Matteo Ruggeri

Costs of Bloodstream Infections Caused by Escherichia coli and Influence of Extended-Spectrum-β-Lactamase Production and Inadequate Initial Antibiotic Therapy

ABSTRACT Escherichia coli is the leading cause of bloodstream infections (BSIs) caused by Gram-negative bacteria. The increasing prevalence of antibiotic-resistant E. coli strains, particularly those producing extended-spectrum β-lactamases (ESBLs), increases the odds that empirically prescribed antimicrobial therapy for these infections will be inadequate, but the economic impact of this risk has not been fully evaluated. In the present retrospective 1-year analysis of 134 consecutive E. coli BSIs in our hospital, we explored the clinical and economic impacts of (i) inadequate initial antimicrobial treatment (IIAT) (i.e., empirical treatment with drugs to which the isolate had displayed in vitro resistance) of these infections and (ii) ESBL production by the bloodstream isolate. Cost data were obtained from the hospital accounting system. Compared with the 107 (79.8%) adequately treated patients, the 27 (20.1%) who received IIAT had a higher proportion of ESBL BSIs (74.0% versus 15.8%), longer (+6 days) and more costly (+EUR 4,322.00) post-BSI-onset hospital stays, and higher 21-day mortality rates (40.7% versus 5.6%). Compared with the 97 non-ESBL infections, the 37 (27.6%) ESBL BSIs were also associated with longer (+7 days) and more costly (+EUR 5,026.00) post-BSI-onset hospital stays and increased 21-day mortality (29.7% versus 6.1%). These findings confirm that the hospital costs and mortality associated with E. coli BSIs are significantly increased by ESBL production and by IIAT.

Cost-effectiveness of boceprevir or telaprevir for previously treated patients with genotype 1 chronic hepatitis C

BACKGROUND & AIMS Randomised controlled trials (RCTs) show that triple therapy (TT) with peginterferon alfa, ribavirin, and boceprevir (BOC) or telaprevir (TVR) is more effective than peginterferon-ribavirin dual therapy (DT) in the treatment of genotype 1 (G1) chronic hepatitis C (CHC) patients with previous relapse (RR), partial response (PAR), and null-response (NR). We assess the cost-effectiveness of TT compared to no therapy in the treatment of patients previously treated with G1 CHC. METHODS The available published literature provided the data source. The target population was made up of previously treated Caucasian patients with G1 CHC and these were evaluated over a lifetime horizon by Markov model. The study was carried out from the perspective of the Italian National Health Service. Outcomes included discounted costs (in euro at 2012 value), life years gained (LYG), quality adjusted life year (QALY), and incremental cost-effectiveness ratio (ICER).The robustness of the results was evaluated by one-way deterministic and multivariable probabilistic sensitivity analyses. RESULTS In RR patients, ICER per LYG compared to no therapy was €9555 for BOC-LEAD-IN-RR and €7910 for TVR-LEAD-IN-RR, being BOC dominated by TVR. In PAR patients, ICER for LYG was €11,947 for BOC-LEAD-IN-PAR and €14,931 for TVR-PAR, being TVR cost-effective compared to BOC (ICER for QALY €22,258). In NR patients, ICER for LYG was €26,499 for TVR-LEAD-IN-NR. The models were sensitive to likelihood of sustained virological response and to BOC/TVR prices. CONCLUSIONS 1st generation HCV PI is highly cost-effective compared to no therapy in RR and PAR G1 CHC patients. TVR dominated BOC in RR, and was cost-effective compared to BOC in PAR patients. In NR patients an assessment of the response after a lead-in period should be performed to improve safety and cost-effectiveness.

The minimum clinically important difference for EQ-5D index: a critical review

The European Quality of Life-5 Dimensions Questionnaire (EQ-5D) is the most common instrument to value health outcomes under the patient’s perspective. Several studies have investigated whether observed changes are meaningful to patients, using a variety of approaches to estimate the minimum clinically important difference (MCID). This study provides an overview of the state of art of the estimation of the MCID for the three-level EQ-5D index based on the UK scoring algorithm, critically assessing the available evidence. The interest in estimation of MCID for the EQ-5D has been increasing in recent years. However, some additional standardization in the estimation procedures may be of value, in order to enhance the ability to make comparisons across measures and disease areas. Further methodological research might also contribute to reducing gaps between theory and practice.

Clinical and economic evaluation of tapentadol extended release and oxycodone/naloxone extended release in comparison with controlled release oxycodone in musculoskeletal pain

Abstract Objective: Chronic pain is a leading cause of disability and represents a relevant societal burden. Opioids are widely used for managing chronic non-cancer pain; however, the high incidence of side effects is often the main reason for discontinuation. Two formulations have recently been studied to improve the tolerability of opioids (tapentadol extended release [ER] and oxycodone/naloxone ER), but a direct comparison between these drugs is not available in the literature. The comparative cost effectiveness of these two drugs has not previously been assessed. The objective of this meta-analysis is a clinical and economic evaluation of tapentadol ER and oxycodone/naloxone ER for the treatment of musculoskeletal pain, by indirect comparison with controlled release (CR) oxycodone. Methods: A structured literature review was conducted to identify published data for the health-economic model. The authors performed a meta-analysis on three selected randomized controlled trials (RCTs) for each treatment (tapentadol ER and oxycodone/naloxone ER). As measure of treatment effect, risk ratio was calculated, compared to the control active treatment (CR oxycodone), for the following outcomes: discontinuation rate due to adverse events, due to gastrointestinal (GE) side effects and central nervous system (CNS) side effects. A Markov model was developed to compare the cost effectiveness of tapentadol ER and oxycodone/naloxone ER. Four health states were defined: (1) patients still on treatment; (2) occurrence of adverse events (gastroenterology, central nervous system); (3) treatment discontinuation as consequence of ineffectiveness of treatment; and (4) treatment discontinuation as consequence of adverse events. Results: Both drugs showed a significant clinical advantage over the active control, CR oxycodone; however, tapentadol ER resulted in a better risk ratio reduction for the primary outcome of discontinuation rate due to adverse events and for the secondary outcome nausea and vomiting. The two drugs gave equivalent results in the capacity of reduction of constipation risk. In the economic evaluation both interventions were cost effective compared with CR oxycodone. However, tapentadol ER showed the most favorable results as in 65% of cases it was less costly and produced a considerable quality adjusted life years (QALY) gain. The higher impact of tapentadol ER on the cost effectiveness results was probably due to the price and the lower incidence of adverse events and related discontinuation rate, resulting in a further economic advantage. Conclusion: Both tapentadol ER and oxycodone/naloxone ER are cost effective interventions compared with CR oxycodone; however, tapentadol ER was shown to provide better clinical outcomes at lower costs.

Hepatocellular carcinoma: cost-effectiveness of screening. A systematic review

Hepatocellular carcinoma (HCC) is one of the most common tumors worldwide. HCC is a potential target for cancer surveillance (or screening) as it occurs in well-defined, at-risk populations. Curative therapy is possible only for small tumors and screening strategy has been recommended by the US, Italian, and other international liver societies and is practiced widely, but its benefits are not clearly established. The objective of this study was to review the available evidence with respect to the cost-effectiveness of key technologies in the prevention HCC. The literature search was conducted with the support of PubMed. Firstly we selected articles by reading the abstracts. Secondly, we read the articles and the revision was further restricted, with the following as inclusion criteria: (1) full economic evaluation of HCC screening programs; (2) comparison between HCC techniques; (3) outcome measures expressed in terms of quality adjusted life years (QALY); (4) full text availability. The initial review of the literature yielded 346 articles. Of those, 288 were excluded at the first stage. Of those excluded, 108 did not meet the target, 106 did not present the cost analysis, 33 did not analyze the treatment of the disease, and in 41 the abstract was not available. Of the 58 included in the first step, seven examined the cost-effectiveness of different HCC screening techniques, seven investigated the cost-effectiveness of HCC screening versus no screening, and one looked at the cost-effectiveness of timing for HCC surveillance and monitoring, while 43 were about HBV vaccination and screening. We included only the seven articles examining the cost-effectiveness of different HCC screening techniques. In general, incidence is the key parameter which determines the cost-effectiveness of HCC screening. Discrepancies in the results exist when determining the type of technology to be used. Ultrasound (US) alone or in association with alpha fetoprotein (AFP) technology is likely to be the most cost effective and the use of computed tomography (CT) gives controversial results.

Sevelamer Is Cost-Saving vs. Calcium Carbonate in Non-Dialysis-Dependent CKD Patients in Italy: A Patient-Level Cost-Effectiveness Analysis of the INDEPENDENT Study.

Objectives: To conduct a cost-effectiveness analysis of sevelamer versus calcium carbonate in patients with non-dialysis-dependent CKD (NDD-CKD) from the Italian NHS perspective using patient-level data from the INDEPENDENT-CKD study. Methods: Patient-level data on all-cause mortality, dialysis inception and phosphate binder dose were obtained for all 107 sevelamer and 105 calcium carbonate patients from the INDEPENDENT-CKD study. Hospitalization and frequency of dialysis data were collected post hoc for all patients via a retrospective chart review. Phosphate binder, hospitalization, and dialysis costs were expressed in 2012 euros using hospital pharmacy, Italian diagnosis-related group and ambulatory tariffs, respectively. Total life years (LYs) and costs per treatment group were calculated for the 3-year period of the study. Bootstrapping was used to estimate confidence intervals around outcomes, costs, and cost-effectiveness and to calculate the cost-effectiveness acceptability curve. A subgroup analysis of patients who did not initiate dialysis during the INDEPENDENT-CKD study was also conducted. Results: Sevelamer was associated with 0.06 additional LYs (95% CI -0.04 to 0.16) and cost savings of EUR -5,615 (95% CI -10,066 to -1,164) per patient compared with calcium carbonate. On the basis of the bootstrap analysis, sevelamer was dominant compared to calcium carbonate in 87.1% of 10,000 bootstrap replicates. Similar results were observed in the subgroup analysis. Results were driven by a significant reduction in all-cause mortality and significantly fewer hospitalizations in the sevelamer group, which offset the higher acquisition cost for sevelamer. Conclusions: Sevelamer provides more LYs and is less costly than calcium carbonate in patients with NDD-CKD in Italy.

The cost-effectiveness of alternative strategies against HBV in Italy.

INTRODUCTION Nowadays, guidelines for the management of HBV infection in Italy, recommend using vaccines but the screening test among non-vaccinated people is useful to detect people that have a clear presence of the virus without symptoms of the disease. Thanks to the screening test, people infected with HBV are administered traditional therapy in order to stop the progression to cirrhosis, liver failure and hepatocellular carcinoma (HCC). These diseases cause the decrease of Qol and cause a high consumption of resources for the health system. The aim of this study is to evaluate the cost-effectiveness of a strategy (test strategy) involving the administration of the screening test to patients at risk and the treatment of the infected according to the protocol therapy. This programme is compared with a strategy (no test strategy) which does not include a screening and treats patients affected by cirrhosis or HCC. METHODS We created a Markov model following the natural history of the disease and considering the antigen HBeAg to evaluate the cost effectiveness of the test strategy. The analysis was carried out considering a third-party payer perspective. The time horizon considered was 40 cycles of one year. Patients who resulted positive to the test were administered either interferon treatment; or lamivudine or adefovir or entecavir or tenofovir, consistently with the Italian guidelines. Treatments were administered to patients included in the no-test arm after cirrhosis symptoms or HCC. RESULTS The results of the base case analysis show that patients following the test strategy compared with patients of the no-test approach cost €17,179/QALY. The Monte Carlo simulation based on a probabilistic sensitivity analysis points out that in 95% of the scenarios assumed, the cost per QALY would be under a hypothetical threshold of €40,000 which is the amount that international guidelines for decision makers are likely to consider sustainable for a health system. In conclusion, anti-hbv test to all high-risk categories should be highly recommended.

Long-term albumin administration in decompensated cirrhosis (ANSWER): an open-label randomised trial

BACKGROUND Evidence is scarce on the efficacy of long-term human albumin (HA) administration in patients with decompensated cirrhosis. The human Albumin for the treatmeNt of aScites in patients With hEpatic ciRrhosis (ANSWER) study was designed to clarify this issue. METHODS We did an investigator-initiated multicentre randomised, parallel, open-label, pragmatic trial in 33 academic and non-academic Italian hospitals. We randomly assigned patients with cirrhosis and uncomplicated ascites who were treated with anti-aldosteronic drugs (≥200 mg/day) and furosemide (≥25 mg/day) to receive either standard medical treatment (SMT) or SMT plus HA (40 g twice weekly for 2 weeks, and then 40 g weekly) for up to 18 months. The primary endpoint was 18-month mortality, evaluated as difference of events and analysis of survival time in patients included in the modified intention-to-treat and per-protocol populations. This study is registered with EudraCT, number 2008-000625-19, and ClinicalTrials.gov, number NCT01288794. FINDINGS From April 2, 2011, to May 27, 2015, 440 patients were randomly assigned and 431 were included in the modified intention-to-treat analysis. 38 of 218 patients died in the SMT plus HA group and 46 of 213 in the SMT group. Overall 18-month survival was significantly higher in the SMT plus HA than in the SMT group (Kaplan-Meier estimates 77% vs 66%; p=0·028), resulting in a 38% reduction in the mortality hazard ratio (0·62 [95% CI 0·40-0·95]). 46 (22%) patients in the SMT group and 49 (22%) in the SMT plus HA group had grade 3-4 non-liver related adverse events. INTERPRETATION In this trial, long-term HA administration prolongs overall survival and might act as a disease modifying treatment in patients with decompensated cirrhosis. FUNDING Italian Medicine Agency.

Extending influenza vaccination to individuals aged 50-64: a budget impact analysis

OBJECTIVES Influenza (vernacular name, flu) is a viral infection that causes a high consumption of resources. Several studies have been carried out to provide an economic evaluation of the vaccination programs against influenza. Nevertheless, there is still a lack of evidence about the dynamic effects resulting from the reduction of the transmission power. This study considers the impact on contagiousness of alternative strategies against influenza in people aged 50-64 in Italy, France, Germany, and Spain. METHODS By using the Influsim 2.0 dynamic model, we have determined the social benefits of different coverage levels in every country compared with the ones currently recommended. We have subsequently performed a Budget Impact Analysis to determine whether the currently recommended coverage results from an optimal budget allocation. A probabilistic sensitivity analysis was also conducted. RESULTS We found that in Germany, the optimal coverage level is 38.5 percent, in France 32.4 percent, in Italy 32.75 percent, and 28.3 percent in Spain. By extending the coverage level, social saving tends to increase up to 100 percent for France and Italy and up to 80 percent for Germany and Spain. CONCLUSIONS Decision makers should allocate the budget for vaccination against influenza consistently with the estimation of the optimal coverage level and with the dynamic effects resulting from the reduction of the transmission power.

COST-EFFECTIVENESS ANALYSIS OF HERPES ZOSTER VACCINATION IN ITALIAN ELDERLY PERSONS.

OBJECTIVES Herpes zoster (HZ) is characterized by a painful skin rash. Its main complication is postherpetic neuralgia (PHN), pain persisting or occurring after the rash onset. HZ treatment aims to reduce acute pain, impede the onset complications, and disease progression. The aim of this study was to assess the cost-effectiveness of HZ vaccination compared with no vaccination strategy, within the Italian context. METHODS The natural history of HZ and PHN was mapped through a Markov model with lifetime horizon. A population of patients aged between 60 and 79 years was hypothesized. Third party payer (Italian National Health Service, I-NHS) and societal perspectives were adopted. Data were derived from literature. RESULTS AND CONCLUSIONS The incremental cost-effectiveness ratio of the vaccination equaled EUR 11,943 per quality-adjusted life-year (QALY) under the I-NHS perspective and EUR 11,248 per QALY under the societal perspective. Considering a cost-effectiveness threshold of EUR 30,000/QALY, the multi-way sensitivity analysis showed that vaccination is cost-effective regardless of the perspective adopted, in 99 percent of simulations.