Enzyme Inhibitors In Patients Research Articles

The influence of obesity on the parameters of the kallikrein-kinin system and proteolysis in chronic biliary pancreatitis

Background. Clinical practice and science have accumulated data that obese patients suffer from severe forms of acute and chronic pancreatitis, which is explained by the accumulation of fat around the pancreas, a decreased activity of pancreatic enzymes. The purpose of the study is to describe the features of the kallikrein-kinin system and proteolysis in chronic biliary pancreatitis (CBP), depending on the presence of comorbid obesity. Materials and methods. One hundred and thirty-seven patients with chronic biliary pancreatitis were examined and divided into two groups depending on the presence of comorbid obesity: group I consisted of 22 patients with CBP and group II — of 115 patients with CBP and obesity. Results. The obtained results proved that an increase in body weight of patients with CBP lead to a more severe kallikrein-kinin system imbalance, with enhanced activation of inflammation and a decrease in the protective effect of the proteolysis. An increase in the degree of obesity in patients with CBP was accompanied by a more severe kallikrein-kinin system and proteolytic imbalance with an increase in the proteolytic enzymes level that have a damaging effect on the hepatic and pancreatic tissues and have a pro-inflammatory activity, as well as by a decrease in the content of the proteolytic enzyme inhibitors, which reliably weakened the protective effect of kallikrein-kinin system and proteolysis. Conclusions. 1) It was proved that there is a higher activity of the kallikrein-kinin system (accor­ding to proteolytic activation and kallikrein levels) and a decrease in the activity of proteolytic enzyme inhibitors (α2-macroglobulin and kininase II) in patients with chronic biliary pancreatitis and comorbid obesity compared to those without obesity (p < 0.05). 2) An increase in the degree of obesity lead to an increase of proteolytic activity and a decrease in the content of the proteolytic enzyme inhibitors in patients with chronic biliary pancreatitis. It was proved the aggravating effect of obesity on the kallikrein-kinin system and proteolytic imbalance, which must be taken into account while forming a comprehensive treatment of such patients.

Angiotensin Converting Enzyme Inhibitors: Interaction Issues in Patients with Glaucoma and Arterial Hypertension. Review

The purpose of the review is to evaluate the interaction of angiotensin-converting enzyme inhibitors in patients with glaucoma and concomitant arterial hypertension using literature data. Glaucoma is the main cause of blindness and visual impairment, as well as the main cause of irreversible blindness worldwide. Pharmacotherapy, laser or surgical treatments are used to reduce IOP levels, as well as prevent deterioration of visual field defects. However, 40 % of patients develop glaucomatous neuropathy despite ongoing therapy. This prompts the investigation of alternative causes of damage to the optic nerve, and abnormal blood pressure levels, both too low and too high, are considered as a possible risk factor. Arterial hypertension occurs in 48–65 % of patients with glaucoma and is the most common systemic disease in patients with glaucoma. Currently, angiotensin converting enzyme (ACE) inhibitors are considered the “gold standard” in the treatment of arterial hypertension, in the pathogenesis of which activation of the renin-angiotensin system (RAS) plays an important role. The renin-angiotensin system (RAS) is a hormonal system responsible for regulating blood pressure and fluid and electrolyte balance in the body. Local tissue-specific RAS were found, including in the structures of the eyeball: cornea, aqueous humor, iris, ciliary body, vitreous body, retina. These data indicate that the local RAS plays an important role in the regulation of the physiology of the eye and may become a target in the development of new antiglaucoma drugs. Animal studies, as well as studies in various patient groups, show that systemic antihypertensive drugs that inhibit the RAS, such as ACE inhibitors, reduce IOP. These studies support the concept that RAS inhibitory drugs may be potential antiglaucoma drugs in the future, as ACE inhibitors can improve the outflow of intraocular fluid, thereby reducing IOP.

Comparison of clinical outcomes of angiotensin receptor blockers with angiotensin-converting enzyme inhibitors in patients with acute myocardial infarction.

Angiotensin receptor blockers (ARBs) are considered an alternative to angiotensin-converting enzyme inhibitors (ACEIs) in patients with acute myocardial infarction (AMI), but in the era of extensive use of preventive therapies and percutaneous coronary intervention, this has not been adequately evaluated in Asians. This retrospective cohort study used data from the Taiwan National Health Insurance Research Database. In total, 52,620 patients initially hospitalized due to AMI between 2002 and 2015 were assessed. After propensity score matching, 14,993 patients each were assigned to ACEI and ARB groups. Patients who received ARBs had significantly lower all-cause mortality (adjusted hazard ratio [aHR]: 0.82; 95% confidence interval [CI]: 0.75-0.90) and hospitalization for heart failure (aHR: 0.92; 95% CI: 0.85-0.99) compared with those who received ACEIs at 18 month follow-up. No significant difference was observed between the two groups in terms of major adverse cardiovascular events (aHR: 098; 95% CI: 0.90-1.07), cardiovascular death (aHR: 0.82; 95% CI: 0.68-1.00), ischemia stroke (aHR: 0.93; 95% CI: 0.77-1.11), and nonfatal myocardial infarction (aHR: 1.04; 95% CI: 0.93-1.17). ARBs showed benefits in many subgroups in terms of all-cause mortality and cardiovascular death. Real-world data demonstrate that ARBs might be associated with lower all-cause mortality and hospitalization for heart failure compared with ACEIs among patients with AMI.

Early initiation of angiotensin-converting enzyme inhibitor in patients with scleroderma renal crisis: a nationwide inpatient database study.

To evaluate the effectiveness of early initiation of angiotensin-converting enzyme inhibitor (ACEi) in patients with scleroderma renal crisis (SRC). This was a retrospective cohort study using a nationwide inpatient database in Japan from July 2010 to March 2020. All hospitalized patients with SRC were divided into those who received ACEi within 2 days of admission (early ACEi group) and those who did not (control group). Propensity-score overlap weighting analysis was performed to adjust for confounding factors. The primary outcome was the composite of in-hospital mortality or haemodialysis dependence at discharge. Of the 475 eligible patients, 248 (52.2%) were in the early ACEi group and 227 (47.8%) were in the control group. After overlap weighting, the primary outcome was significantly lower in the early ACEi group than in the control group (40.1% vs 49.0%; odds ratio, 0.69; 95% CI: 0.48, 1.00; P = 0.049). The present study showed that early initiation of ACEi was associated with lower composite outcome of in-hospital mortality or haemodialysis dependence at discharge in patients with SRC. Further prospective studies are warranted to verify the present findings.

Effectiveness of sacubitril-varsartan versus angiotensin converting enzyme inhibitors in patients hospitalized for acute heart failure: a retrospective cohort study of the RICA registry.

Sacubitril-valsartan has been shown to reduce hospitalizations and mortality in patients with heart failure (HF) and reduced ejection fraction. The PIONEER-HF trial demonstrated that initiation of the drug during acute HF hospitalization reduced NT-proBNP levels and a post-hoc analysis of the trial found a reduction in HF hospitalizations and deaths. Real-life studies in the elderly population are scarce. The aim of our study was to assess the effectiveness of sacubitril-valsartan versus angiotensin converting enzyme inhibitors (ACEI) in elderly patients who initiate this treatment during hospitalization for acute HF. We conducted a retrospective cohort study using the Spanish acute heart failure registry (RICA) comparing rehospitalizations and deaths at 3 months and 1 year among patients aged 70 years or older who had initiated treatment with sacubitril-valsartan during hospitalization for acute HF versus those treated with ACEI. One hundred and ninety-nine patients hospitalized between October 2016 and November 2020 were included, with a median age of 82 years and high rate of comorbidity. Of these, 107 were treated with sacubitril-valsartan and 92 with ACEI. The adjusted OR for readmission for HF at 3 months was 0.906 (95% CI: 0.241-3.404) and for the combined variable readmission for HF or death at 3 months was 0.696 (95% CI: 0.224-2.167). The adjusted OR for HF readmission at one year was 0.696 (95% CI: 0.224 -2.167). and for the combined variable HF readmission or death at one year 0.724 (95% CI: 0.325-1.612). Treatment with sacubitril-valsartan initiated early in hospitalization for HF in elderly patients with high comorbidity was associated with a trend towards a reduction in readmissions and death due to HF compared to treatment with ACEI, which did not reach statistical significance either at 3 months or 1 year of follow-up.

Role of angiotensin-converting enzyme inhibitors in patients with aortic stenosis

Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-2 receptor blockers (ARBs) are used extensively in the treatment of arterial hypertension. There is a widespread belief that these drugs are contraindicated in patients with underlying aortic stenosis due to their vasodilatory effect, which could result in hypotension and syncope. Nonetheless, these drugs may significantly benefit such patients with their proven cardioprotective benefits and positive effects on left ventricular remodelling. Despite widespread concerns about their safety, the currently available studies do not report any significant side effects. Оn the contrary, they find improved survival rates, a reduction in adverse cardiovascular events, and a reduction in symptoms. Further clinical studies and trials are necessary to assess the safety of ACEIs in patients with hypertension and underlying aortic stenosis and their effects on cardiac function and survival.

Phase 1 study to evaluate the effects of rifampin on pharmacokinetics of pevonedistat, a NEDD8-activating enzyme inhibitor in patients with advanced solid tumors

SummaryPevonedistat (TAK-924/MLN4924) is an investigational small molecule inhibitor of the NEDD8-activating enzyme that has demonstrated clinical activity across solid tumors and hematological malignancies. Here we report the results of a phase 1 study evaluating the effect of rifampin, a strong CYP3A inducer, on the pharmacokinetics (PK) of pevonedistat in patients with advanced solid tumors (NCT03486314). Patients received a single 50 mg/m2 pevonedistat dose via a 1-h infusion on Days 1 (in the absence of rifampin) and 10 (in the presence of rifampin), and daily oral dosing of rifampin 600 mg on Days 3–11. Twenty patients were enrolled and were evaluable for PK and safety. Following a single dose of pevonedistat at 50 mg/m2, the mean terminal half-life of pevonedistat was 5.7 and 7.4 h in the presence and in the absence of rifampin, respectively. The geometric mean AUC0–inf of pevonedistat in the presence of rifampin was 79% of that without rifampin (90% CI: 69.2%–90.2%). The geometric mean Cmax of pevonedistat in the presence of rifampin was similar to that in the absence of rifampin (96.2%; 90% CI: 79.2%–117%). Coadministration of pevonedistat with rifampin, a strong metabolic enzyme inducer, did not result in clinically meaningful decreases in systemic exposures of pevonedistat. The study results support the recommendation that no pevonedistat dose adjustment is needed for patients receiving concomitant CYP3A inducers.ClinicalTrials.gov identifierNCT03486314.

Aprocitentan (a Dual Endothelin-Receptor Antagonist) for Treatment-Resistant Hypertension.

Treatment-resistant hypertension (TRH) is associated with increased cardiovascular risks and progression of chronic kidney disease. The pathophysiology of TRH is multifactorial, including overactivity of the renin-angiotensin-aldosterone system and sympathetic nervous system, endothelial dysfunction, and volume overload. Endothelin-1 is a vasoconstrictive peptide that causes neurohormonal and sympathetic activation, increased aldosterone synthesis and secretion, endothelial dysfunction, vascular hypertrophy and remodeling, and fibrosis. Endothelin-1 acts through 2 receptors, ETA and ETB. Activation of ETA receptors in vascular smooth muscle cells results in vasoconstriction, whereas ETB receptor activation results in vasoconstriction in the vascular smooth muscle cells and vasodilation through nitric oxide release in endothelial cells. Aprocitentan is novel, oral, dual endothelin-receptor antagonist that has demonstrated a more favorable tolerability and safety profile in early clinical trials compared with other endothelin-receptor antagonists studied. Phase 2 trial data support a significant reduction in blood pressure compared to placebo and similar blood pressure reduction compared to a moderately dosed angiotensin-converting enzyme inhibitor in patients with essential hypertension. An ongoing phase 3 randomized clinical trial is evaluating aprocitentan's efficacy and safety in patients with TRH receiving multiple antihypertensives. Additional research is needed to determine aprocitentan's role in therapy, but this agent may be a suitable treatment option for TRH.

Angiotensin-converting enzyme inhibitors in patients with Alport syndrome: can all patients benefit?

Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) are prescribed to slow the progression of kidney disease in patients with Alport syndrome. In a recent publication by Yamamura etal. the authors showed an association of ACEi or ARB treatment with delay in ESKD, even for those patients with severe, truncating mutations. Despite these encouraging findings, there remain a number of clinical questions about the use of ACEi and ARBs in Alport syndrome.

Use of angiotensin converting enzyme inhibitors in patients receiving therapeutic plasma exchange with a centrifuge-based apheresis system.

Angiotensin-converting enzyme inhibitors (ACEi) are frequently used antihypertensive medications with additional advantages such as reducing proteinuria and cardiovascular events. ACEi are commonly held at least 24 hours before a therapeutic plasma exchange (TPE) to reduce possibility of adverse events (AEs) including adverse drug reactions (ADR). The objective of this study was to determine if ACEi use increases the risk of ADR in patients receiving TPE with a conventional centrifuge-based apheresis system. This is a retrospective chart review study (n=252; 52% male). Binary logistic regression was used to analyze the association of ACEi use and AEs. Of 171 patients who had AE during TPE, only 38 patients were taking ACEi. There was no significant association between ACEi use and AEs after adjustments (odds ratio=0.885, 95% confidence interval: 0.468, 1.674). Our results suggest that risk of AEs is not higher in patients taking ACEi receiving TPE using a centrifuge-based machine. Randomized controlled prospective trials may be needed to further investigate this matter.

Enasidenib for the treatment of relapsed or refractory acute myeloid leukemia with an isocitrate dehydrogenase 2 mutation

ABSTRACT Introduction Isocitrate dehydrogenase 2 (IDH2) is a key metabolic enzyme that converts isocitrate to α-ketoglutarate (αKG). Somatic point mutations in IDH2 confer a gain-of-function in blast cells resulting in overproduction of D-2-hydroxyglutarate (D-2HG). High intracellular concentrations of D-2HG inhibit α-ketoglutarate-dependent dioxygenases including histone, DNA and RNA demethylases, leading to histone, DNA and RNA hypermethylation, and cell differentiation blockade. In vitro and in vivo preclinical studies have demonstrated that inhibition of IDH2-mutant enzymes with enasidenib decrease intracellular D-2HG levels, reverse epigenetic dysregulation, and release the differentiation block. The US Food and Drug Administration (FDA) approved enasidenib, a mutant-IDH2 enzyme inhibitor for patients with relapsed or refractory (R/R) IDH2-mutated AML. Areas covered We review the biology and prognostic significance of IDH2 mutations in AML and discuss the pharmacology, clinical efficacy, and toxicity profile of enasidenib. We highlight areas of ongoing preclinical and clinical research. Expert opinion Enasidenib was FDA approved due to high response rates, durability of the responses that translated into an impressive OS in that heavily pretreated population. Promising ongoing clinical trials are evaluating combination therapies with enasidenib frontline.

Phase I study assessing the mass balance, pharmacokinetics, and excretion of [14C]-pevonedistat, a NEDD8-activating enzyme inhibitor in patients with advanced solid tumors

SummaryPevonedistat (TAK-924/MLN4924) is an investigational small-molecule inhibitor of the NEDD8-activating enzyme that has demonstrated preclinical and clinical activity across solid tumors and hematological malignancies. Here we report the results of a phase I trial characterizing the mass balance, pharmacokinetics, and clearance pathways of [14C]-pevonedistat in patients with advanced solid tumors (NCT03057366). In part A (n = 8), patients received a single 1-h intravenous infusion of [14C]-pevonedistat 25 mg/m2. In part B (n = 7), patients received pevonedistat 25 or 20 mg/m2 on days 1, 3, and 5 in combination with, respectively, docetaxel 75 mg/m2 or carboplatin AUC5 plus paclitaxel 175 mg/m2 on day 1 every 3 weeks. Following the single dose of [14C]-pevonedistat 25 mg/m2 in part A, there was a parallel log-linear decline in plasma and whole blood pevonedistat concentration, with systemic exposure of unchanged pevonedistat representing 41% of drug-related material (i.e., unchanged pevonedistat and its metabolites). The mean terminal half-life of pevonedistat and drug-related material in plasma was 8.4 and 15.6 h, respectively. Pevonedistat distributed preferentially in whole blood with a mean whole-blood-to-plasma ratio for pevonedistat AUC∞ of 40.8. By 1 week post dose, the mean recovery of administered radioactivity was 94% (41% in urine and 53% in feces). The pevonedistat safety profile during both study parts was consistent with previous clinical experience, with no new safety signals observed. In part B, pevonedistat in combination with docetaxel or carboplatin plus paclitaxel was generally well tolerated. ClinicalTrials.gov identifier: NCT03057366.

The impact of a multifaceted intervention to reduce potentially inappropriate prescribing among discharged\xa0older adults: a before-and-after study

BackgroundPotentially inappropriate prescribing (PIP) is associated with the incidence of adverse drug reactions, drug-related hospitalization and other negative outcomes in older adults. After hospitalization, older adults might be discharged with several types of PIPs. Studies have found that the lack of healthcare professionals’ (HCPs) knowledge regarding PIP is one of the major contributing factors in this issue. The purpose of this study is to investigate the impact of a multifaceted intervention on physicians’ and clinical pharmacists’ behavior regarding potentially inappropriate medication (PIM) and potential prescribing omission (PPO) among hospitalized older adults.MethodsThis is a before-and-after study that took place in a tertiary Malaysian hospital. Discharge medications of patients ≥65 years old were reviewed to identify PIMs/PPOs using version 2 of the STOPP/START criteria. The prevalence and pattern of PIM/PPO before and after the intervention were compared. The intervention targeted the physicians and clinical pharmacists and it consisted of academic detailing and a newly developed smartphone application (app).ResultsThe study involved 240 patients before (control group) and 240 patients after the intervention. The prevalence of PIM was 22% and 27% before and after the intervention, respectively (P = 0.213). The prevalence of PPO in the intervention group was significantly lower than that in the control group (42% Vs. 53.3%); P = 0.014. This difference remained statistically significant after controlling for other variables (P = 0.015). The intervention was effective in reducing the two most common PPOs; the omission of vitamin D supplements in patients with a history of falls (P = 0.001) and the omission of angiotensin converting enzyme inhibitor in patients with coronary artery disease (P = 0.03).ConclusionsThe smartphone app coupled with academic detailing was effective in reducing the prevalence of PPO at discharge. However, it did not significantly affect the prevalence or pattern of PIM.

Higher doses of loop diuretics limit uptitration of angiotensin-converting enzyme inhibitors in patients with heart failure and reduced ejection fraction

BackgroundLoop diuretics are frequently prescribed to patients with heart failure and reduced ejection fraction (HFrEF) for the treatment of congestion; however, they might hamper uptitration of inhibitors of the renin–angiotensin system.MethodsLoop diuretic dose at baseline was recorded in 2338 patients with HFrEF enrolled in BIOSTAT-CHF, an international study of HF patients on loop diuretic therapy who were eligible for uptitration of angiotensin-converting enzyme inhibitors (ACEi)/mineralocorticoid receptor antagonists (MRA). The association between loop diuretic dose and uptitration of ACEi/MRA to percentage of target dose was adjusted for a previously published model for likelihood of uptitration and a propensity score.ResultsBaseline median loop diuretic dose was 40 [40–100] mg of furosemide or equivalent. Higher doses of loop diuretics were associated with higher NYHA class and higher levels of NT-proBNP, more severe signs and symptoms of congestion, more frequent MRA use, and lower doses of ACEi reached at 3 and 9 months (all P < 0.01). After propensity adjustment, higher doses of loop diuretics remained significantly associated with poorer uptitration of ACEi (Beta per log doubling of loop diuretic dose: − 1.66, P = 0.021), but not with uptitration of MRAs (P = 0.758). Higher doses of loop diuretics were independently associated with an increased risk of all-cause mortality or HF hospitalization [HR per doubling of loop diuretic dose: 1.06 (1.01–1.12), P = 0.021].ConclusionsHigher doses of loop diuretics limited uptitration of ACEi in patients with HFrEF and were associated with a higher risk of death and/or HF hospitalization, independent of their lower likelihood of uptitration and higher baseline risk.Graphic abstractThis figure was created with images adapted from Servier Medical Art licensed under a Creative Commons Attribution 3.0

Potential prescribing omissions in patients with cardiovascular disease.

Aims Potential prescribing omissions (PPOs) of medications are a frequent form of inadequate prescription drug practices. The objective of this study was to identify PPOs in a sample of elderly patients with cardiovascular disease. Methods Quasi-experimental study. Data were collected from a population database. We included patients who were older than 65years and had a diagnosis of hypertension, dyslipidaemia, diabetes mellitus, coronary heart disease, heart failure or atrial fibrillation in Colombia. PPOs were determined in a random sample of patients by the START-2 (Screening Tool to Alert doctors to Right Treatment) criteria. The impact of the PPO was determined after an educational intervention with the doctors who were responsible for treating said patients. Results A total of 630 patients, with a median age of 72years (interquartile range: 68-78years), were included; 56.2% were women. The most frequent diagnoses were arterial hypertension (94.1%, n=593) and dyslipidaemia (56.5%, n=356). We identified 100 patients (15.9%) with omissions equalling 139 PPOs, and the most common PPOs were due to a lack of angiotensin-converting enzyme inhibitors in patients associated with heart failure or coronary heart disease (n=23, 16.5%) and a lack of statins (n=20; 14.4%) and aspirin (n=20; 14.4%) in coronary heart disease. Prescription adjustments were achieved in 35 patients (25.2%). Conclusions Potential prescribing omissions are common in elderly patients with cardiovascular disease. Educational interventions may contribute to a reduced PPO frequency and improve the quality of prescription drug administration.

Decreased Risk of Radiation Pneumonitis With Coincident Concurrent Use of Angiotensin-converting Enzyme Inhibitors in Patients Receiving Lung Stereotactic Body Radiation Therapy.

Angiotensin-converting enzyme inhibitors (ACEi) have demonstrated decreased rates of radiation-induced lung injury in animal models and clinical reports have demonstrated decreased pneumonitis in the setting of conventionally fractionated radiation to the lung. We tested the role of ACEi in diminishing rates of symptomatic (grade ≥2) pneumonitis in the setting of lung stereotactic body radiation therapy (SBRT). We analyzed patients treated with thoracic SBRT to 48 to 60 Gy in 4 to 5 fractions from 2006 to 2014. We reviewed pretreatment and posttreatment medication profiles to document use of ACEi, angiotensin receptor blockers, bronchodilators, aspirin, PDE-5 inhibitors, nitrates, and endothelin receptor antagonists. Pneumonitis was graded posttreatment based on Common Terminology Criteria for Adverse Events Version 4.0. Univariate and multivariate analysis was performed and time to development of pneumonitis was evaluated by the Kaplan-Meier method. A total of 189 patients were evaluated with a median follow-up of 24.8 months. The overall 1-year rate of symptomatic pneumonitis was 13.2%. The 1-year rate of symptomatic pneumonitis was 4.2% for ACEi users versus 16.3% in nonusers (P=0.03). On univariate analysis, the odds of developing grade 2 or greater pneumonitis were significantly lower for patients on ACEi (P=0.03). On multivariate analysis, after controlling for clinicopathologic characteristics and dosimetric endpoints, there was a significant association between ACEi use and decreased risk of clinical pneumonitis (P=0.04). Angiotensin receptor blockers or other bronchoactive medications did not show significant associations with development of pneumonitis. Incidental concurrent use of ACEi demonstrated efficacy in diminishing rates of symptomatic pneumonitis in the setting of lung SBRT.

The Role of Angiotensin-Converting Enzyme Inhibitors in Patients with Chronic Subdural Hematoma: A Scandinavian Population-Based Multicenter Study.

To investigate the role of angiotensin converting enzyme (ACE) inhibitors in the recurrence of chronic subdural hematoma (cSDH) after burr hole surgery. A retrospective review was conducted of a Scandinavian multicenter, population-based cohort of 1252 adults with cSDH who underwent with burr hole surgery between January 1, 2005, and December 31, 2010. The risk of cSDH recurrence was assessed in users of ACE inhibitors, users of angiotensin II receptor blockers (ARBs), and those without ACE inhibitor treatment (no ACE inhibitor group) using univariable and multivariable regression analyses. The cohort included 98 (7.8%) ACE inhibitor users and 63 (5%) ARB-only users. The recurrence rate was 16.3% (n= 16) in the ACE inhibitor group, compared with 13.3% (n= 153) in the no ACE inhibitor group (P= 0.39) and 14.3% (n= 9) in the ARB group (P= 0.73). When comparing groups, age (P= 0.01), Charlson Comorbidity Index (P= 0.01), use of platelet inhibitors (P= 0.001) and use of anticoagulants (P= 0.01) differed between the ACE inhibitor and no ACE inhibitor groups. Only age differed significantly between the ACE inhibitor and ARB groups (P= 0.03). In the analyses adjusted for differences in baseline characteristics, ACE inhibitor treatment did not influence the risk of recurrence (odds ratio, 1.2; 95% confidence interval, 0.7-2.2; P= 0.46). In this population-based study, the use of ACE inhibitors was not associated with the risk of recurrence following burr hole surgery for cSDH.

Angiotensin II receptor blockers versus angiotensin-converting enzyme inhibitors in patients with stable coronary artery disease: Prevalence, correlates, and prognostic impact (from the CORONOR study)

BackgroundIn international guidelines for patients with stable coronary artery disease (CAD), angiotensin-converting enzyme inhibitors (ACE-I) are recommended while angiotensin II receptor blockers (ARB) are proposed as an alternative in case of intolerance. There are no real-life data on the frequency and correlates of ARB use in this setting. MethodsWe studied 3363 outpatients included in a prospective registry on stable CAD (the CORONOR study) and receiving an ARB or an ACE-I at inclusion. ResultsAltogether, 944 patients received an ARB (28.1%). Factors positively and independently associated with ARB use versus ACE-I use were a history of hypertension, the absence of prior myocardial infarction, age, female gender, estimated glomerular filtration rate <60ml/min/m2, and left ventricular ejection fraction ≥40%. In the whole study population, the hazard ratio (HR) for the combined endpoint (cardiovascular death, myocardial infarction, stroke) of patients with ARB use was 0.95 (0.69–1.31) (p=0.765) (patients with ACE-I use as reference). Similar results were observed when the analysis was restricted to a propensity-matched cohort: HR=0.91 (0.62–1.34) (p=0.632). ConclusionsOur study shows that a significant proportion of stable CAD patients are treated with ARB rather than with ACE-I in modern practice. Several correlates of ARB prescription were identified. Our results suggest that patients receiving ARB have similar outcome than patients receiving ACE-I.

HIF prolyl hydroxylase inhibitors for the treatment of renal anaemia and beyond.

Small-molecule stabilizers of hypoxia inducible factor (HIF) are being developed for the treatment of renal anaemia. These molecules inhibit prolyl hydroxylase domain-containing (PHD) enzymes, resulting in HIF activation and increased production of erythropoietin. Currently, renal anaemia is treated with recombinant human erythropoietin or related analogues, referred to as conventional erythropoiesis stimulating agents (ESAs). Advantages of PHD enzyme inhibitors over conventional ESAs include their oral administration and their simpler - and potentially cheaper - production. Importantly, inhibition of PHD enzymes is likely to have a range of consequences other than increasing levels of erythropoietin, and these effects could be beneficial - for instance by reducing the need for parenteral iron - but might in some instances be harmful. Several companies are currently testing PHD enzyme inhibitors in patients with renal anaemia and have reported clear evidence of efficacy without serious safety concerns. A central question that current studies are beginning to address is whether using PHD enzyme inhibitors will influence hard end points, including mortality and the rate of cardiovascular events. In terms of approaches to therapy, the exquisite specificity of conventional ESAs is a striking contrast to the pleiotropic effects of activating HIF. Excitingly, PHD inhibitors could also be useful for conditions besides renal anaemia, such as protection from ischaemic injury.

Effect of anti-heart failure therapy on diastolic function in children with single-ventricle circulations.

Children with functionally univentricular circulations have chronic volume loading of the systemic ventricle, potentially affecting ventricular function. Medications including angiotensin-converting enzyme inhibitors and β-blockers are used to treat ventricular dysfunction, despite limited evidence of their efficacy in this population. To determine the effects of angiotensin-converting enzyme inhibitors on elevated filling pressures in children with single ventricle physiology. We performed a single-centre, retrospective review of patients with single ventricle physiology who underwent multiple cardiac catheterisations between 1991 and 2013. Study population comprised of patients who commenced or had optimised dosing of angiotensin-converting enzyme inhibitors between assessments in response to high ventricular filling pressures. Patients undergoing interventions influencing loading conditions between assessments were excluded. A total of 17 patients were identified, with dominant morphologic right ventricle in eight patients (47.1%). Among them, 11 (64.7%) were pre-Fontan and six (35.3%) were post-Fontan completion. Median inter-assessment interval was 9.4 months (range 7.3-19.1). There was a reduction in end-diastolic pressure from 13 to 10 mmHg (p=0.002), mean pulmonary artery pressure from 16 to 13 mmHg (p=0.049), and mean atrial pressure from 12 to 9 mmHg (p=0.001). There was one cardiac transplant, and there were no patient deaths at median follow-up after 31 months. We observed a reduction in ventricular end-diastolic pressure, pulmonary artery pressure, and mean atrial pressure following treatment with angiotensin-converting enzyme inhibitors in patients with single ventricle physiology. Our study provides insights into the potential impact of anti-heart failure therapy in single ventricle circulations and calls for larger, controlled studies to assess for a therapeutic response.