The efficacy and safety of rituximab in treating childhood nephrotic syndrome: an Italian perspective.

BACKGROUND: Nephrotic syndrome is a disorder characterized by proteinuria, hypoalbuminemia and dyslipidemia. Low-dose alternate-day steroid regimen is the standard of care. In case of relapse or significant adverse events, steroid-sparing agents may be used. This analysis was aimed at assessing the efficacy and safety of rituximab for the treatment of children with nephrotic syndrome. RESULTS: Four studies were included in the final meta-analysis. The end-point of our analysis was the percentage of patients in remission at 6 months. Pooled data from the four studies favours the use of rituximab (RR 5.25, 95 % CI: 3.05-9.06; p < 0.0001). As regards the safety data, rituximab has a limited number of adverse effects, the most common of which occur during the infusions. CONCLUSIONS: In Italy, the off-label use of drugs is regulated by Law 648/96. In our opinion, there are three scientific requirements to merit a conditional national reimbursement for rituximab in nephrotic syndrome: 1. favourable clinical efficacy and safety data; 2. no available alternatives; 3. outcome data collecting by AIFA through prescribers. In conclusion, our results report a significant incremental benefit of adding rituximab to corticosteroid and/or calcineurin inhibitors for the treatment of nephrotic syndrome.

Long-term outcomes in chronic obstructive pulmonary disease patients: exploring the effects of inhalatory devices and their influence on the outcome.

PURPOSE: Numerous systematic reviews have examined the outcomes in patients with chronic obstructive pulmonary disease managed with different therapeutic strategies. However, no such studies have specifically focused on the effect of inhalation devices. METHODS: A standard PubMed search was carried out in which we identified all randomized placebo-controlled trials conducted in patients with moderate-to-severe or severe chronic obstructive pulmonary disease. The clinical end points were exacerbations rate, incidence of pneumonia, and mortality. Meta-regression was employed to assess the effect of the device. For the incidence of exacerbations, an equivalence analysis was also carried out. RESULTS: A total of 37 studies were analyzed. Four different devices were used across these trials (Respimat(®), HandiHaler(®), Diskus, and Turbuhaler(®)). Our meta-regression analysis failed to show any significant difference between devices with regard to exacerbation rate. Equivalence was shown for some comparisons (HandiHaler(®) vs Respimat(®)), but not for others. In analyzing mortality, Respimat(®) was shown to worsen this end point in comparison with Turbuhaler(®) and HandiHaler(®). Moreover, Turbuhaler(®) showed a protective effect over Diskus in the incidence of pneumonia. CONCLUSION: The results of our analysis represent the first attempt to explore the effect of the type of device on long-term outcomes. One important limitation was that most drugs were associated with one particular device, and so the effects of drugs and devices could not be reliably differentiated from one another.

Repeated-intermittent use of ulipristal acetate for the management of uterine fibroids: an Italian pharmacoeconomic evaluation.

BACKGROUND: The aim of this paper was to evaluate an Italian pharmacoeconomic profile of repeated-intermittent (from 4 to 10 cycles) use of ulipristal acetate 5 mg (UPA 5 mg) in comparison with the use of UPA 5 mg before surgery (2 cycles) for the management of symptomatic uterine fibroids. METHODS: The pharmacoeconomic analysis was performed in two steps: 1) estimating an incremental cost-effectiveness ratio (ICER); 2) assuming a nationwide prediction of future expenditure in the Italian scenario. Effectiveness data were derived from the randomized-controlled trial, whilst quality of life and costs data were retrieved from the published literature. RESULTS: In comparison with the use of UPA 5 mg before surgery, the values of ICER per patient were the following: 1) €20,600 euros (UPA 5 mg 4 cycles); 2) €26,884 (UPA 5mg 6 cycles); 3) €30,244 (UPA 5 mg 8 cycles); 4) €31,906 (UPA 5 mg 10 cycles). In comparison with the use of UPA 5 mg before surgery plus subsequent surgery, the saving per patient for the National Healthcare System (NHS) by adding repeated-intermittent use of UPA 5 mg were the following: 1) €26 million (UPA 5 mg 4 cycles); 2) €17.6 million (UPA 5mg 6 cycles); 3) €8.9 million (UPA 5 mg 8 cycles); 4) €0.2 million (UPA 5 mg 10 cycles). CONCLUSIONS: The results showed that repeated-intermittent use of UPA 5 mg for the long-term treatment of uterine fibroids has a favourable pharmacoeconomic profile up to 10 repeated cycles and may be a cost-saving treatment option for the NHS. Although the data are encouraging, more data are needed regarding the benefits and risks of long-term treatment with UPA.

Economic analysis of not running tenders for recombinant Factor VIII procurement: a simplified analysis to estimate an otherwise unknown pharmacoeconomic index.

BACKGROUND: Two approaches to the procurement of recombinant Factor VIII products are used by health systems: (A) the most common approach where acquisition tenders are not carried out; (B) the approach tested in the UK in which procurement is based on tenders. The respective cost-effectiveness is not known. OBJECTIVE: To estimate the incremental cost-effectiveness ratio (ICER) for the comparison A vs B. METHODS: The analysis evaluated: (i) Factor VIII cost with/without tenders; (ii) inhibitor development caused by switching between products; (iii) clinical and economic consequences of inhibitors. Information on these items was obtained from a literature search. Because of the scarce evidence available on some items, our analysis considered the 'most favourable' scenario-that is, some extreme though reasonable assumptions were adopted that were intentionally biased towards improving the ICER of the no-tender option. RESULTS AND DISCUSSION: We estimated an ICER for A vs B of £486 409 (€657 139; £1=€1.351) per quality-adjusted life year (QALY). Since pharmacoeconomic thresholds are ∼£30 000 per QALY, our results indicate that the cost-effectiveness of acquisition strategies that avoid tenders is prohibitive. Because of the simplified nature of our analysis, this estimate is preliminary. CONCLUSIONS: The 'true' ICER of A vs B remains unknown, but its value is likely to be even worse than the unfavourable ICER of £486 409 (€657 139) per QALY.

Second-line treatments for advanced gastric cancer: Interpreting outcomes by network meta-analysis.

AIM: To study the effectiveness of second-line treatments for advancer gastric cancer by application of Bayesian network meta-analysis. METHODS: Our search covered the literature up to February 2015. The following 6 treatments were evaluated: (1) irinotecan (camptothecins); (2) paclitaxel (taxanes class); (3) docetaxel (taxanes); (4) everolimus (mammalian target of rapamycin inhibitors); (5) ramucirumab (vascular endothelial growth factor receptor 2 inhibitors); (6) ramucirumab + paclitaxel. Our methodology was based on standard models of Bayesian network meta-analysis. The reference treatment was best supportive care (BSC). The end-point was overall survival. Median survival was the outcome measure along with 95% credible intervals. RESULTS: Our search identified a total of 7 randomized controlled trials. These trials included 2298 patients (in 15 treatment arms) in whom a total of 6 active treatments were evaluated as well as BSC. There were 21 head-to-head comparisons (6 direct, 15 indirect). The difference in survival between each of two active treatments (paclitaxel and ramucirumab + paclitaxel) vs BSC was statistically significant, while the other 4 showed no statistical difference. In the 6 head-to-head comparisons between active treatments, no significant survival difference was demonstrated. CONCLUSION: Our results indicate that both paclitaxel monotherapy and ramucirumab + paclitaxel determine a significant prolongation in survival as compared with BSC.

First-line treatments for chronic lymphocytic leukaemia: interpreting efficacy data by network meta-analysis.

When multiple treatments are available, network meta-analysis can synthesize evidence and rank relative effectiveness. We applied this approach to current treatments for previously untreated chronic lymphocytic leukaemia. Data search was conducted in PubMed and websites of regulatory agencies (year 2000 through present time). Our analysis included randomized controlled trials assessing treatments for previously untreated chronic lymphocytic leukaemia. The endpoint of the analysis was the rate of progression-free survival at 3 years. At least two reviewers abstracted study data and outcomes. Agents examined for their relative effectiveness included four monotherapies (chlorambucil, fludarabine, bendamustine, alemtuzumab) and four combination treatments (cyclophosphamide + fludarabine, cyclophosphamide + cladribine, cyclophosphamide + fludarabine + rituximab, cyclophosphamide + fludarabine + alemtuzumab). A Bayesian network meta-analysis was conducted to comparatively evaluate these treatments. Nine trials (3620 patients) were included in the analysis. Odds ratio (with 95 % credible intervals) was estimated for all direct and indirect comparisons. Combinations treatments were found to be significantly more effective than single-agent treatments. Ranking in effectiveness was as follows: (1) cyclophosphamide + fludarabine + rituximab, (2) alemtuzumab, (3) cyclophosphamide + fludarabine + alemtuzumab, (4) cyclophosphamide + fludarabine and (at same ranking) cyclophosphamide + cladribine, (6) fludarabine, (7) bendamustine and (8) chlorambucil. Bendamustine fared worse in our analysis than in its pivotal trial. Overall, the estimated rankings appeared to be robust according to probabilistic analysis. Numerous indirect comparisons were assessed in the absence of RCTs. In conclusion, we generated an updated synthesis of the effectiveness of these treatments and we ranked them according to a Bayesian probabilistic model. In our probabilistic analysis, cyclophosphamide + fludarabine + rituximab ranked first in the base case while the worst-case scenario of this analysis placed this treatment at a remarkable second place.

Subcutaneous Biological Treatments for Moderate to Severe Psoriasis: Interpreting Safety Data by Network Meta-Analysis.

BACKGROUND: When multiple treatments are available, network meta-analysis can synthesize evidence and rank their relative profile in terms of effectiveness and/or safety. We applied this approach to the safety of subcutaneous biologicals used in the treatment of moderate to severe psoriasis. METHODS: Our literature search covered the articles published from January 2000 to September 2014 and was restricted to randomized controlled trials. The agents eligible for our analysis were subcutaneous biological drugs used in patients with moderate to severe psoriasis. A network meta-analysis was conducted using the Bayesian model. The analysis was aimed to compare the safety of these treatments based on 95 % credible intervals and to consequently generate a ranking in safety across the treatments. Two safety end-points were considered: any serious adverse events (AE) and any infectious AE. Risk difference was the outcome measure. The analysis estimated 95 % credible intervals for all direct and indirect comparisons as well as the ranking histogram across the treatments which was determined according to model-based probabilistic analysis. RESULTS: Our literature search selected a total of 13 randomized controlled trials of which three evaluated adalimumab, five ustekinumab (45 and 90 mg), four etanercept (both high-dose and low-dose) and one high-dose etanercept and ustekinumab (45 and 90 mg). For both end-points of any serious AE and any infectious AE, the Bayesian analysis showed no significant difference in all indirect head-to-head comparisons between active agents. For the end-point of any serious AE, the ranking was ustekinumab 45 mg and ustekinumab 90 mg (at the same rank), followed by placebo and by adalimumab and high-dose etanercept (at the same rank). For any infectious AE, the ranking was: low-dose etanercept, placebo, ustekinumab 45 mg and ustekinumab 90 mg, adalimumab and high-dose etanercept. CONCLUSION: Our analysis synthesized the current evidence on the safety of subcutaneous biological treatments for patients with moderate to severe psoriasis and was successful in defining their respective rankings.

Testing the therapeutic equivalence of novel oral anticoagulants for thromboprophylaxis in orthopedic surgery and for prevention of stroke in atrial fibrillation.

BACKGROUND: In studying the comparative effectiveness of novel oral anticoagulants (NOACs) in orthopedic surgery and in non-valvular atrial fibrillation, previous meta-analyses have found no proof of difference in head-to-head indirect comparisons between individual agents. However, the question of their therapeutic equivalence remains unanswered. OBJECTIVES: The objective of this analysis was to test the equivalence of three NOACs (dabigatran, rivaroxaban, apixaban) in orthopedic surgery and four NOACs (dabigatran, rivaroxaban, apixaban, and edoxaban) in non-valvular atrial fibrillation. METHODS: Standard pairwise meta-analysis and network meta-analysis for indirect comparisons were combined with equivalence testing. The endpoint was venous thromboembolism in orthopedic surgery and a composite of stroke or systemic embolism in atrial fibrillation. Comparisons were expressed as risk difference (RD). Margins for equivalence testing were derived from the original trials. RESULTS: Our results indicate that rivaroxaban and apixaban (but not dabigatran) are equivalent for thromboprophylaxis in orthopedic surgery. In atrial fibrillation, all the four NOACs we tested were found to meet the criterion of therapeutic equivalence. Some concern, however, is raised by some findings focused on adverse events of these agents, in which the equivalence was not proven in all analyses. CONCLUSIONS: Regardless of clinical implications, our results can be the basis to develop local acquisition tenderings on NOACS. In Italy, a new law has been issued according to which equivalence analyses have become a mandatory prerequisite for local tenderings.

[Direct and indirect costs of luteinising hormone-releasing hormone analogues in the treatment of locally advanced or metastatic prostate cancer in Italy]. / Analoghi sintetici dell'ormone di rilascio dell'ormone luteinizzante per il trattamento del carcinoma prostatico localmente avanzato o metastatico: analisi dei costi diretti e indiretti nello scenario italiano

BACKGROUND: When analyzing the use of luteinizing hormone-releasing hormone (LHRH) analogues for different clinical indications, current available evidence does not support a presumed drug class effect among the various LHRH in the treatment of prostate cancer. METHODS: The following search key words were entered in the PubMed database and the NICE and FDA websites: "LHRH agonist AND prostatic cancer", "androgen deprivation therapy", "androgen suppression", "buserelin", "leuprorelin", "goserelin","triptorelin", "degarelix". The direct costs included the following items: follow-up visits, diagnostic exams (e.g. prostate-specific antigen PSA) and drug costs. The indirect costs included working days lost by the patient. RESULTS: With intermittent therapy as a reference, leuprorelin injectable solution of 22,25 mg was associated with the lowest cost and degarelix with the highest cost. However, given the mandatory presence of a nurse for drug injection, the buserelin depot formulation was associated with the lowest cost. If the costs for hospital visits were added to drug costs, differences between the various therapeutic strategies were less remarkable. CONCLUSIONS: Our study showed how various factors (e.g. route of administration, frequency of administration, presence of a nurse for drug reconstitution and injection) should be taken into account by decision makers in addition to the price of drugs.

Biological drugs for the treatment of rheumatoid arthritis by the subcutaneous route: interpreting efficacy data to assess statistical equivalence.

BACKGROUND: No equivalence analysis has yet been conducted on the effectiveness of biologics in rheumatoid arthritis. Equivalence testing has a specific scientific interest, but can also be useful for deciding whether acquisition tenders are feasible for the pharmacological agents being compared. METHODS: Our search covered the literature up to August 2014. Our methodology was a combination of standard pairwise meta-analysis, Bayesian network meta-analysis and equivalence testing. The agents examined for their potential equivalence were etanercept, adalimumab, golimumab, certolizumab, and tocilizumab, each in combination with methotrexate (MTX). The reference treatment was MTX monotherapy. The endpoint was ACR50 achievement at 12 months. Odds ratio was the outcome measure. The equivalence margins were established by analyzing the statistical power data of the trials. RESULTS: Our search identified seven randomized controlled trials (2846 patients). No study was retrieved for tocilizumab, and so only four biologics were evaluable. The equivalence range was set at odds ratio from 0.56 to 1.78. There were 10 head-to-head comparisons (4 direct, 6 indirect). Bayesian network meta-analysis estimated the odds ratio (with 90% credible intervals) for each of these comparisons. Between-trial heterogeneity was marked. According to our results, all credible intervals of the 10 comparisons were wide and none of them satisfied the equivalence criterion. A superiority finding was confirmed for the treatment with MTX plus adalimumab or certolizumab in comparison with MTX monotherapy, but not for the other two biologics. CONCLUSION: Our results indicate that these four biologics improved the rates of ACR50 achievement, but there was an evident between-study heterogeneity. The head-to-head indirect comparisons between individual biologics showed no significant difference, but failed to demonstrate the proof of no difference (i.e. equivalence). This body of evidence presently precludes any option of undertaking competitive tenderings for the procurement of these agents.

New oral anticoagulants in acute coronary syndrome: is there any advantage over existing treatments?

BACKGROUND: After an acute coronary syndrome, dual antiplatelet therapy with clopidogrel plus aspirin is still a standard of care, but several new approaches have been investigated. OBJECTIVES: The present study re-examined the studies published thus far on this topic to evaluate the effectiveness of dual antiplatelet therapy in comparison to some of these new approaches (mainly, ticagrelor + aspirin and dual therapy plus a new oral anticoagulant [NOAC]; i.e., "triple therapy"). MATERIALS AND METHODS: The clinical material was directly derived from that reported in recent meta-analyses. Our re-analysis relied on standard equivalence methods in which interpretation is based on Relative Risks (RRs) along with their 95% Confidence Intervals (CI). The equivalence margins employed in our statistical testing were directly derived from those reported in randomized studies. RESULTS: The equivalence margins were initially set at RR ranging from 0.775 to 1.29. According to these margins, triple therapy based on any NOAC proved to be superior to dual therapy alone, but at the same time demonstrated its equivalence with dual therapy. The results for apixaban-based triple therapy were inconclusive (not superior, not not-inferior, not equivalent and, of course, not inferior to the controls). Those for rivaroxaban-based triple therapy showed that this combination treatment was superior to dual therapy alone and failed to meet the criterion of equivalence. In the comparison between rivaroxaban-based triple therapy and ticagrelor + aspirin, the RR was 1 and its 95% CI remained within a post-hoc margin of ± 15%. CONCLUSIONS: Even if one considers the most effective NOAC in combination with clopidogrel + ticagrelor, this triple therapy is not more effective than ticagrelor + aspirin. On the other hand, the increased risk of bleeding with triple regimens is well demonstrated. We therefore conclude that these triple regimens did not play any important roles in the patients experiencing an acute coronary syndrome.

Intravenous proton pump inhibitors for stress ulcer prophylaxis in critically ill patients: determining statistical equivalence according to evidence-based methods.

BACKGROUND: Although intravenous proton pump inhibitors (PPIs) are considered at least as effective as H2-receptors antagonists for stress ulcer prophylaxis (SUP) in critically ill patients, there is no data on whether there is also the proof of no difference among these agents. METHODS: The clinical material was the same as that reported in previous meta-analyses and included all trials comparing intravenous PPIs vs. H2-receptor antagonists for SUP in critically ill patients. Our methodology was a combination of meta-analysis and equivalence testing based on confidence intervals (CIs). The end-point was the rate of overt bleeding. All PPIs evaluated in the included trials were separately studied. The equivalence margins were derived from power calculation data of the original trials. RESULTS: Our analysis involved 8 randomized trials for 851 patients. Two comparisons were made (pantoprazole vs. H2-receptor antagonists and omeprazole vs. H2-receptor antagonists). The following RDs were estimated: pantoprazole, RD = -1.2%, 95% CI: -3.5% to +1.2%; omeprazole, RD = -3.0%, 95% CI: -7.2% to +1.3%. The 95% CIs confidence intervals for RDs remained within the ± 6% margin. These results indicate that intravenous pantoprazole and intravenous omeprazole are equivalent, Conclusion: These two PPIs, when administered by intravenous route, are equivalent according to reasonable equivalence margins. This conclusion can be the basis to develop local acquisition tenders on these drugs. One advantage of this approach is that the feasibility of administrative decisions can directly be tested on clinical grounds and on the basis of standard evidence-based methods.