Updated cost-effectiveness analysis of supplemental glutamine for parenteral nutrition of intensive-care patients.

BACKGROUND/OBJECTIVES: Intravenous (i.v.) glutamine supplementation of parenteral nutrition (PN) can improve clinical outcomes, reduce mortality and infection rates and shorten the length of hospital and/or intensive care unit (ICU) stays compared with standard PN. This study is a pharmacoeconomic analysis to determine whether i.v. glutamine supplementation of PN remains both a highly favourable and cost-effective option for Italian ICU patients. SUBJECTS/METHODS: A previously published discrete event simulation model was updated by incorporating the most up-to-date and clinically relevant efficacy data (a clinically realistic subgroup analysis from a published meta-analysis), recent cost data from the Italian health-care system and the latest epidemiology data from a large Italian ICU database (covering 230 Italian ICUs and more than 77,000 patients). Sensitivity analyses were performed to test the robustness of the results. RESULTS: Parenteral glutamine supplementation can significantly improve ICU efficiency in Italy, as the additional cost of supplemented treatment is more than completely offset by cost savings in hospital care. Supplementation was more cost-effective (cost-effectiveness ratio (CER)=[euro ]35,165 per patient discharged alive) than standard, non-supplemented PN (CER=[euro ]40,156 per patient discharged alive), and it resulted in mean cost savings of [euro ]4991 per patient discharged alive or [euro ]1047 per patient admitted to the hospital. Sensitivity analyses confirmed the robustness of these results. CONCLUSIONS: Alanyl-glutamine supplementation of PN is a clinically and economically attractive strategy for ICU patients in Italy and may be applicable to selected ICU patient populations in other countries.

Glucose metabolism is inhibited by caspases upon the induction of apoptosis.

Rapidly proliferating cells, such as cancer cells, have adopted aerobic glycolysis rather than oxidative phosphorylation to supply their energy demand; this phenomenon is known as 'the Warburg effect'. It is now widely accepted that during apoptosis the loss of energy production, orchestrated by caspases, contributes to the dismantling of the dying cell. However, how this loss of energy production occurs is still only partially known. In the present work, we established that during apoptosis the level of cellular ATP decreased in a caspase-dependent manner. We demonstrated that this decrease in ATP content was independent of any caspase modification of glucose uptake, ATP consumption or reactive oxygen species production but was dependent on a caspase-dependent inhibition of glycolysis. We found that the activity of the two glycolysis-limiting enzymes, phosphofructokinase and pyruvate kinase, were affected by caspases, whereas the activity of phosphoglycerate kinase was not, suggesting specificity of the effect. Finally, using a metabolomic analysis, we observed that caspases led to a decrease in several key metabolites, including phosphoserine, which is a major regulator of pyruvate kinase muscle isozyme activity. Thus, we have established that during apoptosis, caspases can shut down the main energy production pathway in cancer cells, leading to the impairment in the activity of the two enzymes controlling limiting steps of glycolysis.

GAPDH binds to active Akt, leading to Bcl-xL increase and escape from caspase-independent cell death.

Increased glucose catabolism and resistance to cell death are hallmarks of cancers, but the link between them remains elusive. Remarkably, under conditions where caspases are inhibited, the process of cell death is delayed but rarely blocked, leading to the occurrence of caspase-independent cell death (CICD). Escape from CICD is particularly relevant in the context of cancer as apoptosis inhibition only is often not sufficient to allow oncogenic transformation. While most glycolytic enzymes are overexpressed in tumors, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is of particular interest as it can allow cells to recover from CICD. Here, we show that GAPDH, but no other glycolytic enzymes tested, when overexpressed could bind to active Akt and limit its dephosphorylation. Active Akt prevents FoxO nuclear localization, which precludes Bcl-6 expression and leads to Bcl-xL overexpression. The GAPDH-dependent Bcl-xL overexpression is able to protect a subset of mitochondria from permeabilization that are required for cellular survival from CICD. Thus, our work suggests that GAPDH overexpression could induce Bcl-xL overexpression and protect cells from CICD-induced chemotherapy through preservation of intact mitochondria that may facilitate tumor survival and chemotherapeutic resistance.

Pharmacoeconomic evaluation of tiotropium bromide in the long-term treatment of chronic obstructive pulmonary disease (COPD) in Italy.

The randomized, double-blind trial UPLIFT(®) demonstrated in 5,993 patients with moderate to very severe COPD that 4 years of tiotropium bromide therapy were associated with improvements in lung function, exacerbations, quality of life, and mortality compared with placebo. The pharmacoeconomic evaluation was performed through a probabilistic, patient-level simulation Markov model. Routine COPD care (RC) was compared with the inclusion of tiotropium bromide on it. The analysis was conducted over a lifetime horizon, with 1 year cycles and a 3.5% annual discount rate. Patients were characterized by gender, age, height, smoking status, and forced expiratory volume in 1 s (FEV1). FEV1 time trend was modeled according to the annual decline recorded in UPLIFT®. Mortality derived from that of the general Italian population was adjusted by smoking status and FEV1. Health utilities derived from published Italian observational studies and were varied in time according to UPLIFT® data. Exacerbation rates were derived from a published Italian observational prospective study. The cost perspective was that of the Italian National Health Service. Healthcare resource consumption for RC and exacerbations derived from Italian observational studies were valued according to current price and tariffs. Simulated patients in the tiotropium arm gained an average (95% CI) 0.50 (-1.63 to 6.27) Life Years (LYs) and 0.42 (-0.25 to 3.05) Quality-Adjusted Life Years (QALYs). The incremental lifetime cost resulted €3,357 (-€10,669 to €29,820). The incremental cost-effectiveness ratio (ICER) was €6,698/LY and €7,916/QALY. In the cost-effectiveness acceptability curve (CEAC), tiotropium had a 90% probability of being cost-effective for a willingness to pay (WTP) threshold of € 10,000/QALY.

Cost-utility of add-on omalizumab in difficult-to-treat allergic asthma in Italy.

OBJECTIVE: Omalizumab (OM), an innovative biological treatment for difficult asthma with perennial sensitisations, is an humanized monoclonal anti-IgE antibody that binds free circulating IgE; inhibits mast cell and basophil activation by combining free IgE, leads to IgE receptor down-regulation, thus blocking the inflammatory cascade. AIM OF THE STUDY: To assess real-world cost-utility ofadd-on OM in Italy. METHODS: changes in clinical and economical outcomes, and in quality of life (QoL) associated with add-on OM in adults (n=23) with severe dfficult asthma were compared with those recorded before OM in the same subjects. Variables were: lung function; IgE levels; health status; ACT score; QoL (SGRQ); n. GP and specialist visits; emergency visits; hospitalizations, and concomitant pharmacological treatments. Further indices were: changes in Health-related QoL; total health-care costs, and incremental cost/utility. Data were statistically compared (Student's T test), and p < 0.01 was accepted for statistical significance. RESULTS: asthma clinical outcomes and patients' health-related quality of life improved significantly by adding OM, and both costs for drugs and hospital care dropped significantly (p < 0.01). The net economic effect was a 350 Euro increase in overall monthly costs; when related to health benefits, it corresponded to an incremental cost/utility ratio ofabout 26,000 Euro/QALY, which represents a quite favourable figure in terms of willingness to pay for health benefits in industrialised countries. CONCLUSIONS: Omalizumab added to an optimised therapy significantly improves clinical outcomes in difficult-to-treat, persistent allergic asthma. Costs also increased, but proved justified by health benefits achieved.

Cost-effectiveness analysis of LHRH agonists in the treatment of metastatic prostate cancer in Italy.

OBJECTIVES: Luteinizing hormone-releasing hormone (LHRH) agonists represent one of the main cost factors in the management of patients with metastatic prostate cancer. We compared the cost-effectiveness of the five different 3-month formulations of LHRH agonists currently available for advanced prostate cancer in Italy, because these differ both in their capacity to suppress testosterone and in their acquisition costs. METHODS: A probabilistic, patient-level simulation model was developed to compare the cost-effectiveness, from the perspective of the Italian National Health Service (INHS), of leuprorelin 11.25 mg and 22.5 mg, triptorelin 11.25 mg, buserelin 9.9 mg, and goserelin 10.8 mg. The model incorporated testosterone-dependent progression-free and cancer-specific survival functions, LHRH agonist effectiveness data, and national costs and tariffs. Cox's proportional hazard models were used to compute total and progression-free survival functions based on clinical data from 129 patients with metastatic prostate cancer treated in an Italian center. Bayesian random effects models were employed to summarize evidence from published literature on testosterone suppression obtained with the available LHRH agonists. RESULTS: Estimated total survival was ≈5 years, with a maximum difference between treatment options of ≈2 months. There was a mean difference of almost €2,500 in lifetime total costs between the least costly option (leuprorelin 22.5 mg) and the most expensive (goserelin). In the incremental cost-effectiveness analysis, leuprorelin 22.5 mg dominated all alternatives except buserelin, which had an incremental cost-effectiveness ratio versus leuprorelin 22.5 mg of ≈€12,000 per life-month gained. CONCLUSIONS: Based on modelling with meta-analysis of comparative survival data, leuprorelin 22.5 mg was the most cost-effective treatment of the available depot formulation LHRH agonists.

miR-210 is overexpressed in late stages of lung cancer and mediates mitochondrial alterations associated with modulation of HIF-1 activity.

Following the identification of a set of hypoxia-regulated microRNAs (miRNAs), recent studies have highlighted the importance of miR-210 and of its transcriptional regulation by the transcription factor hypoxia-inducible factor-1 (HIF-1). We report here that miR-210 is overexpressed at late stages of non-small cell lung cancer. Expression of miR-210 in lung adenocarcinoma A549 cells caused an alteration of cell viability associated with induction of caspase-3/7 activity. miR-210 induced a loss of mitochondrial membrane potential and the apparition of an aberrant mitochondrial phenotype. The expression profiling of cells overexpressing miR-210 revealed a specific signature characterized by enrichment for transcripts related to 'cell death' and 'mitochondrial dysfunction', including several subunits of the electron transport chain (ETC) complexes I and II. The transcript coding for one of these ETC components, SDHD, subunit D of succinate dehydrogenase complex (SDH), was validated as a bona fide miR-210 target. Moreover, SDHD knockdown mimicked miR-210-mediated mitochondrial alterations. Finally, miR-210-dependent targeting of SDHD was able to activate HIF-1, in line with previous studies linking loss-of-function SDH mutations to HIF-1 activation. miR-210 can thus regulate mitochondrial function by targeting key ETC component genes with important consequences on cell metabolism, survival and modulation of HIF-1 activity. These observations help explain contradictory data regarding miR-210 expression and its putative function in solid tumors.

Glycolysis inhibition sensitizes tumor cells to death receptors-induced apoptosis by AMP kinase activation leading to Mcl-1 block in translation.

Most cancer cells exhibit increased glycolysis for generation of their energy supply. This specificity could be used to preferentially kill these cells. In this study, we identified the signaling pathway initiated by glycolysis inhibition that results in sensitization to death receptor (DR)-induced apoptosis. We showed, in several human cancer cell lines (such as Jurkat, HeLa, U937), that glucose removal or the use of nonmetabolizable form of glucose (2-deoxyglucose) dramatically enhances apoptosis induced by Fas or by tumor necrosis factor-related apoptosis-inducing ligand. This sensitization is controlled through the adenosine monophosphate (AMP)-activated protein kinase (AMPK), which is the central energy-sensing system of the cell. We established the fact that AMPK is activated upon glycolysis block resulting in mammalian target of rapamycin (mTOR) inhibition leading to Mcl-1 decrease, but no other Bcl-2 anti-apoptotic members. Interestingly, we determined that, upon glycolysis inhibition, the AMPK-mTOR pathway controlled Mcl-1 levels neither through transcriptional nor through posttranslational mechanism but rather by controlling its translation. Therefore, our results show a novel mechanism for the sensitization to DR-induced apoptosis linking glucose metabolism to Mcl-1 downexpression. In addition, this study provides a rationale for the combined use of DR ligands with AMPK activators or mTOR inhibitors in the treatment of human cancers.

Economic evaluation of treatment with orlistat in Italian obese patients.

UNLABELLED: The XENDOS study showed that behavioural and pharmacological therapy can decrease the risk of metabolic disorders in obese patients. METHODS: A probabilistic Bayesian Markov model simulating the outcomes of orlistat treatment on the obese Italian population has been developed with the WinBUGS software. The model integrates an algorithm to estimate cardiovascular risk based on Framingham Heart Study equations. Analyses adopted the societal cost perspective, including direct medical costs borne by both the National Health Service and the patient, since orlistat is not included in the Italian reimbursement list. RESULTS: The simulation on the Italian obese population estimated an average increase in quality-adjusted life expectancy, a reduction of cardiovascular events and new diabetes cases. The average incremental cost-utility ratio is euro75.3 (7.6-180.6) x 1000/QALY. The subgroup analysis showed that the benefits are relatively greater in older patients and in patients with impaired glucose tolerance (IGT). Two hypotheses have been explored to estimate the impact of a potential reimbursement decision by the Italian NHS: (1) orlistat is given to every obese patient; (2) orlistat is given only to obese IGT patients with a previous glucose tolerance general screening program to assess their eligibility. The cost utility of the strategies are euro42.3 (-22.16-108.7) and euro10.16 (-60.4-38.76) x 1000/QALY, respectively. CONCLUSION: Orlistat shows a good pharmacoeconomic profile and, in particular, the strategy of a screening programme to identify and treat the IGT subgroup has a cost-utility value of about euro10000/QALY. This value is lower than that of several therapeutic strategies commonly accepted and reimbursed in developed countries.

Cost-effectiveness and healthcare budget impact in Italy of inhaled corticosteroids and bronchodilators for severe and very severe COPD patients.

Current practice guidelines for the treatment of COPD recommend the use of combined inhaled corticosteroids and long-acting bronchodilators in severe and very severe patients (GOLD stages III and IV). The aim of this study was to evaluate, through a simulation model, the economic consequences of this recommendation in Italy. We developed a cost-effectiveness analysis (CEA) on five alternative therapeutic strategies (salmeterol/fluticasone, SF; formoterol! budesonide, FB; salmeterol alone, S; fluticasone alone, F; control, C). Published data on the Italian COPD population and efficacy data from international reference trials were fitted in a disease progression model based on a Markov chain representing severity stages and death. The yearly total direct costs of treating COPD patients in Italy was estimated at approximately Euro 7 billion, with a mean cost per patient per year of around Euro 2450. Mean survival of the cohort is 11.5 years. The C and F strategies were dominated (ie, are associated with worse outcomes and higher costs) by all alternatives. SF and FB were the most effective strategies, with a slight clinical superiority of SF, but they were also marginally more expensive than S. Incremental cost-effectiveness of SF vs S was Euro 679.5 per avoided exacerbation and Euro 3.3 per symptom-free day. Compared with current practice, the recommended use of combined inhaled corticosteroids and long-acting bronchodilators for severe and very severe COPD patients has the potential for improving clinical outcomes without increasing healthcare costs.