Sacubitril/Valsartan in Patients Hospitalized With Decompensated Heart Failure.

BACKGROUND: The efficacy and safety of sacubitril/valsartan in patients hospitalized with heart failure (HF) across the spectrum of left ventricular ejection fraction (EF) has not been described. OBJECTIVES: Data from randomized trials of sacubitril/valsartan in HF patients with EF ≤40% (PIONEER-HF [Comparison of Sacubitril/Valsartan Versus Enalapril on Effect of NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode] trial) and >40% (PARAGLIDE-HF [Prospective comparison of ARNI with ARB Given following stabiLization In DEcompensated HFpEF] trial) following recent worsening heart failure (WHF) were pooled to examine treatment effect across the EF spectrum. METHODS: The PIONEER-HF and PARAGLIDE-HF trials were double-blind, randomized trials of sacubitril/valsartan vs control therapy (enalapril or valsartan, respectively). All participants in the PIONEER-HF trial and 69.5% in the PARAGLIDE-HF trial were enrolled during hospitalization for HF after stabilization. The remainder in the PARAGLIDE-HF trial were enrolled ≤30 days after a WHF event. The primary endpoint of both trials was time-averaged proportional change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline through weeks 4 and 8. Adjudicated clinical endpoints were analyzed through the end of follow-up, adjusting for trial. RESULTS: The pooled analysis included 1,347 patients (881 from PIONEER-HF, 466 from PARAGLIDE-HF). Baseline characteristics included median age 66 years, 36% women, 31% Black, 34% de novo HF, and median EF 30%. The reduction in NT-proBNP was 24% greater with sacubitril/valsartan vs control therapy (n = 1,130; ratio of change = 0.76; 95% CI: 0.69-0.83; P < 0.0001). Cardiovascular death or hospitalization for HF was reduced by 30% with sacubitril/valsartan vs control therapy (HR: 0.70; 95% CI: 0.54-0.91; P = 0.0077). This effect was consistent across the spectrum of EF ≤60%. Sacubitril/valsartan increased symptomatic hypotension (risk ratio: 1.35; 95% CI: 1.05-1.72). CONCLUSIONS: In patients stabilized after WHF, sacubitril/valsartan led to a greater reduction in plasma NT-proBNP and improved clinical outcome compared with control therapy, in particular across the spectrum of EF ≤60%. (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect of NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode [PIONEER-HF]; NCT02554890; Changes in NT-proBNP, Safety, and Tolerability in HFpEF Patients With a WHF Event [HFpEF Decompensation] Who Have Been Stabilized and Initiated at the Time of or Within 30 Days Post-decompensation [PARAGLIDE-HF]; NCT03988634).

Genetic Studies in Infants with Congenital Nephrotic Syndrome: A Case Series.

Information on the genetic profile of congenital nephrotic syndrome (CNS) from India is scarce. The management of CNS is largely supportive of the setting of developing countries, mainly via the administration of intravenous albumin infusions, angiotensin-converting enzyme inhibitors, and levothyroxine. Inadequate infrastructure and management facilities, including genetic analyses, further hamper the outcome. These infants may progress to end-stage renal disease, and mortality is high in infancy. Here, we report a case series of four infants (aged 14-60 days) with CNS from our center with genetic mutations (including mutations in the NPHS1 and LAMB2 genes) that were not described in previous reports from India. Although responsiveness to enalapril has been documented in anecdotal reports of NPHS1 mutations, our case series of four infants did not exhibit any response to enalapril. Our case series adds to the existing literature regarding the genetic profile of CNS in India.

Impact of a combination of pimobendan, furosemide, and enalapril on heart rate variability in naturally occurring, symptomatic, myxomatous mitral valve degeneration dogs.

BACKGROUND: Pimobendan, diuretics, and an angiotensin-converting enzyme inhibitor (ACEi) are widely used for the management of chronic valvular heart disease in dogs; however, the effects of that combination on heart rate variability (HRV) are unknown. The purpose of this study was to assess the HRV of symptomatic myxomatous mitral valve degeneration (MMVD) dogs in response to therapy with a combination of pimobendan, diuretics, and ACEi. RESULTS: MMVD stage C (n = 17) dogs were enrolled and a 1-hour Holter recording together with echocardiography, blood pressure measurement, and blood chemistry profiles were obtained before and 1, 3, and 6 months after oral treatment with pimobendan (0.25 mg/kg), enalapril (0.5 mg/kg), and furosemide (2 mg/kg) twice daily. The results revealed that MMVD stage C dogs at the baseline had lower values of time-domain indices, low frequency (LF), high frequency (HF), and total power, as well as higher value of LF/HF. Triple therapy significantly increases these parameters in MMVD stage C dogs (P < 0.05). A positive moderate correlation was observed between time domain parameters and a left ventricular internal diastole diameter normalized to body weight (P < 0.05). CONCLUSIONS: It can be concluded that MMVD stage C dogs possess low HRV due to either the withdrawal of parasympathetic tone or enhanced sympathetic activation, and a combination therapy was shown to enhance cardiac autonomic modulation inferred from the increased heart rate variability. Therefore, a combination therapy may be useful for restoring normal autonomic nervous system activity in dogs with MMVD stage C.

Comparing Cardiovascular Outcomes and Costs of Perindopril-, Enalapril- or Losartan-Based Antihypertensive Regimens in South Africa: Real-World Medical Claims Database Analysis.

INTRODUCTION: Differences in class or molecule-specific effects between renin-angiotensin-aldosterone system (RAAS) inhibitors have not been conclusively demonstrated. This study used South African data to assess clinical and cost outcomes of antihypertensive therapy with the three most common RAAS inhibitors: perindopril, losartan and enalapril. METHODS: Using a large, South African private health insurance claims database, we identified patients with a hypertension diagnosis in January 2015 receiving standard doses of perindopril, enalapril or losartan, alone or in combination with other agents. From claims over the subsequent 5 years, we calculated the risk-adjusted rate of the composite primary outcome of myocardial infarction, ischaemic heart disease, heart failure or stroke; rate of all-cause mortality; and costs per life per month (PLPM), with adjustments based on demographic characteristics, healthcare plan and comorbidity. RESULTS: Overall, 32,857 individuals received perindopril, 16,693 losartan and 13,939 enalapril. Perindopril-based regimens were associated with a significantly lower primary outcome rate (205 per 1000 patients over 5 years) versus losartan (221; P < 0.0001) or enalapril (223; P < 0.0001). The risk-adjusted all-cause mortality rate was lower with perindopril than enalapril (100 vs. 139 deaths per 1000 patients over 5 years; P = 0.007), but not losartan (100 vs. 94; P = 0.650). Mean (95% confidence interval) overall risk-adjusted cost PLPM was Rands (ZAR) 1342 (87-8973) for perindopril, ZAR 1466 (104-9365) for losartan (P = 0.0044) and ZAR 1540 (77-10,546) for enalapril (P = 0.0003). CONCLUSION: In South African individuals with private health insurance, a perindopril-based antihypertensive regimen provided better clinical and cost outcomes compared with other regimens.

Safety and efficacy of intralesional injection of enalapril versus triamcinolone acetonide in the treatment of keloids.

INTRODUCTION: Keloids are pathologic conditions characterized by fibroblast hyper-proliferation and excess collagen deposition. Enalapril, one of the angiotensin-converting enzyme inhibitors, has recently been highlighted as a new therapeutic modality in treating keloids. This study evaluates the effectiveness of intralesional injection of enalapril versus triamcinolone acetonide (TAA) in keloids. METHODS: Forty patients with multiple keloids were enrolled in our study. Enalapril and TAA were injected intralesionally in one session per month for three sessions. The clinical outcomes were assessed via the Vancouver Scar Scale (VSS) and the Patient and Observer Scar Assessment Scale (POSAS). RESULTS: In both groups, according to VSS and POSAS, there was a high statistically significant difference (p-value ≤ 0.01) before treatment, at the end of each session, and 3 months after treatment. There was no significant difference between both groups regarding degree of improvement. Patients treated with TAA developed more significant complications than those in the enalapril group (p-value < 0.05). CONCLUSIONS: Both enalapril and TAA had the same clinical effect. Enalapril could be a safe alternative to steroids in the treatment of keloid and hypertrophic scars. Further studies on enalapril are needed on a large sample of patients with further focus on the mechanism of this innovative drug.

Prevalent and Incident Anemia in PARADIGM-HF and the Effect of Sacubitril/Valsartan.

BACKGROUND: Anemia is common in patients with heart failure with reduced ejection fraction and is associated with poor clinical outcomes. Renin-angiotensin system blockers lower hemoglobin and may induce anemia. OBJECTIVES: The authors investigated whether concomitant neprilysin inhibition might ameliorate this effect of renin-angiotensin system blockers in PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure). METHODS: Anemia was defined as hemoglobin <120 g/L in women and <130 g/L in men at screening. The authors investigated the effect of randomized treatment on clinical outcomes according to anemia status, change in hemoglobin from baseline, and the incidence of anemia. RESULTS: Of 8,239 participants with a baseline hemoglobin measurement, 1,677 (20.4%) were anemic. Patients with anemia had a more severe heart failure profile, worse kidney function, greater neurohormonal derangement, and worse clinical outcomes. Sacubitril/valsartan, compared with enalapril, decreased the risk of cardiovascular death or heart failure hospitalization similarly in patients with (HR: 0.84; 95% CI: 0.71-1.00) and without anemia (HR: 0.78 [95% CI: 0.71-0.87]; P value for interaction = 0.478). Between baseline and 12 months, hemoglobin decreased by 1.5 g/L (95% CI: 1.2-1.7 g/L) with sacubitril/valsartan compared with 2.3 g/L (95% CI: 2.0-2.6 g/L) with enalapril: mean difference 0.8 g/L (95% CI: 0.5-1.2 g/L; P < 0.001). Patients assigned to sacubitril/valsartan were less likely to develop anemia at 12 months (321 of 2,806 [11.4%]) compared with patients randomized to enalapril (440 of 2,824 [15.6%]) (OR: 0.70 [95% CI: 0.60-0.81]; P < 0.001). These findings were similar in PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction) (sacubitril/valsartan vs valsartan). There was biomarker evidence of increased iron utilization with sacubitril/valsartan. CONCLUSIONS: Irrespective of anemia status, sacubitril/valsartan compared with enalapril, decreased mortality and hospitalization. Hemoglobin decreased less with sacubitril/valsartan and the incidence of new anemia was lower with sacubitril/valsartan. (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure [PARADIGM-HF] trial; NCT01035255).

Enalapril attenuated CFA provoked arthritic manifestation by modulating proinflammatory and anti-inflammatory cytokine network.

Enalapril with documented anti-inflammatory potential was evaluated in current investigation to explore its anti-arthritic efficacy. For anti-arthritic evaluation of enalapril, CFA-instigated arthritic model was employed after which various parameters comprising paw volume, body weight, arthritic index, hematological and biochemical parameters, radiographic analysis and level of various cytokines were estimated. Enalapril demonstrated significant (p˂0.001) anti-arthritic activity by suppressing paw volume, arthritic index while preserved CFA instigated weight loss. Likewise, enalapril also normalized the hematological and biochemical alterations, suppressed the level of proinflammatory cytokines with elevation of anti-inflammatory cytokines. Radiographic and histopathological analysis also further validates the anti-arthritic attribute of enalapril where enalapril preserved the normal architecture of arthritis induced joints. Outcomes of the study pointed out a notable anti-arthritic activity of enalapril. However detailed mechanistic studies are still required to point out the exact mechanism of action.

Effect of vinpocetine alone and in combination with enalapril in experimental model of diabetic cardiomyopathy in rats: possible involvement of PDE-1/TGF-ß/ Smad 2/3 signalling pathways.

OBJECTIVE: Diabetic cardiomyopathy (DC) is one of the severe secondary complications of diabetes mellitus in humans. Vinpocetine is an alkaloid having pleiotropic pharmacological effects. The present study is designed to investigate the effect of vinpocetine in DC in rats. METHODS: Rats were fed a high-fat diet for nine weeks along with single dose of streptozotocin after the second week to induce DC. The haemodynamic evaluation was performed to assess the functional status of rats using the Biopac system. Cardiac echocardiography, biochemical, oxidative stress parameters and inflammatory cytokine level were analysed in addition to haematoxylin-eosin and Masson's trichome staining to study histological changes, cardiomyocyte diameter and fibrosis, respectively. Phosphodiesterase-1 (PDE-1), transforming growth factor-ß (TGF-ß) and p-Smad 2/3 expression in cardiac tissues were quantified using western blot/RT-PCR. KEY FINDING: Vinpocetine treatment and its combination with enalapril decreased the glucose levels compared to diabetic rats. Vinpocetine improved the echocardiographic parameters and cardiac functional status of rats. Vinpocetine decreased the cardiac biochemical parameters, oxidative stress, inflammatory cytokine levels, cardiomyocyte diameter and fibrosis in rats. Interestingly, expressions of PDE-1, TGF-ß and p-Smad 2/3 were ameliorated by vinpocetine alone and in combination with enalapril. CONCLUSIONS: Vinpocetine is a well-known inhibitor of PDE-1 and the protective effect of vinpocetine in DC is exerted by inhibition of PDE-1 and subsequent inhibition of the expression of TGF-ß/Smad 2/3.

Budget Impact Analysis of Utilization of Sacubitril/Valsartan for the Treatment of Heart Failure With Reduced Ejection Fraction in the Philippines.

OBJECTIVES: This study aimed to estimate the financial and economic impact of sacubitril/valsartan compared with enalapril for the treatment and prevention of hospitalization/rehospitalization because of heart failure with reduced ejection fraction (HFrEF). METHODS: The budget impact analysis was guided by the Philippine Reference Case and ISPOR's Principles of Good Practice for Budget Impact Analysis. A government-funded healthcare payer perspective and a societal perspective were considered. Data collection was guided by the pathways of disease progression and care. Collection of costing data followed a bottom-up approach. The model was based on a Markov model used in a study in Thailand. RESULTS: Over the next 5 years, there will be 17 625 less hospitalizations (∼5.1% less than enalapril arm) and 7968 less cardiovascular-related deaths (∼7.0% less than enalapril arm). In 5 years, the total cost of treating patients with HFrEF with sacubitril/valsartan at current market coverage and annual growth conditions is ₱15.430 billion, which is ₱11.077 billion higher than fully treating with enalapril only. The total required additional investment with treatment of sacubitril/valsartan compared with the full enalapril arm are ₱407 million (at 30-day coverage), ₱800 million (at 60-day coverage), and ₱1.181 billion (at 90-day coverage). If hospitalizations costs alone are considered, only the 30-day coverage is cost-saving. If a societal perspective is considered, all options are cost-saving where at least ₱4.003 billion is saved by the economy. CONCLUSION: The initial investment required to treat patients with HFrEF with sacubitril/valsartan is high; nevertheless, the year-on-year cost deficit shrinks in favor of investing in sacubitril/valsartan treatment.

Urinary cGMP (Cyclic Guanosine Monophosphate)/BNP (B-Type Natriuretic Peptide) Ratio, Sacubitril/Valsartan, and Outcomes in Heart Failure With Reduced Ejection Fraction: An Analysis of the PARADIGM-HF Trial.

BACKGROUND: The ratio of ucGMP (urinary cyclic guanosine monophosphate) to BNP (B-type natriuretic peptide) is thought to reflect the responsiveness of tissues to natriuretic peptides. METHODS: We examined the relationship between ucGMP/BNP ratio and clinical outcomes, the effect of sacubitril/valsartan, compared with enalapril, on the ucGMP/BNP ratio, and the efficacy of sacubitril/valsartan on clinical outcomes according to baseline ucGMP/BNP ratio in PARADIGM-HF trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure). ucGMP/BNP ratio was available at baseline (N=2031), 1 month (N=1959), and 8 months after randomization (N=1746). The primary outcome was a composite of heart failure hospitalization or cardiovascular death. RESULTS: Compared with the lowest tertile of baseline ucGMP/BNP ratio, patients in the higher tertiles had a lower risk of the primary outcome (tertile 1, reference; tertile 2, hazard ratio 0.57 [95% CI, 0.45-0.71]; tertile 3, hazard ratio, 0.54 [0.43-0.67]). Compared with baseline, the ucGMP/BNP ratio at 1 month and 8 months after randomization was higher with sacubitril/valsartan than with enalapril: ratio of geometric mean ratios at 1 month, 1.38 (95% CI, 1.27-1.51) and 8 months, 1.32 (95% CI, 1.20-1.45), and this difference was consistent across tertiles of ucGMP/BNP ratio at baseline (Pinteraction=0.19 and 0.91, respectively). The effect of sacubitril/valsartan, compared with enalapril, was consistent across tertiles of ucGMP/BNP ratio at baseline for all outcomes (Pinteraction ≥0.31). CONCLUSIONS: In patients with heart failure and reduced ejection fraction, higher ucGMP/BNP ratio was associated with better outcomes. Sacubitril/valsartan increased the ucGMP/BNP ratio, compared with enalapril, and the effect of sacubitril/valsartan on clinical outcomes was not modified by baseline ucGMP/BNP ratio. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique Identifier: NCT01035255.

Risk Factors of Dementia in Patients with Cerebral Vascular Diseases Based on Taiwan National Health Insurance Data.

INTRODUCTION: Vascular factors have been shown to be associated with increased risk of dementia. However, clinical trials have so far been unsuccessful, suggesting new approaches are needed. The aim of this study was to use population-based real-world data to investigate risk factors and preventive factors for dementia, including the effects of traditional Chinese medicine (TCM). METHODS: This is a retrospective cohort study using LHID2000, a dataset randomly selected from Taiwan's National Health Insurance Research Database. Subjects with occlusion and stenosis of precerebral and cerebral arteries, cerebral atherosclerosis without mention of cerebral infarction, and transient cerebral ischemia were included. Subjects with dementia at baseline were excluded. The primary endpoint was dementia. Data for demographic and clinical comorbid status and treatments administered at baseline in 2000 and at the end of follow-up in 2013 were included. RESULTS: A total of 4,207 subjects with cerebral vascular disease and no cognitive impairment were included, of whom 392 converted to dementia during an average 5.15-year (SD: 3.79) follow-up. Depression (adjusted HR: 1.54, 95% confidence interval [CI]: 1.13-2.09), osteoporosis (adjusted HR: 1.34, 95% CI: 1.04-1.74), and the use of enalapril (adjusted HR: 1.37, 95% CI: 1.09-1.73) were risk factors for dementia, while nitroglycerin (adjusted HR: 0.67, 95% CI: 0.53-0.85) was a protecting factor, in subjects with cerebrovascular diseases without mention of cerebral infarction. In total, statins were shown to be associated with decreased risk of dementia (HR: 0.73, 95% CI: 0.59-0.91); however, no one statin subtype or TCM had such an effect. CONCLUSION: Depression, osteoporosis, and the use of enalapril were associated with a higher risk of dementia, while nitroglycerin might be a protecting factor for dementia, in subjects with cerebrovascular diseases without mention of cerebral infarction.

Neurorretinitis bilateral y nefritis lúpica membranosa: dos manifestaciones infrecuentes en el lupus juvenil / Bilateral neuroretinitis and membranous lupus nephritis: 2 infrequent manifestations in juvenile lupus

Joven de 15 años, previamente sana, se presentó con dolor abdominal, vómitos, diarrea, eritema malar, edema palpebral y en miembros inferiores, artralgias, rigidez matinal y visión borrosa bilateral. Estudios de laboratorio y por imágenes junto con la clínica permitieron realizar el diagnóstico de síndrome nefrótico secundario a lupus eritematoso sistémico. Al examen oftalmológico se constató 8/10 de visión en ambos ojos y edema de papila bilateral con estrella macular parcial, hallazgos compatibles con una neurorretinitis bilateral. La biopsia renal estableció el diagnóstico de nefritis lúpica membranosa. Se inició tratamiento inmunosupresor, con mejoría clínica gradual. Si bien el lupus eritematoso sistémico con nefritis lúpica membranosa y neurorretinitis es una asociación muy infrecuente, frente a un paciente con neurorretinitis bilateral debemos considerar el lupus eritematoso sistémico dentro de los diagnósticos diferenciales (AU)

Fifteen-year-old female patient, previously healthy, referred to our center for presenting abdominal pain, vomiting, diarrhea, malar erythema, palpebral and lower limb edema, arthralgia, morning stiffness and bilateral blurred vision. Laboratory and imaging studies together with the clinic allowed the diagnosis of nephrotic syndrome secondary to systemic lupus erythematosus. Ophthalmology examination revealed a visual acuity of 8/10 in both eyes and bilateral disc edema with partial macular star, findings compatible with bilateral neuroretinitis. Renal biopsy established the diagnosis of membranous lupus nephritis. Immunosuppressive treatment was started, obtaining gradual clinical improvement. Although systemic lupus erythematosus with membranous lupus nephritis and neuroretinitis is a very infrequent association, when faced with a patient with bilateral neuroretinitis, we must consider systemic lupus erythematosus within the differential diagnoses (AU)

The Novel, Clinical-Stage Soluble Guanylate Cyclase Activator BI 685509 Protects from Disease Progression in Models of Renal Injury and Disease.

Activation of soluble guanylate cyclase (sGC) to restore cyclic guanosine monophosphate (cGMP) and improve functionality of nitric oxide (NO) pathways impaired by oxidative stress is a potential treatment of diabetic and chronic kidney disease. We report the pharmacology of BI 685509, a novel, orally active small molecule sGC activator with disease-modifying potential. BI 685509 and human sGC α1/ß1 heterodimer containing a reduced heme group produced concentration-dependent increases in cGMP that were elevated modestly by NO, whereas heme-free sGC and BI 685509 greatly enhanced cGMP with no effect of NO. BI 685509 increased cGMP in human and rat platelet-rich plasma treated with the heme-oxidant ODQ; respective EC50 values were 467 nM and 304 nM. In conscious telemetry-instrumented rats, BI 685509 did not affect mean arterial pressure (MAP) or heart rate (HR) at 3 and 10 mg/kg (p.o.), whereas 30 mg/kg decreased MAP and increased HR. Ten days of BI 685509 at supratherapeutic doses (60 or 100 mg/kg p.o., daily) attenuated MAP and HR responses to a single 100 mg/kg challenge. In the ZSF1 rat model, BI 685509 (1, 3, 10, and 30 mg/kg per day, daily) coadministered with enalapril (3 mg/kg per day) dose-dependently reduced proteinuria and incidence of glomerular sclerosis; MAP was modestly reduced at the higher doses versus enalapril. In the 7-day rat unilateral ureteral obstruction model, BI 685509 dose-dependently reduced tubulointerstitial fibrosis (P < 0.05 at 30 mg/kg). In conclusion, BI 685509 is a potent, orally bioavailable sGC activator with clear renal protection and antifibrotic activity in preclinical models of kidney injury and disease. SIGNIFICANCE STATEMENT: BI 685509 is a novel small soluble guanylate cyclase (sGC) molecule activator that exhibits an in vitro profile consistent with that of an sGC activator. BI 685509 reduced proteinuria and glomerulosclerosis in the ZSF1 rat, a model of diabetic kidney disease (DKD), and reduced tubulointerstitial fibrosis in a rat 7-day unilateral ureteral obstruction model. Thus, BI 685509 is a promising new therapeutic agent and is currently in phase II clinical trials for chronic kidney disease and DKD.

Influence of Age, Heart Failure and ACE Inhibitor Treatment on Plasma Renin Activity in Children: Insights from a Systematic Review and the European LENA Project.

BACKGROUND: Plasma renin activity (PRA) has gained relevance as prognostic marker in adults with heart failure. The use of PRA as a clinically meaningful parameter in children and children with heart failure requires a thorough knowledge of the factors that influence PRA to correctly assess PRA levels. We aim to evaluate the influence of age, heart failure and angiotensin-converting enzyme inhibitor (ACEi) on PRA levels in children. METHODS: We conducted a systematic literature search to identify studies on PRA levels in healthy children and in children with heart failure. In addition, we analysed PRA data measured before (n = 35, aged 25 days-2.1 years), 4 hours after (n = 34) and within the first 8 days of enalapril treatment (n = 29) in children with heart failure from the European project Labeling of Enalapril from Neonates up to Adolescents (LENA). RESULTS: Age has a profound effect on PRA levels in healthy children, as PRA levels in the literature are up to about 7 times higher in neonates than in older children. Children with heart failure younger than 6 months showed 3-4 times higher PRA levels than healthy peers in both the literature and the LENA studies. In the LENA studies, the ACEi enalapril significantly increased median predose PRA by a factor of 4.5 in children with heart failure after 4.7 ± 1.6 days of treatment (n = 29, p < 0.01). Prior to treatment with enalapril, LENA subjects with symptomatic heart failure (Ross score ≥3) had a significantly higher PRA than LENA subjects with asymptomatic heart failure of comparable age (Ross score ≤2, p < 0.05). CONCLUSIONS: Age, heart failure and ACEi treatment have a notable influence on PRA and must be considered when assessing PRA as a clinically meaningful parameter. CLINICAL TRIAL REGISTRATION: The trials are registered on the EU Clinical Trials Register (https://www.clinicaltrialsregister.eu). TRIAL REGISTRATION NUMBERS: EudraCT 2015-002335-17, EudraCT 2015-002396-18.

Preventing cardiotoxicity in patients with breast cancer and lymphoma: protocol for a multicentre randomised controlled trial (PROACT).

INTRODUCTION: Anthracyclines are included in chemotherapy regimens to treat several different types of cancer and are extremely effective. However, it is recognised that a significant side effect is cardiotoxicity; anthracyclines can cause irreversible damage to cardiac cells and ultimately impaired cardiac function and heart failure, which may only be evident years after exposure. The PROACT trial will establish the effectiveness of the ACE inhibitor enalapril maleate (enalapril) in preventing cardiotoxicity in patients with breast cancer and non-Hodgkin's lymphoma (NHL) receiving anthracycline-based chemotherapy. METHODS AND ANALYSIS: PROACT is a prospective, randomised, open-label, blinded end-point, superiority trial which will recruit adult patients being treated for breast cancer and NHL at NHS hospitals throughout England. The trial aims to recruit 106 participants, who will be randomised to standard care (high-dose anthracycline-based chemotherapy) plus enalapril (intervention) or standard care alone (control). Patients randomised to the intervention arm will receive enalapril (starting at 2.5 mg two times per day and titrating up to a maximum dose of 10 mg two times per day), commencing treatment at least 2 days prior to starting chemotherapy and finishing 3 weeks after their last anthracycline dose. The primary outcome is the presence or absence of cardiac troponin T release at any time during anthracycline treatment, and 1 month after the last dose of anthracycline. Secondary outcomes will focus on cardiac function measured using echocardiogram assessment, adherence to enalapril and side effects. ETHICS AND DISSEMINATION: A favourable opinion was given following research ethics committee review by West Midlands-Edgbaston REC, Ref: 17/WM/0248. Trial findings will be disseminated through engagement with patients, the oncology and cardiology communities, NHS management and commissioning groups and through peer-reviewed publication. TRIAL REGISTRATION NUMBER: NCT03265574.

The Influence of Structural Variants of the CES1 Gene on the Pharmacokinetics of Enalapril, Presumably Due to Linkage Disequilibrium with the Intronic rs2244613.

Variants in the CES1 gene encoding carboxylesterase 1 may affect the metabolism of enalapril to the active metabolite enalaprilat. It was shown that the A allele of rs71647871 and the C allele of rs2244613 led to a decrease in plasma enalaprilat concentrations. This study aimed to estimate the effect of structural haplotypes of CES1 containing the pseudogene CES1P1, or a hybrid of the gene and the pseudogene CES1A2, on the pharmacokinetics of enalapril. We included 286 Caucasian patients with arterial hypertension treated with enalapril. Genotyping was performed using real-time PCR and long-range PCR. Peak and trough plasma enalaprilat concentrations were lower in carriers of CES1A2. The studied haplotypes were in linkage disequilibrium with rs2244613: generally, the A allele was in the haplotype containing the CES1P1, and the C allele was in the haplotype with the CES1A2. Thus, carriers of CES1A2 have reduced CES1 activity against enalapril. Linkage disequilibrium of the haplotype containing the CES1P1 or CES1A2 with rs2244613 should be taken into account when genotyping the CES1 gene.

The Correlation between Two Angiotensin-Converting Enzyme Inhibitor's Concentrations and Cognition.

Both lisinopril and enalapril are angiotensin-converting enzyme (ACE) drugs and widely used in the treatment of hypertension. Enalapril does not cross the blood-brain barrier, but lisinopril is centrally active. Our goal was to find out if there was a link between the actual concentration of ACE inhibitors and cognition and if there was a detectable difference between the two types of ACE inhibitors. Asymptomatic, non-treated patients were diagnosed by screening and the hypertension was confirmed by ambulatory blood pressure monitoring (ABPM). A battery of cognitive tests was used to assess the impact of randomly assigning participants to receive either lisinopril or enalapril. All neurocognitive functions were measured, especially the most affected by conditions of compromised perfusion pressures, such as hypertension, which are attention and executive functions. The lisinopril concentration showed a significant inverse correlation with mosaic test (coeff. = -0.5779) and seemed to have a significant negative effect on perceptual motor skills (coeff. = -0.5779), complex attention (coeff. = -0.5104) and learning (coeff. = -0.5202). Compared with enalapril, lisinopril is less successful in improving the components of cognitive functions.

Cost-effectiveness of folic acid therapy for primary prevention of stroke in patients with hypertension.

BACKGROUND: For hypertensive patients without a history of stroke or myocardial infarction (MI), the China Stroke Primary Prevention Trial (CSPPT) demonstrated that treatment with enalapril-folic acid reduced the risk of primary stroke compared with enalapril alone. Whether folic acid therapy is an affordable and beneficial treatment strategy for the primary prevention of stroke in hypertensive patients from the Chinese healthcare sector perspective has not been thoroughly explored. METHODS: We performed a cost-effectiveness analysis alongside the CSPPT, which randomized 20,702 hypertensive patients. A patient-level microsimulation model based on the 4.5-year period of in-trial data was used to estimate costs, life years, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) for enalapril-folic acid vs. enalapril over a lifetime horizon from the payer perspective. RESULTS: During the in-trial follow-up period, patients receiving enalapril-folic acid gained an average of 0.016 QALYs related primarily to reductions in stroke, and the incremental cost was $706.03 (4553.92 RMB). Over a lifetime horizon, enalapril-folic acid treatment was projected to increase quality-adjusted life years by 0.06 QALYs or 0.03 life-year relative to enalapril alone at an incremental cost of $1633.84 (10,538.27 RMB), resulting in an ICER for enalapril-folic acid compared with enalapril alone of $26,066.13 (168,126.54 RMB) per QALY gained and $61,770.73 (398,421.21 RMB) per life-year gained, respectively. A probabilistic sensitivity analysis demonstrated that enalapril-folic acid compared with enalapril would be economically attractive in 74.5% of simulations at a threshold of $37,663 (242,9281 RMB) per QALY (3x current Chinese per capita GDP). Several high-risk subgroups had highly favorable ICERs < $12,554 (80,976 RMB) per QALY (1x GDP). CONCLUSIONS: For both in-trial and over a lifetime, it appears that enalapril-folic acid is a clinically and economically attractive medication compared with enalapril alone. Adding folic acid to enalapril may be a cost-effective strategy for the prevention of primary stroke in hypertensive patients from the Chinese health system perspective.

Antihypertensive treatment with calcium channel blockers and renal protection: focus on lercanidipine and lercanidipine/enalapril.

OBJECTIVE: The aim of the study was to review the literature on clinical pharmacology of lercanidipine and experimental and clinical evidence and evaluate its ability to reduce proteinuria and preserve renal function when used as monotherapy or in combination with the angiotensin-converting enzyme (ACE) inhibitor enalapril. MATERIALS AND METHODS: MEDLINE/PubMed was searched for appropriate keywords. RESULTS: Lercanidipine, a third-generation calcium channel blocker, has been shown to have a unique pharmacological and clinical profile, which translates into favorable renal hemodynamic changes. The fixed-dose combination lercanidipine/enalapril has been proposed to overcome unmet therapeutic needs, often as the initial treatment in the high-risk patient. CONCLUSIONS: Lercanidipine may be regarded as an ideal antihypertensive drug for patients at renal risk and possibly the preferred choice among calcium channel blocker drugs.

Reviewing the Modern Therapeutical Options and the Outcomes of Sacubitril/Valsartan in Heart Failure.

Sacubitril/valsartan (S/V) is a pharmaceutical strategy that increases natriuretic peptide levels by inhibiting neprilysin and regulating the renin-angiotensin-aldosterone pathway, blocking AT1 receptors. The data for this innovative medication are mainly based on the PARADIGM-HF study, which included heart failure with reduced ejection fraction (HFrEF)-diagnosed patients and indicated a major improvement in morbidity and mortality when S/V is administrated compared to enalapril. A large part of the observed favorable results is related to significant reverse cardiac remodeling confirmed in two prospective trials, PROVE-HF and EVALUATE-HF. Furthermore, according to a subgroup analysis from the PARAGON-HF research, S/V shows benefits in HFrEF and in many subjects having preserved ejection fraction (HFpEF), which indicated a decrease in HF hospitalizations among those with a left ventricular ejection fraction (LVEF) < 57%. This review examines the proven benefits of S/V and highlights continuing research in treating individuals with varied HF characteristics. The article analyses published data regarding both the safeness and efficacy of S/V in patients with HF, including decreases in mortality and hospitalization, increased quality of life, and reversible heart remodeling. These benefits led to the HF guidelines recommendations updating and inclusion of S/V combinations a key component of HFrEF treatment.