Cost-effectiveness analyses of sacubitril-valsartan for heart failure.

The objective of this study was to evaluate the pharmacoeconomic value of sacubitril-valsartan for the treatment of heart failure (HF). PubMed, Embase, Cochrane Library, ScienceDirect, Scopus, CNKI, Wanfang, and VIP databases were searched systematically and the retrieval time ended in August 2019. According to the criteria of inclusion and exclusion, the quality of studies included was evaluated as per the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) scale, and the results were extracted and analyzed systematically. The total of 11 cost-effectiveness studies was identified, 10 were performed in the developed countries and 1 in Thailand. All the patients in the studies had chronic heart failure with reduced ejection fraction (HFrEF). Totally, the quality of all the 11 studies was reported to be of an average score of 20.5. Study perspective and time horizons were described in the 11 studies. All included studies discounted the cost or effectiveness. Only 1 study estimated direct and indirect costs; 10 studies evaluated direct cost. The incremental cost-effectiveness ratio (ICER) of sacubitril-valsartan treating HFrEF was $13,150 per quality-adjusted life-years (QALY) in Thailand and $86,735 in Singapore. In European countries, the ICER was from $21,786 to $34,576 per QALY and mean value was $25,410.6 per QALY. In the USA, ICER values ranged from $47,099 to $143,891 per QALY, and mean value was $73,383.5 per QALY; ICER was $30,090 per QALY in Colombia. With the exception of Thailand and Singapore, the ICER of other countries in the included literature was below the implemented country-specific thresholds. Based on existing literatures, with the exception of Thailand and Singapore, sacubitril-valsartan for the treatment of HFrEF is a better cost-effective therapy with ICER basically below the implemented country-specific thresholds. Sacubitril-valsartan was not considered a cost-effective treatment for heart failure with reduced ejection fraction in Thailand and Singapore with the current economic evaluation evidences, but with the willingness-to-pay (WTP) of other counties, sacubitril-valsartan was found to be a cost-effective treatment compared with comparator. Drug cost, time horizon, and hospitalization were the most influential variables across studies. Four studies indicated that with the longer time horizon, the lower ICER value would gain. Further studies are warranted to better evaluate comprehensive utility value of sacubitril-valsartan on heart failure.

Association of PON1 genotype and haplotype with susceptibility to coronary artery disease and clinical outcomes in dual antiplatelet-treated Han Chinese patients.

PURPOSE: The aim of this study was to evaluate the association of PON1 genetic variants with the susceptibility to coronary artery disease (CAD) and with the clinical endpoints in aspirin and clopidogrel (dual antiplatelet therapy)-treated Han Chinese patients with CAD after percutaneous coronary intervention (PCI). METHODS: A total of 538 Han Chinese patients undergoing PCI and receiving dual-antiplatelet therapy were sequentially recruited to the study and followed for up to 1 year. Healthy controls (n = 539) were enrolled during the same period. All study participants were genotyped for five genetic variants in PON1 and the cytochrome P450 2C19*2 mutation (CYP2C19*2). The effect of genetic variants on disease risk and clinical outcome of major adverse cardiac events (MACE) within 1 year or bleeding within 6 months was assessed. RESULTS: CYP2C19*2 was associated with a higher risk of MACE (adjusted P = 0.0098), but a lower risk of bleeding events (adjusted P = 0.0016). The PON1 Q192R polymorphism was significantly associated with a lower risk of bleeding events [odds ratio (OR) 0.61, 95% confidence interval (CI) 0.43-0.87, adjusted P = 0.0066). The haplotype bearing the PON1 -126C allele was associated with a higher risk to CAD (OR 1.48, 95% CI 1.04-2.09, P = 0.029) and a higher risk of bleeding events (OR 1.68, 95% CI 1.10-2.56, P = 0.017) compared to the most frequent haplotype. The transcription activity of haplotype p-162A-126C-108C in the PON1 promoter was 2.6-fold higher than that of the most frequent haplotype (p-162G-126G-108T). CONCLUSIONS: Based on these results, we suggest that the haplotype-bearing PON1 -126C allele contributes to the disease risk and the risk of bleeding events in dual antiplatelet-treated CAD patients after PCI.

[Progress in genetic and epigenetic research on in-stent restenosis after percutaneous coronary interventions].

Coronary heart disease is one of the most important causes of death in human, and consumes vast medical resources. Percutaneous coronary intervention (PCI) has been a significant breakthrough for its treatment. However, clinical application has been hampered by in-stent restenosis (ISR). Although drug eluting stent (DES) has reduced the occurrence of restenosis, incidence of ISR is still about 5% to 10%. The main reasons for restenosis after PCI are hyperplasia of vascular endothelial cells and smooth muscle cell migration. The exact mechanism of personalized differences in restenosis is not clear yet, but there may be a variety of risk factors. In addition to aging, smoking and diabetes, an increasing number of studies have found that genetic and epigenetic factors play an important role in ISR. In this article, authors have reviewed genetic and epigenetic factors on the progression of ISR, which may help to determine the genetic risk factors in patients with ISR after PCI.

The influence of genetic polymorphisms and interacting drugs on initial response to warfarin in Chinese patients with heart valve replacement.

PURPOSE: Compared with genetic factors, drug interactions were largely unexplored in warfarin pharmacogenetic studies. This study sought to systematically investigate the effects of genetic polymorphisms of VKORC1, STX4A, CYP2C9, CYP3A4, and GGCX and interacting drugs on the initial responses to warfarin in Chinese patients with heart valve replacement (HVR). METHODS: A retrospective study was conducted in 809 patients starting warfarin therapy after HVR. The relationships between 12 polymorphisms plus 47 drugs and primary outcomes of the time to the first international normalized ratio (INR) ≥ 1.8 and the time to the first INR > 3.5 and the secondary outcomes of the proportion of time INR < 1.8, the proportion of time INR > 3.5, and the daily warfarin dose in the first 28 days after the initiation of warfarin treatment were analyzed. RESULTS: Genetic polymorphisms and interacting drugs could significantly affect the primary and secondary outcomes. The time to the first INR ≥ 1.8 was significantly influenced by the body surface area (BSA), VKORC1 g.3588G > A allele, and CYP2C9*3 allele, with hazard ratio (HR; 95% confidence interval [CI]) of 0.34 (0.17-0.66), 2.71 (2.2-3.35) and 1.43 (1.07-1.93) respectively. The time to the first INR > 3.5 was affected not only by BSA, VKORC1 g.3588G > A allele, and CYP2C9*3 allele with HR (95%CI) of 0.26 (0.07-0.99), 2.76 (1.61-4.72), and 3.09 (2.02-4.74) respectively, but also by age and interacting drugs, including fluconazole, amiodarone, and simvastatin with HR (95%CI) of 1.02 (1.01-1.04), 2.66 (1.16-6.08), 1.78 (1.17-2.73), and 5.33 (1.67-16.96) respectively. CONCLUSIONS: Not only VKORC1 and CYP2C9 genotypes, but also interacting drugs, had a significant impact on the variability of the initial response to warfarin.

Antitumor and apoptotic activities of the chemical constituents from the ethyl acetate extract of Artemisia indica.

Cancer is one of the most eminent diseases of modern times and numerous natural products derived from medicinal plants have been identified as potential sources of antitumor drugs. A successful anticancer drug must target or inhibit tumor cells whilst causing minimal damage to healthy cells. The present study aimed to investigate the antitumor efficacy of ethyl acetate extract, and other isolated compounds from Artemisia indica, on MCF­7, BHY, Miapaca­2, Colo­205 and A­549 cell lines. The apoptotic activity of the compounds was studied using flow cytometry. The different cancer cell lines were treated with the ethyl acetate extract and varying concentrations of compounds (denoted a­g) isolated from the A. indica. The cytotoxicity was evaluated by MTT assay and the apoptotic properties of the compounds and the extract were assessed using flow cytometry. In MCF­7 cells, the effect on mitochondrial membrane potential loss (ΛΨm) induced by compounds b and d was also studied. Bioassay­guided fractionation of the ethyl acetate extract from the shoot and root parts of A. indica led to the identification of the compounds a­g as: 5­hydroxy­3,7,4'­trimethoxyflavone; ludartin; maackiain; lupeol; cis­matricaria ester; trans­matricaria ester; and 6­methoxy­7,8­methylenedioxy coumarin, respectively. All the compounds exhibited mild to potent inhibition of cell proliferation in all the cell lines, with the half maximal inhibitory concentration values ranging from 25.18­88.12 µM. Ludartin and lupeol were observed to have the most potent inhibitory effects. Based on the initially identified antiproliferative effects, these two compounds were evaluated for their effects on cell cycle phase distribution, DNA damage and their effects on mitochondrial membrane potential loss (ΛΨm). The two compounds induced DNA damage and mitochondrial membrane potential loss in MCF­7 cells. The results of the current study suggest that lupeol and ludartin, isolated from A. indica, produce anticancer effects by inducing DNA damage and a reduction of mitochondrial membrane potential, and may be used as potent anticancer agents, subsequent to further study.

[Kinetic turbidimetric limulus assay of bacterial endotoxin in the replacement solution of on-line hemodiafiltration].

OBJECTIVE: To determine bacterial endotoxin in the replacement solution of on-line hemodiafiltration (on-line HDF) using kinetic turbidimetric limulus test. METHODS AND RESULTS: Validation test was performed with the replacement solution of on-line HDF in which quantified standard endotoxin was added. The recovery rates of endotoxin from the replacement solution and its dilutions at 1/5, 1/10, and 1/20 were 58.17%, 106.7%, 99.00% and 98.79%, respectively, suggesting that the optimal dilution was at 1/10. Standard endotoxin was added into the replacement solution of on-line HDF of 3 batches (040408, 040511,040527), and the recovery rates in their dilution at 1/10 were 76.32%, 99.00% and 96.24%, respectively. The standard endotoxin in the working curve was 1.00, 0.125, and 0.0156 Eu/ml (endotoxin unit/ml), and the dilution at 1/10 of the replacement solution is effective to eliminate the interference in limulus test. CONCLUSION: Kinetic turbidimetric limulus test provide a means to detect endotoxin in the replacement solution of on-line HDF.