotensive events were also less frequent in the ACEI omission group (RR: 0.49, 95% CI: 0.28 to 0.86, P = .02) than in the continuation group. However, postoperative hypertensive events were more frequent in the omission group than in the continuation group (RR: 1.95, 95%: CI: 1.14 to 3.34, P = .01). The transient preoperative interruption of ACEI therapy is associated with a decreased risk of intraoperative hypotension. ClinicalTrials.gov: NCT01669434.

Perioperative Management of ACE Inhibitor Therapy: Challenges of Clinical Decision Making Based on Surrogate Endpoints

Journal of Hospital MedicineVolume 13, Issue 10 p. 724-726 Editorial Perioperative Management of ACE Inhibitor Therapy: Challenges of Clinical Decision Making Based on Surrogate Endpoints Duminda N. Wijeysundera MD, PhD, FRCPC, Corresponding Author Duminda N. Wijeysundera MD, PhD, FRCPC d.wijeysundera@utoronto.ca Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada Department of Anesthesia and Pain Management, Toronto General Hospital, Toronto, Ontario, Canada Department of Anesthesia, University of Toronto, Toronto, Ontario, CanadaAddress for correspondence: Duminda N. Wijeysundera, MD PhD FRCPC; Li Ka Shing Knowledge Institute, St. Michael's Hospital, 30 Bond Street, Toronto, Ontario Canada M5B 1W8; E-mail: d.wijeysundera@utoronto.caSearch for more papers by this author Duminda N. Wijeysundera MD, PhD, FRCPC, Corresponding Author Duminda N. Wijeysundera MD, PhD, FRCPC d.wijeysundera@utoronto.ca Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada Department of Anesthesia and Pain Management, Toronto General Hospital, Toronto, Ontario, Canada Department of Anesthesia, University of Toronto, Toronto, Ontario, CanadaAddress for correspondence: Duminda N. Wijeysundera, MD PhD FRCPC; Li Ka Shing Knowledge Institute, St. Michael's Hospital, 30 Bond Street, Toronto, Ontario Canada M5B 1W8; E-mail: d.wijeysundera@utoronto.caSearch for more papers by this author First published: 25 July 2018 https://doi.org/10.12788/jhm.3062Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume13, Issue10October 2018Pages 724-726 RelatedInformation

Angiotensin converting enzyme inhibitors and interstage failure in infants with hypoplastic left heart syndrome.

Angiotensin converting enzyme inhibitors are commonly prescribed medications after the Norwood procedure. There are little data that can be used to determine if angiotensin converting enzyme inhibitors improve interstage outcomes in children with single ventricle defects. The objective of this study was to investigate the relationship between angiotensin converting enzyme inhibitors and interstage failure among infants born with hypoplastic left heart syndrome. We conducted a retrospective cohort study using data from the National Pediatric Cardiology Quality Improvement Collaborative database (collected between 2008 and 2015). We used logistic regression models to assess the exposure-outcome associations and propensity score matching to account for differences in baseline patient characteristics associated with use of angiotensin converting enzyme inhibitors. A total of 1487 neonates participated in the study. Thirty-nine percent of patients were prescribed angiotensin converting enzyme inhibitors after the Norwood procedure; 11% experienced interstage failure (death, heart transplantation, and not being a candidate for the second-stage surgery). Before propensity score matching, patients receiving angiotensin converting enzyme inhibitors were significantly more likely to experience interstage failure, compared to patients not on angiotensin converting enzyme inhibitors (OR = 1.44; 95% CI: 1.04, 1.99; P = 0.03). Although there was an increased odds of interstage failure among patients receiving angiotensin converting enzyme inhibitors compared to patients not receiving angiotensin converting enzyme inhibitors in the propensity score-matched cohort, this association was not significantly different (adjusted OR = 1.29; 95% CI: 0.88, 1.95; P = 0.18). Angiotensin converting enzyme inhibitor therapy did not demonstrate a beneficial effect on interstage failure among infants with hypoplastic left heart syndrome, even when patient characteristics associated with the use of angiotensin converting enzyme inhibitors were considered.

Angiotensin-converting enzyme (ACE) I/D and bradykinin B2 receptor T/C genes polymorphism in patients with ACE inhibitors-related cough

BackgroundAngiotensin-converting enzyme (ACE) inhibitors-related cough had been reported to contribute for discontinuation of ACE inhibitors therapy. The role of ACE I/D and bradykinin B2 receptor T/C genes in ACE inhibitors-related cough is still unclear. ObjectivesTo determine ACE I/D and bradykinin B2 receptor T/C genes polymorphisms in patients with ACE-inhibitors-related cough. Subjects and methodsAn analytical study with cross-sectional design was conducted at Saiful Anwar General Hospital from June 2013 to September 2014. We used the polymerase chain reaction to genotype ACE I/D and bradykinin B2 receptor T/C genes. Data on both ACE I/D and bradykinin B2 receptor T/C genes polymorphisms in cough and non cough group of hypertensive patients treated with ACE inhibitors in our Hospital during the period were analyzed using multiple logistic regression. Moreover, a meta-analysis was performed to summarize findings from other regions. ResultsA total of 18 patients with cough (21%) and 67 patients without cough (79%) of hypertensive patients treated with ACE inhibitors from our Hospital during the period were analyzed for this study. In our population, no correlation was observed between ACE inhibitors-related cough and both ACE I/D (p = 0.560) and bradykinin B2 receptor T/C (p = 0.475) genes polymorphism. However, our meta-analysis of five studies consisting of 267 patients with cough and 346 patients without cough revealed that higher risk of ACE inhibitors-related cough was 1.82-fold associated with T allele of bradykinin B2 receptor T/C gene polymorphism (p = 0.0310). ConclusionsWhile the evidence in our meta-analysis suggests strong role for bradykinin gene polymorphism in ACE inhibitors-related cough, however, in our population, we did not find any association.

Cost-Effectiveness of Interventions to Prevent and Manage Diabetes—A Systematic Review and Update

Many interventions are available for preventing type 2 diabetes (DM) and managing DM, but their cost-effectiveness (CE) varies greatly. Previously, we conducted a systematic cost-effectiveness (CE) review of all DM interventions covering studies between 1985 and 2007. Here, we update the study for Jan 20to July 2017. We used the same search strategies (databases, MeSH terms and keywords, exclusion criteria and study quality assessment tool) to select studies. We grouped interventions by CE ratios (CER) in cost per quality-adjusted life years (QALY) or life year gained (LYG)—cost saving (CER ≤ 0); very cost-effective (0 &amp;lt; CER ≤ $25,000); cost-effective ($25,000 &amp;lt; CER ≤ $50,000); marginally cost-effective ($50,000 &amp;lt; ICER ≤ $100,000); or not cost-effective (&amp;gt;$100,000)—and whether evidence was strong, supportive, or uncertain. We used the median CER to represent the CE of an intervention if multiple evaluations exist. Costs and CER were expressed as 2015 U.S. dollars. The initial search yielded 18,195 titles; 46 prevention and 110 management papers were included in the review. Interventions that were cost-saving or very cost-effective with strong evidence included: for preventing type 2 DM, 1) imposing taxes on sweetened beverages and 2) structured lifestyle intervention and metformin in people at high risk; for management of DM and its complications, 1) ACE inhibitor therapy for intensive hypertension (HTN) control, 2) self-monitoring of blood glucose, 3) comprehensive foot care to prevent ulcers, 4) multi-component coordinated care with peer support for managing HTN, hyperglycemia, hyperlipidemia, and chronic kidney disease, and early detection of DM complications. The CERs of other interventions ranged from $30,000 to $4,817,000 per QALY or &amp;lt;$25,000 per QALY with a high degree of uncertainty. Our results provide critical information for making evidence-based clinical and public health policy decisions. Disclosure K.R. Siegel: None. X. Zhou: None. B. Ng: None. S. Jawanda: None. K. Proia: None. X. Zhang: None. P. Zhang: None.

Abstract 265: Angiotensin-Converting-Enzyme Inhibition in Stable Coronary Artery Disease and Cardiomyopathy With Mid-range Ejection Fraction: Insights From the PEACE Trial

Background: There have been significant advances in the treatment of patients with cardiomyopathy with reduced ejection fraction (EF &lt;40%). However, there is a dearth of information in the treatment of patients with cardiomyopathy and mid-range ejection fraction (EF 40 to 50%). Current guidelines state to treat these patients as patients with cardiomyopathy and preserved ejection fraction. The Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) trial was conducted on patients with stable coronary artery disease and normal or slightly reduced left ventricular function to evaluate the benefit of an ACE inhibitor, trandolapril, versus modern conventional therapy. This trial did not show any advantage from treating these subjects with an ACE inhibitor. Our goal is to elucidate further whether ACE inhibitors reduce death in patients with cardiomyopathy and mid-range ejection fraction. Methods: PEACE Trial data was used to evaluate the effect of ACE inhibitors in a subgroup of patients with cardiomyopathy and mid-range ejection fraction (40-50%). A chi-square test and a t-test were used to examine and compare the binary and continuous variables of demographic and health characteristics between experimental and comparison groups. A chi-square test was used to compare the difference in outcomes between the two groups. The statistical analyses were performed using SAS version 9.4. All tests were conducted using an α=0.05 as the probability of a Type I error. Results: We studied a subgroup of subjects from the PEACE trial with cardiomyopathy and mid-range ejection fraction (n=2512 of 8290 total subjects). Subjects were randomly assigned to the interventional group (n=1247) and the placebo group (n=1265). There were no significant differences in baseline demographic and health characteristics between the two groups. The risks of composite outcomes (death from cardiovascular causes, death from noncardiovascular causes, nonfatal myocardial infarction, and stroke) (RR 0.88, 95% CI 0.78-0.99; P=0.03) and death from any causes (RR 0.85, 95% CI 0.73-0.99; P=0.03) were lower in subjects treated with trandolapril. Conclusion: This study unveiled the benefit of ACE inhibitors among patients with cardiomyopathy and mid-range EF.

Management of Renin-Angiotensin-Aldosterone System Blockade in Kidney Transplant Recipients

Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are the cornerstone treatment in chronic kidney disease patients. Despite facilitating a reduction in blood pressure and albuminuria, there are insufficient data in kidney transplant recipients (KTRs). They are often administered for hypertension and polycythemia treatment. The aim of this study was to investigate the frequency and route of administration of ACEIs and ARBs and their early clinical effects in the KTR population. In a cross-sectional, retrospective study we analyzed 874 medical records of all KTRs treated in our unit in 2014. A total of 391 KTRs (44.7%) using ARBs or ACEIs were qualified for the study. The primary reasons for renin-angiotensin-aldosterone system antagonist administration were hypertension (59.1%), polycythemia (19.2%), and proteinuria (18.2%). Among the studied KTRs, 86.7% of patients were treated with ACEIs and 12.2% were treated with ARBs. The majority of patients treated with ACEIs and ARBs received these agents in a dose range below 25% and between 25% and 49% of their maximal dose, respectively. Both the mean serum creatinine level and estimated glomerular filtration rate (chronic kidney disease epidemiology collaboration) remained fairly stable and urine protein excretion (g/24 hours) was significantly reduced after 3 months of ACEI and ARB therapy. The serum potassium level increased significantly, while hemoglobin concentration dropped significantly.In KTRs, renin-angiotensin-aldosterone system antagonists were applied mainly due to hypertension, proteinuria, and polycythemia. ACEIs and ARBs were effective in the reduction of proteinuria and hemoglobin, but graft function was stable and the increase of serum potassium was not of clinical significance.

Addition of Digoxin Improves Cardiac Function in Children With the Dilated Cardiomyopathy With Ataxia Syndrome: A Mitochondrial Cardiomyopathy

BackgroundThe dilated cardiomyopathy with ataxia syndrome (DCMA) is a rare mitochondrial disorder characterized by progressive cardiomyopathy, prolonged QT interval and early death in childhood related to intractable heart failure. We present a case series of 9 children with DCMA who demonstrated functional improvement and favourable left ventricular remodeling only after digoxin was added to their medical therapy. MethodsA retrospective review of 46 patients with DCMA followed at the Alberta Children’s Hospital from 2005 to 2017 identified 9 patients who were treated with digoxin and had serial echocardiography data. For each subject, we calculated the difference between baseline and follow-up for left ventricular ejection fraction (LVEF), end-diastolic dimension (LVEDD), and end-systolic dimension (LVESD) as determined by echocardiography. ResultsPatients were on average 45.6 ± 59 months of age when digoxin was started with a mean LVEF of 40% ± 11% when digoxin was started. Seven patients were on angiotensin-converting enzyme inhibitors (ACEIs) at the time of initiation of digoxin, and all were on β-receptor antagonists (BB). After being on digoxin for a mean of 11.7 ± 10.9 months, average LVEF improved to 55% ± 10% (P = 0.0005), and there were significant decreases in the Z-scores for LVEDD (+2.1 ± 1.9 to +0.65 ± 1.4, P = 0.02) and LVESD (+3.83 ± 2.07 to +1.79 ± 1.76, P = 0.01). ConclusionsIn children with DCMA, we report that digoxin seems to have additive beneficial properties when combined with ACEI and BB therapy. This novel observation may have implications for the medical treatment of mitochondrial cardiomyopathies.

Angiotensin-converting Enzyme Inhibitors-induced Angioedema

Abstract Angiotensin-converting enzyme inhibitors (ACEI) are widely used drugs nowadays in treating patients diagnosed with cardiovascular disorders. We present two consecutive cases of acquired angioedema caused by the administration of enalapril and lisinopril in patients with indication for ACE-inhibitors therapy. Rigorous follow-up of side effects of ACEI is required, due to these possible life-threatening adverse reactions.

Evaluating the Safety and Tolerability of Sacubitril/Valsartan for HFrEF Managed Within a Pharmacist Clinic

The objective of this research was to describe the use of pharmacist-managed sacubitril/valsartan therapy in a multi-center, outpatient cardiac group. Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNi), is a novel agent for the treatment of heart failure. An ARNi is recommended by national guidelines to be used in place of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) therapy for patients who remain symptomatic. A retrospective chart review was performed to identify patients initiated and fully titrated on sacubitril/valsartan therapy from July 7, 2015 to March 7, 2017. Fifty-two of the 72 symptomatic heart failure with reduced ejection fraction (HFrEF) patients prescribed sacubitril/valsartan during the 21-month period were included in this analysis. The average ejection fraction was 26%. The average age was 69years. At baseline, 26.9% of patients were not on ACEi/ARB therapy and 13.5% were on target-dose therapy. After completing the uptitration process, the maximally tolerated dose of sacubitril/valsartan was 5.8% low-dose, 7.7% mid-dose, and 86.5% target-dose. Loop and thiazide diuretic use decreased significantly. There was a significant mean reduction in systolic blood pressure of 6mmHg with no significant changes in serum creatinine, blood urea nitrogen, or potassium levels. With close monitoring and follow-up, ARNi therapy was a safe alternative to ACEi/ARB therapy for chronic symptomatic HFrEF when initiated within a pharmacist clinic.