Retrospective analysis of neoplasms in patients using angiotensin receptor blockers.

In recent years, regulatory agencies have raised concerns about the presence of potentially carcinogenic substances in certain formulations of Angiotensin Receptor Blockers (ARBs). Specifically, nitrosamines and azido compounds have been identified in some ARB products. Nitrosamines are known to have carcinogenic properties and are associated with an increased risk of neoplasms. Spontaneous safety reports from the EudraVigilance Data Analysis System (EVDAS) database were analyzed to investigate cases of neoplasms associated with ARBs. A disproportionality analysis was conducted, calculating the reporting odds ratio (ROR) and 95% confidence intervals (CIs) using a case/non-case approach for each ARB drug. The EVDAS database contained 68,522 safety reports related to ARBs (including Azilsartan, Candesartan, Irbesartan, Olmesartan, Losartan, Valsartan, and Telmisartan), among which 3,396 (5%) cases were associated with neoplasms. The majority of these cases were reported in Germany (11.9%), followed by France (9.7%). Approximately 70% of the reports were submitted by healthcare professionals such as physicians and nurses. Among the ARBs, valsartan had the highest ROR for neoplasm (ROR 1.949, 95% CI 1.857-2.046). This association remained significant when comparing ARBs with other classes of antihypertensive drugs, including ACE inhibitors, beta-blockers, calcium channel blockers, and diuretics. Our study identifies a possible signal of an association between ARBs, particularly valsartan, and the risk of neoplasms. However, further observational and analytical studies are necessary to confirm these findings and elucidate the underlying mechanisms.

Effects of angiotensin receptor-neprilysin inhibitor on ketone body metabolism in pre-heart failure/heart failure patients.

Recently, a mild elevation of the blood ketone levels was found to exert multifaceted cardioprotective effects. To investigate the effect of angiotensin receptor neprilysin inhibitors (ARNIs) on the blood ketone body levels, 46 stable pre-heart failure (HF)/HF patients were studied, including 23 who switched from angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) to ARNIs (ARNI group) and 23 who continued treatment with ACE inhibitors or ARBs (control group). At baseline, there were no significant differences in the total ketone body (TKB) levels between the two groups. Three months later, the TKB levels in the ARNI group were higher than the baseline values (baseline to 3 months: 71 [51, 122] to 92 [61, 270] µmol/L, P < 0.01). In the control group, no significant change was observed between the baseline and 3 months later. A multiple regression analysis demonstrated that the initiation of ARNI and an increase in the blood non-esterified fatty acid (NEFA) levels at 3 months increased the percentage changes in the TKB levels from baseline to 3 months (%ΔTKB level) (initiation of ARNI: P = 0.017, NEFA level at 3 months: P < 0.001). These results indicate that ARNI administration induces a mild elevation of the blood TKB levels in pre-HF/HF patients.

Efficacy and Safety of Sacubitril/Valsartan in Hemodialysis Patients with Chronic Heart Failure: A Retrospective Study at a Single Center.

BACKGROUND Heart failure and end-stage renal disease often coexist, and management of heart failure can be challenging in patients during hemodialysis. Sacubitril-valsartan (SV) is the first drug to receive regulatory approval for use in patients with chronic heart failure with reduced ejection fraction (HFrEF) and New York Heart Association (NYHA) classification II, III, or IV. This study aimed to evaluate the efficacy and safety of SV for use in chronic heart failure patients on maintenance hemodialysis (MHD). MATERIAL AND METHODS From September 2021 to October 2022, 28 patients on MHD with chronic heart failure at the hemodialysis center of Shaanxi Second Provincial People's Hospital were regularly followed. During the 12-week follow-up period, all patients were administered SV at doses of 100-400 mg per day. Biochemical indicators, echocardiographic parameters, life quality scores, and adverse events were evaluated. RESULTS We enrolled 28 patients. Compared with the baseline levels, NYHA class III in these patients treated with SV was significantly decreased from 60.71% to 32.14% (P<0.05), left ventricular ejection fraction (LVEF) was significantly improved from 44.29±8.92% to 53.32±7.88% (P<0.001), the Physical Component Summary (PCS) score was significantly improved from 40.0±6.41 to 56.20±9.86 (P<0.001), and the Mental Component Summary (MCS) score was significantly improved from 39.99±6.14 to 52.59±11.0 (P<0.001). CONCLUSIONS We demonstrated that SV improved NYHA classification and LVEF values of patients on MHD with chronic heart failure and also improved their quality of life.

Determination of valsartan and pitavastatin using synchronous spectrofluorimetry and augmented least squares chemometric models: A comparative study with greenness and blueness assessment.

Hypertension and hyperlipidemia are two common conditions that require effective management to reduce the risk of cardiovascular diseases. Among the medications commonly used for the treatment of these conditions, valsartan and pitavastatin have shown significant efficacy in lowering blood pressure and cholesterol levels, respectively. In this study, synchronous spectrofluorimetry coupled to chemometric analysis tools, specifically concentration residual augmented classical least squares (CRACLS) and spectral residual augmented classical least squares (SRACLS), was employed for the determination of valsartan and pitavastatin simultaneously. The developed models exhibited excellent predictive performance with relative root mean square error of prediction (RRMSEP) of 2.253 and 2.1381 for valsartan and pitavastatin, respectively. Hence, these models were successfully applied to the analysis of synthetic samples and commercial formulations as well as plasma samples with high accuracy and precision. Besides, the greenness and blueness profiles of the determined samples were also evaluated to assess their environmental impact and analytical practicability. The results demonstrated excellent greenness and blueness scores with AGREE score of 0.7 and BAGI score of 75 posing the proposed method as reliable and sensitive approach for the determination of valsartan and pitavastatin with potential applications in pharmaceutical quality control, bioanalytical studies, and therapeutic drug monitoring.

The concentration of maternal sacubitril/valsartan transferred into human milk is negligible.

Background: Peripartum cardiomyopathy (PPCM) is a common cause of heart failure (HF) in the peripartum. Some medications are considered safe while breastfeeding. However, sacubitril/valsartan (Entresto), while efficacious, is not recommended in breastfeeding women due to concerns about adverse infant development, and no published data suggest otherwise. Objectives: This study aimed to assess the transfer of sacubitril/valsartan into human milk and evaluate the infant's risk of drug exposure. Methods: The InfantRisk Human Milk Biorepository released samples and corresponding health information from five breastfeeding maternal-infant dyads exposed to sacubitril/valsartan. Sacubitril, valsartan, and LBQ657 (sacubitril active metabolite) concentrations were determined using liquid chromatography-mass spectrometry (LC/MS/MS) from timed samples 0, 1, 2, 4, 6, 8, 10, and 12 h following medication administration at steady state conditions. Results: Valsartan levels were below the detection limit of 0.19 ng/mL in all milk samples. Sacubitril was measurable in all milk samples of the five participants, peaking 1 h after drug administration at a mean concentration of 1.52 ng/mL for a total infant dose of 0.00049 mg/kg/12 h and a relative infant dose (RID) calculated at 0.01%. The maximum concentration of its active metabolite LBQ657 in the milk samples was observed 4 h after medication administration and declined over the remaining 12-h dosing interval, for an average concentration of 9.5 ng/mL. The total infant dose was 0.00071 mg/kg/12 h, and the RID was 0.22%. Two mothers reported continuing to breastfeed while taking sacubitril/valsartan; both mothers stated observing no negative effects in their breastfed infants. Conclusion: The transfer of sacubitril/valsartan into human milk is minimal. These concentrations are unlikely to pose a significant risk to breastfeeding infants, with a combined calculated RID of <0.25%, which is far lower than the industry safety standards (RID <10%).

Study on the Effects of Angiotensin Receptor/Neprilysin Inhibitors on Renal Haemodynamics in Healthy Dogs.

An angiotensin receptor/neprilysin inhibitor (ARNI), a heart failure treatment, is a combination drug made up of sacubitril, a neprilysin inhibitor, and valsartan, a vascular receptor blocker. No human or veterinary studies regarding the effect of ARNI on renal haemodynamics in the absence of cardiac or renal issues exist. Therefore, we investigated the effect of ARNI on renal haemodynamics in five healthy dogs. ARNI was administered to all five dogs at an oral dose of 20 mg/kg twice daily for 4 weeks. Renal haemodynamics were assessed on the day before ARNI administration (BL), on Day 7, and on Day 28. The glomerular filtration rate (GFR) significantly increased on Day 28 compared to BL and Day 7, whereas renal plasma flow increased on Day 7 and Day 28 compared to BL. Systolic blood pressure significantly decreased between BL and Day 28. Plasma atrial natriuretic peptide (ANP) concentrations increased on Day 7 compared to BL. Additionally, ANP concentrations increased on Day 28 in three of the five dogs. Different ANP concentrations were observed in the remaining two dogs. Both urine output volume and heart rate remained relatively stable and did not exhibit significant change. In conclusion, ARNI may enhance renal haemodynamics in healthy dogs. ARNI could be a valuable drug for treating both heart and kidney disease in dogs.

Aptamer Proteomics for Biomarker Discovery in Heart Failure With Preserved Ejection Fraction: The PARAGON-HF Proteomic Substudy.

BACKGROUND: Prognostic markers and biological pathways linked to detrimental clinical outcomes in heart failure with preserved ejection fraction (HFpEF) remain incompletely defined. METHODS AND RESULTS: We measured serum levels of 4123 unique proteins in 1117 patients with HFpEF enrolled in the PARAGON-HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) trial using a modified aptamer proteomic assay. Baseline circulating protein concentrations significantly associated with the primary end point and the timing and occurrence of total heart failure hospitalization and cardiovascular death were identified by recurrent events regression, accounting for multiple testing, adjusted for age, sex, treatment, and anticoagulant use, and compared with published analyses in 2515 patients with heart failure with reduced ejection fraction from the PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and ATMOSPHERE (Efficacy and Safety of Aliskiren and Aliskiren/Enalapril Combination on Morbidity-Mortality in Patients With Chronic Heart Failure) clinical trials. We identified 288 proteins that were robustly associated with the risk of heart failure hospitalization and cardiovascular death in patients with HFpEF. The baseline proteins most strongly related to outcomes included B2M (ß-2 microglobulin), TIMP1 (tissue inhibitor of matrix metalloproteinase 1), SERPINA4 (serpin family A member 4), and SVEP1 (sushi, von Willebrand factor type A, EGF, and pentraxin domain containing 1). Overall, the protein-outcome associations in patients with HFpEF did not markedly differ as compared with patients with heart failure with reduced ejection fraction. A proteomic risk score derived in patients with HFpEF was not superior to a previous proteomic score derived in heart failure with reduced ejection fraction nor to clinical risk factors, NT-proBNP (N-terminal pro-B-type natriuretic peptide), or high-sensitivity cardiac troponin. CONCLUSIONS: Numerous serum proteins linked to metabolic, coagulation, and extracellular matrix regulatory pathways were associated with worse HFpEF prognosis in the PARAGON-HF proteomic substudy. Our results demonstrate substantial similarities among serum proteomic risk markers for heart failure hospitalization and cardiovascular death when comparing clinical trial participants with heart failure across the ejection fraction spectrum. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifiers: NCT01920711, NCT01035255, NCT00853658.

Characterization, Structure, and Inhibition of the Human Succinyl-CoA:glutarate-CoA Transferase, a Putative Genetic Modifier of Glutaric Aciduria Type 1.

Glutaric Aciduria Type 1 (GA1) is a serious inborn error of metabolism with no pharmacological treatments. A novel strategy to treat this disease is to divert the toxic biochemical intermediates to less toxic or nontoxic metabolites. Here, we report a putative novel target, succinyl-CoA:glutarate-CoA transferase (SUGCT), which we hypothesize suppresses the GA1 metabolic phenotype through decreasing glutaryl-CoA and the derived 3-hydroxyglutaric acid. SUGCT is a type III CoA transferase that uses succinyl-CoA and glutaric acid as substrates. We report the structure of SUGCT, develop enzyme- and cell-based assays, and identify valsartan and losartan carboxylic acid as inhibitors of the enzyme in a high-throughput screen of FDA-approved compounds. The cocrystal structure of SUGCT with losartan carboxylic acid revealed a novel pocket in the active site and further validated the high-throughput screening approach. These results may form the basis for the future development of new pharmacological intervention to treat GA1.

Long-Term Outcomes of Sacubitril/Valsartan in Heart Failure with Reduced Ejection Fraction and Coexisting End-Stage Renal Disease.

Sacubitril/valsartan (Entresto) has proven therapeutic effects in heart failure (HF) patients, but its impact on those with advanced chronic kidney disease (CKD) remains unclear, particularly in HF patients with coexisting end-stage renal disease (ESRD). This study aims to assess the long-term survival of patients with heart failure with reduced ejection fraction (HFrEF) and coexisting ESRD treated with sacubitril/valsartan. A retrospective cohort study included 2,860 HFrEF and ESRD patients between January 2008 and December 2020. After propensity score matching, data from a sacubitril/valsartan group (n = 61) and a candesartan or valsartan group (n = 117) were analyzed. Patients on sacubitril/valsartan for at least 9 months had significantly lower 5-year all-cause mortality (39.3%) compared with the non-sacubitril/valsartan group (54.7%) (HR 0.46; 95% CI, 0.25-0.82; P = 0.0094). Left ventricular ejection fraction (LVEF) improvement after 3 years in the sacubitril/valsartan group (14.51 ±18.98) was significantly greater than the non-sacubitril/valsartan group (6.91 ±18.44) (P = 0.0408). Average hospitalizations in sacubitril/valsartan and non-sacubitril/valsartan groups were 1.39 and 0.97, respectively (incidence rate ratio, 1.59; 95% CI, 0.90-2.82; P = 0.1106). Sacubitril/valsartan treatment demonstrated significantly lower 5-year mortality rates and greater LVEF improvement in HFrEF patients with coexisting ESRD compared with candesartan or valsartan. These findings suggest that sacubitril/valsartan is a beneficial treatment option for this patient population.

Real-life effectiveness of sacubitril/valsartan in older Belgians with heart failure, reduced ejection fraction and most severe symptoms.

We assessed the real-world effectiveness of sacubitril/valsartan in patients with chronic heart failure (HF) and reduced ejection fraction (HFrEF) with an emphasis on those with older age (≥ 75 years) or with New York Heart Association (NYHA) class IV, for whom greater uncertainty existed regarding clinical outcomes. We conducted a retrospective cohort study based on patient-level linkage of electronic healthcare datasets. Data from all adults with HFrEF in Belgium receiving a prescription for sacubitril/valsartan between 01-November-2016 and 31-December-2018 were collected, with a follow-up of > 6 years. The total study population comprised 5446 patients, older than the PARADIGM-HF trial participants, and with higher NYHA class (all P < 0.0001). NYHA class improved following sacubitril/valsartan initiation (P < 0.0001 baseline vs. reassessment). Most concomitant medications were reduced. Remarkably, the risk of hospitalization for a cardiovascular reason and for HF was reduced by > 26% in the overall cohort, and in subgroups of patients ≥ 75 years, with NYHA class III/IV (all P < 0.0001) or with NYHA class IV (P < 0.05), vs. baseline. All-cause mortality did not increase in real-world patients with NYHA class III/IV. The results support the long-term beneficial effects of sacubitril/valsartan in older patients and in those experiencing the most severe symptoms.

The role of sacubitril/valsartan in abnormal renal function patients combined with heart failure: a meta-analysis and systematic analysis.

AIMS: This study aimed to investigate the efficacy and safety of sacubitril/valsartan in abnormal renal function (eGFR < 60 ml/min/1.73m2) patients combined with heart failure based on randomized controlled trials (RCTs) and observational studies. METHODS: The Embase, PubMed and the Cochrane Library were searched for relevant studies from inception to December 2023. Dichotomous variables were described as event counts with the odds ratio (OR) and 95% confidence interval (CI) values. Continuous variables were expressed as mean standard deviation (SD) with 95% CIs. RESULTS: A total of 6 RCTs and 8 observational studies were included, involving 17335 eGFR below 60 ml/min/1.73m2 patients combined with heart failure. In terms of efficacy, we analyzed the incidence of cardiovascular events and found that sacubitril/valsartan significantly reduced the risk of cardiovascular death or heart failure hospitalization in chronic kidney disease (CKD) stages 3-5 patients with heart failure (OR: 0.65, 95%CI: 0.54-0.78). Moreover, sacubitril/valsartan prevented the serum creatinine elevation (OR: 0.81, 95%CI: 0.68-0.95), the eGFR decline (OR: 0.83, 95% CI: 0.73-0.95) and the development of end-stage renal disease in this population (OR:0.73, 95%CI:0.60-0.89). As for safety outcomes, we did not find that the rate of hyperkalemia (OR:1.31, 95%CI:0.79-2.17) and hypotension (OR:1.57, 95%CI:0.94-2.62) were increased in sacubitril/valsartan group among CKD stages 3-5 patients with heart failure. CONCLUSIONS: Our meta-analysis proves that sacubitril/valsartan has a favorable effect on cardiac function without obvious risk of adverse events in abnormal renal function patients combined with heart failure, indicating that sacubitril/valsartan has the potential to become perspective treatment for these patients.

Sacubitril/valsartan and cardiovascular biomarkers among patients with recent COVID-19 infection: The PARACOR-19 randomized clinical trial.

AIMS: The PARACOR-19 randomized controlled trial (RCT) was designed to examine the effects of sacubitril/valsartan on markers of cardiac injury, inflammation, structure, and function among patients who have recovered from acute coronavirus disease 2019 (COVID-19) infection. METHODS AND RESULTS: PARACOR-19 was a single-centre, double-blind RCT of patients with cardiovascular risk factors and a history of COVID-19 infection 4-16 weeks prior to enrolment. Patients were randomized to sacubitril/valsartan (titrated to the maximum dose of 97/103 mg twice daily) versus matching placebo. Co-primary endpoints were change from baseline to 12 weeks in high-sensitivity cardiac troponin T (hs-cTnT) and soluble ST2 (sST2). Exploratory endpoints included change from baseline to 12 weeks in additional circulating biomarkers. Overall, 42 patients were randomized between August 2021 and March 2023 (n = 20 sacubitril/valsartan, n = 22 placebo). Median (25th-75th) time from COVID-19 diagnosis to enrolment was 67 (48-80) days. Median age was 67 (62-71) years, 48% were female, and 91% were White. Compared with placebo, sacubitril/valsartan did not have a significant effect on the co-primary endpoints of change from baseline in hs-TnT and sST2 (all p ≥ 0.29). In exploratory analyses, sacubitril/valsartan led to a 46% greater reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP) and 51% greater reduction in C-terminal telopeptide of collagen type I (CITP). Permanent drug discontinuation occurred in four patients in the sacubitril/valsartan group and three patients in the placebo group. There were no deaths and one patient was hospitalized in each group. CONCLUSION: In this pilot RCT of patients who recovered from acute COVID-19, sacubitril/valsartan did not lower hs-cTnT or sST2 compared with placebo. Exploratory analyses suggested potential benefits of sacubitril/valsartan on cardiac wall stress and collagen turnover as measured by NT-proBNP and CITP. Sacubitril/valsartan was well tolerated. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT04883528.

Sacubitril/valsartan for the treatment of non-obstructive hypertrophic cardiomyopathy: An open label randomized controlled trial (SILICOFCM).

AIM: Sacubitril/valsartan treatment reduces mortality and hospitalizations in heart failure with reduced ejection fraction but has limited application in hypertrophic cardiomyopathy (HCM). The aim of this study was to evaluate the effect of sacubitril/valsartan on peak oxygen consumption (VO2) in patients with non-obstructive HCM. METHODS AND RESULTS: This is a phase II, randomized, open-label multicentre study that enrolled adult patients with symptomatic non-obstructive HCM (New York Heart Association class I-III) who were randomly assigned (2:1) to receive sacubitril/valsartan (target dose 97/103 mg) or control for 16 weeks. The primary endpoint was a change in peak VO2. Secondary endpoints included echocardiographic measures of cardiac structure and function, natriuretic peptides and other cardiac biomarkers, and Minnesota Living with Heart Failure quality of life. Between May 2018 and October 2021, 354 patients were screened for eligibility, 115 patients (mean age 58 years, 37% female) met the study inclusion criteria and were randomly assigned to sacubitril/valsartan (n = 79) or control (n = 36). At 16 weeks, there was no significant change in peak VO2 from baseline in the sacubitril/valsartan (15.3 [4.3] vs. 15.9 [4.3] ml/kg/min, p = 0.13) or control group (p = 0.47). No clinically significant changes were found in blood pressure, cardiac structure and function, plasma biomarkers, or quality of life. CONCLUSION: In patients with HCM, a 16-week treatment with sacubitril/valsartan was well tolerated but had no effect on exercise capacity, cardiac structure, or function.

Fabricating Ultrathin Imprinting Layer for Fast Capture of Valsartan via a Metal Affinity-Oriented Surface Imprinting Method.

Rapid separation and enrichment of targets in biological matrixes are of significant interest in multiple life sciences disciplines. Molecularly imprinted polymers (MIPs) have vital applications in extraction and sample cleanup owing to their excellent specificity and selectivity. However, the low mass transfer rate, caused by the heterogeneity of imprinted cavities in polymer networks and strong driving forces, significantly limits its application in high-throughput analysis. Herein, one novel metal affinity-oriented surface imprinting method was proposed to fabricate an MIP with an ultrathin imprinting layer. MIPs were prepared by immobilized template molecules on magnetic nanoparticles (NPs) with metal ions as bridges via coordination, and then polymerization was done. Under the optimized conditions, the thickness of the imprinting layer was merely 1 nm, and the adsorption toward VAL well matched the Langmuir model. Moreover, it took just 5 min to achieve adsorption equilibrium significantly faster than other reported MIPs toward VAL. Adsorption capacity still can reach 25.3 mg/g ascribed to the high imprinting efficiency of the method (the imprinting factor was as high as 5). All evidence proved that recognition sites were all external cavities and were evenly distributed on the surface of the NPs. The obtained MIP NPs exhibited excellent selectivity and specificity toward VAL, with good dispersibility and stability. Coupled with high-performance liquid chromatography, it was successfully used as a dispersed solid phase extraction material to determine VAL in serum. Average recoveries are over 90.0% with relative standard deviations less than 2.14% at three spiked levels (n = 3). All evidence testified that the MIPs fabricated with the proposed method showed a fast trans mass rate and a large rebinding capacity. The method can potentially use high-throughput separation and enrichment of target molecules in batch samples to meet practical applications.

Cardiovascular Outcomes in Hypertension-Treated Patients With Peripheral Artery Disease: The VALUE Trial.

BACKGROUND: Systolic blood pressure (BP) is a key predictor of cardiovascular events, but patients with peripheral artery disease (PAD) are rarely included in hypertension trials. The VALUE trial (Valsartan Antihypertensive Long-Term Use Evaluation) investigated the long-term effects of valsartan- or amlodipine-based treatments on cardiovascular outcomes in patients with hypertension with a high cardiovascular risk. The aim of this subanalysis was to clarify the relationship between achieved BP on treatment and cardiovascular outcomes in patients with hypertension with PAD. METHODS: Patients were followed for 4 to 6 years, and BP was measured regularly. The primary end point was time to the first major adverse cardiovascular event, including myocardial infarction, stroke, cardiovascular death, and heart failure requiring hospitalization. Statistical analyses were performed using Cox regression, adjusting for various baseline covariates. RESULTS: Of the 13 803 participants, 1898 (13.8%) had PAD. During a median follow-up of 4.5 years, patients with PAD had a 23% increased risk of major adverse cardiovascular events compared with patients without PAD. Patients with an achieved systolic BP <130 mm Hg and 130 to 139 mm Hg, compared with those with systolic BP ≥140 mm Hg, were associated with a decreased risk of a major adverse cardiovascular event (hazard ratio, 0.65 [95% CI, 0.43-0.97]; P=0.037; 0.85 [95% CI, 0.74-0.97]; P=0.016, respectively). Additionally, systolic BP <130 mm Hg was associated with a decreased risk of cardiovascular death (hazard ratio, 0.33 [95% CI, 0.12-0.92]; P=0.034). The incidence of the primary outcome did not differ between antihypertensive treatment regimens (P=0.365). CONCLUSIONS: Our results indicate that more intensive BP control is associated with a reduction in cardiovascular morbidity and mortality in patients with hypertensive PAD.

The national financial burden of guideline directed medical therapy for heart failure patients from 2013 to 2021.

BACKGROUND: Guideline Directed Medical Therapy (GDMT) has been revolutionary in improving outcomes of heart failure patients. However, with the addition of more medication classes, the annual cost of these medications on the US healthcare system needs further evaluation. OBJECTIVES: We aim to evaluate the trend of annual cost of GDMT from 2013 to 2021 using the Medicare-part D Database. METHODS: Using Medicare Part D database (2013-2021), we determined the number of beneficiaries receiving these drugs, the total number of 30-day fills for each medication, and the total annual spending on these medications. Linear regression was used to analyze data using Python Programming Language. P value of less than 0.05 was considered to be statistically significant. RESULTS: The estimated annual Medicare- part D spending on empagliflozin had a 50 % increase in cost between 2020 and 2021, which could be attributed to its FDA approval for heart failure with reduced ejection fraction. Empagliflozin cost Medicare 3.73 billion USD in 2021 alone. In addition, sacubitril-valsartan had a strong trajectory since its introduction to the market in 2015. Since its approval in July 2015, it cost Medicare 4.51 billion USD. The Mineralocorticoid Receptor Antagonist class was the least costly class of GDMT. CONCLUSION: The rise in the cost of GDMT is not proportionate amongst the different classes of GDMT. Newer classes of medications cast a significant cost on Medicare in recent years.

Counteracting Angiotensinogen Small-Interfering RNA-Mediated Antihypertensive Effects With REVERSIR.

BACKGROUND: Small-interfering RNA (siRNA) targeting hepatic AGT (angiotensinogen) mRNA depletes AGT, lowering blood pressure for up to 6 months. However, certain situations may require a rapid angiotensin increase. The REVERSIR (RVR) - reverse siRNA silencing technology a potential approach to counteract siRNA effects. METHODS: Spontaneously hypertensive rats received 10 mg/kg AGT siRNA, and 3 weeks later were given AGT-RVR (1, 10, or 20 mg/kg). One week after AGT-RVR dosing, a redose of AGT siRNA assessed its post-AGT-RVR effectiveness for 2 weeks. Additionally, the impact of AGT-RVR after an equihypotensive dose of valsartan (4 mg/kg per day) was examined. RESULTS: Baseline mean arterial pressure (MAP) was 144±1 mm Hg. AGT siRNA reduced MAP by ≈16 mm Hg and AGT by >95%, while renin increased 25-fold. All AGT-RVR doses restored MAP to baseline within 4 to 7 days. Notably, 10 and 20 mg/kg restored AGT and renin to baseline, while 1 mg/kg allowed ≈50% AGT restoration, with renin remaining above baseline. A second AGT siRNA treatment, following 1 mg/kg AGT-RVR, reduced MAP to the same degree as the initial dose, while following 10 mg/kg AGT-RVR, it resulted in ≈50% of the first dose's MAP effect at 2 weeks. The valsartan-induced MAP reduction was unaffected by AGT-RVR. CONCLUSIONS: In spontaneously hypertensive rats, angiotensinogen-RVR dose-dependently reversed AGT siRNA-induced AGT reduction, normalizing MAP. MAP normalization persisted even with 50% recovered AGT levels, likely due to upregulated renin maintaining adequate angiotensin generation. Post-AGT-RVR dosing, a second AGT siRNA dose lowered MAP again.

Extemporaneous combination therapy with nebivolol/valsartan for the treatment of hypertension: a study of real-world evidence in Europe.

OBJECTIVE: To explore real-life use of the extemporaneous combination of nebivolol and valsartan (NV-EXC) in adult hypertensive patients in Europe. METHODS: Retrospective analysis of patients starting NV-EXC treatment conducted using prescription databases in Italy, Germany, Hungary, and Poland. The selection period during which study patients were identified covered a time span ranging from 3 to 9 years (until 30 June 2020) according to availability of the different data sources. Patient demographics, clinical information, and treatment adherence, measured by proportion of days covered, were evaluated. Additionally, the potential eligibility of Italian patients for the single pill combination (SPC) of nebivolol and valsartan over a one-year period was estimated. RESULTS: The study included 170,682 patients initiating NV-EXC across the databases. Most patients were females (from 51 to 60%) and primarily aged over 60 years. Few patients received prescriptions of both available dosages of valsartan (80 and 160 mg) during follow-up (from 3.2 to 8.5%). Common comorbidities included dyslipidemia (19.2%) and diabetes (19.1%). Around 59.5% of patients did not require cardiologic visits during the study period. Adherence to NV-EXC, as indicated by the Italian database, was low in 53.3% of patients, with only 16.1% showing high adherence. The Italian database revealed 680 prevalent NV-EXC users in 2019, estimating a potential 30,222 adult patients eligible for the nebivolol/valsartan SPC. CONCLUSIONS: The combination of nebivolol and valsartan is frequently prescribed for hypertension, but adherence remains a challenge. A potential nebivolol/valsartan SPC holds promise in enhancing adherence and optimizing therapeutic outcomes for hypertension management.