Long-term progression-free survival in patients with chronic lymphocytic leukemia treated with novel agents: An analysis based on indirect comparisons.

OBJECTIVE: In chronic lymphocytic leukemia, growing evidence has accumulated about long-term outcomes of first-line treatments. Our objective was to perform indirect comparisons across first-line treatments. METHODS: We applied the Shiny method, an artificial intelligence technique that analyses Kaplan-Meier curves and reconstructs patient-level data. Reconstructed patient data were then evaluated through standard survival statistics and indirect head-to-head comparisons. The endpoint was progression-free survival (PFS). RESULTS: Seven first-line treatments were studied (1983 patients). Three treatments based on either ibrutinib or venetoclax (i.e., ibrutinib monotherapy, ibrutinib+ rituximab/obinutuzumab, and venetoclax+obinutuzumab) showed a very similar survival pattern. The PFS for these three treatments was significantly better than that of the remaining four treatments (fludarabine+cyclophosphamide+rituximab, chlorambucil+obinutuzumab, bendamustine+rituximab, and chlorambucil monotherapy). Regarding chlorambucil+ obinutuzumab, a significant between-trial variability was found. CONCLUSIONS: Long-term results are particularly favorable to ibrutinib (alone or in combination) and discourage further use of chlorambucil. As in other studies based on the Shiny method, the multi-treatment Kaplan-Meier graph summarized the available evidence in comparative terms. The evidence generated this way contributes to define the place in therapy of individual agents.

Survival with novel hormonal therapies in patients with nonmetastatic castration-resistant prostate cancer: indirect comparison of three randomized phase-III trials.

INTRODUCTION: In recent years, new treatments have been approved for nonmetastatic castration-resistant prostate cancer (M0CRPC). Because direct comparisons between these treatments are not available to guide treatment decisions, indirect comparisons can be of interest. METHODS: Our analysis evaluated second-generation hormone treatments proposed for M0CRPC. We searched multiple databases for articles published between 2010 and 2022. Phase-III clinical trials that studied these agents in M0CRPC patients were eligible. Among these, we included trials reporting overall survival (OS) through Kaplan-Meier curves. We performed the reconstruction of individual patient data from Kaplan-Meier graphs, according to the Shiny method, to indirectly compare the efficacy of the different agents. Indirect comparisons included testing for equivalence according to FDA criteria. Confidence intervals (CI) were 95% in all analyses except equivalence testing, where 90%CIs were used. RESULTS: Three studies met these inclusion criteria. Apalutamide (hazard ratio [HR]: 0.75, 95% confidence interval [CI] 0.64-0.88), darolutamide (HR 0.70, 95%CI 0.58-0.84), and enzalutamide (HR 0.77, 95%CI 0.65-0.90) were all significantly more effective than the placebo. Our results showed no difference in OS between any of these three agents, and in testing for equivalence, our estimates of HR met the 0.75-1.33 level. CONCLUSIONS: While the Shiny method has confirmed its validity in reconstructing individual patient data, our indirect comparisons based on mature OS demonstrated similar efficacy and substantial equivalence among these three second-generation androgen receptor inhibitors.

Evaluation of maintenance treatment with PARP inhibitors in ovarian carcinoma patients responding to platinum therapy: Use of restricted mean survival time as an index of efficacy.

BACKGROUND: Maintenance therapy using poly (ADP-ribose) polymerase inhibitors (PARPIs) is an important therapeutic option in advanced ovarian cancer after platinum-based chemotherapy. MATERIALS AND METHODS: We evaluated randomized studies (n = 5) describing the effect of maintenance therapy with PARPIs; they were obtained mainly by searching PubMed. Patient data for the analysis were derived from progression-free survival curves. Restricted mean survival time (RMST) and 95% confidence interval were estimated for individual arms of each trial. RESULTS: The three PARPIs used (olaparib, niraparib, rucaparib) all showed a higher effectiveness than placebo. The gains in progression-free survival were 6 - 8 months. CONCLUSION: Maintenance therapy studies provide evidence that olaparib, niraparib, rucaparib are effective treatments for advanced ovarian cancer.

Medical therapy, radiofrequency ablation or cryoballoon ablation as first-line treatment for paroxysmal atrial fibrillation: interpreting efficacy through restricted mean survival time and network meta-analysis.

When multiple treatments are available, network meta-analysis can evaluate data to rank the relative effectiveness. We applied this approach to first-line treatments for paroxysmal atrial fibrillation (medical therapy, radiofrequency ablation or cryoballoon ablation). Individual trials were analysed based on the restricted mean survival time (RMST). Randomised controlled trials (RCT) assessing first-line treatments for paroxysmal atrial fibrillation were referenced from PubMed and the websites of regulatory agencies. The primary end-point was atrial fibrillation recurrence-free survival at 12 months. The treatments assessed for their relative effectiveness were medical therapy, radiofrequency ablation and cryoballoon ablation. Individual trials were examined based on RMST. A Bayesian network meta-analysis was conducted to comparatively evaluate these treatments. Five trials were included in the analysis: two compared radiofrequency with medical treatment and three cryoballoon ablation with medical treatment. The indirect comparison of radiofrequency ablation vs cryoballoon ablation was assessed in the absence of RCTs. Differences in RMST (with 95% credible intervals) were estimated for all binary comparisons (direct or indirect). Radiofrequency and cryoballoon ablation showed significantly increased effectiveness compared with medical treatment. In the indirect comparison, radiofrequency showed a non-significant advantage over cryoballoon ablation. The ranking of effectiveness was as follows: (1) radiofrequency; (2) cryoballoon ablation; (3) medical treatment. In conclusion, we found that radiofrequency was the most effective treatment for paroxysmal atrial fibrillation according to a Bayesian probabilistic model.

First-line treatments for chronic lymphocytic leukemia: Analysis of 7 trials based on the restricted mean survival time.

OBJECTIVE: The purpose of this study was to assess the effectiveness of the newest first-line treatments for chronic lymphocytic leukemia (CLL), used alone or in combination, in comparison with standard treatments. MATERIALS AND METHODS: We selected 15 cohorts of patients published in 7 clinical trials. The restricted mean survival time (RMST) was used for analyzing survival curves, performing the comparisons and ranking the treatments based on their effectiveness. The endpoint was progression-free survival (PFS). RESULTS: 15 patient cohorts receiving 11 different first-line treatments were studied. Overall, all of the newest treatments had a positive effect on PFS compared with the old standards. As compared with chlorambucil monotherapy, the improvement in PFS resulting from targeted therapies ranged from 5.4 to 7.3 months per patient. Excluding chlorambucil alone or combined with obinutuzumab, the remaining 11 targeted treatments showed nearly identical values of PFS. Numerically but not statistically, ibrutinib plus venetoclax was associated with the longest PFS. Post-hoc pairwise comparisons were calculated to better interpret these results. CONCLUSION: Our results provide an updated overview of the efficacy of the newest first-line treatments for CLL. Our findings confirm the good performance of RMST in this type of analyses.

Trastuzumab biosimilar in metastatic breast cancer: Evaluating equivalence with originator using network meta-analysis
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OBJECTIVE: The European Medicines Agency (EMA) and the Food and Drug Administration (FDA) have recently approved four different trastuzumab biosimilars, marketed by different pharmaceutical companies. Biosimilars, unlike their originators, are typically supported by less clinical data about safety and efficacy. The objective of our analysis was to demonstrate that one of the approved trastuzumab biosimilars (MYL-1401O) is as effective as its originator in terms of hazard ratio (HR) of progression-free survival (PFS). MATERIALS AND METHODS: We carried out a network meta-analysis to compare the HR values for biosimilar, originator, and standard of care (SOC). Our analysis included a preliminary pairwise meta-analysis. The pooled HR for all pairwise comparisons was the output of the analysis (fixed-effect inverse variance method), along with 95% confidence intervals (CIs). The indirect comparison between biosimilar and SOC was performed using a network meta-analysis software. RESULTS: We estimated an HR of 0.59 (95% CI: 0.52 - 0.66) for the comparison between PFS values of originator and SOC, 0.97 (95% CI: 0.74 - 1.28) for biosimilar vs. originator, and 0.61 (95% CI: 0.44 - 0.83) for biosimilar vs. SOC. Our network meta-analysis increased the overall number of evaluated patients from 458 to 1,955. CONCLUSION: According to the network meta-analysis, MYL-1401O biosimilar is as effective as its originator in terms of HR of PFS.
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Inhibitors in Hemophilia A: A Pharmacoeconomic Perspective.

A discussion of the main pharmacoeconomic issues related to inhibitors in hemophilia A cannot be separated from an analysis of the most relevant clinical questions. In the field of inhibitors, the clinical evidence includes several controversial topics, such as high-titer versus low-titer inhibitors, the influence of factor VIII products on inhibitor risk, effectiveness of different immune tolerance induction (ITI) treatments, the role of bypassing agents, and development of new non-factor-VIII compounds. In terms of pharmacoeconomic data, numerous cost estimates have been reported in these fields, but this information is strongly influenced by the wide between-country differences in unit costs. Quite reliable data are, however, available regarding expenditure for replacement therapy in patients without inhibitors, increased lifetime costs caused by high-titer inhibitors, and cost of pharmacological interventions aimed at eradicating inhibitors. As regards the cost-effectiveness ratio, the data on ITI are not conclusive; nonetheless, irrespective of the specific treatments employed for inducing tolerance, their costs seem to be offset by the subsequent savings in the cost per patient. Other issues, such as the cost of low-titer inhibitors in patients with hemophilia A and effectiveness of pharmacological interventions aimed at eradicating low-titer inhibitors are not supported by sound data and will require further research. Finally, although the efficacy and safety profiles of novel treatments (e.g., emicizumab, Roche) warrant long-term clinical studies, the economic advantages of these new compounds might be very substantial both in patients with inhibitors and in those at risk of developing inhibitors.

"Total evidence" network meta-analysis as a tool for improving the assessment of biosimilars: application to etanercept in rheumatoid arthritis
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Since biosimilars generally have undergone less clinical research than originators, their place in therapy can be strengthened by increasing the amount of clinical evidence supporting their approval. This report describes an approach in which a "total evidence" network meta-analysis is performed that compares the biosimilar not only with the originator but also with the previous standard of care. This analysis was retrospectively applied to etanercept biosimilar in rheumatoid arthritis (end-point = ACR50). Using an increased number of evaluated patients (1,003 for network meta-analysis vs. 596 for equivalence trial), our results confirmed the equivalence index previously estimated from the approval trial of biosimilar.
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Evolocumab and alirocumab: exploring original procurement models to manage the reimbursement of these innovative treatments.

BACKGROUND: PCSK9 inhibitors (evolocumab and alirocumab) pose a challenge of sustainability because the potential patients are extremely numerous and the budget impact at the drugs' full price would be prohibitive. We have studied the reimbursability of these agents by constructing a series of price-volume simulations that used a model previously employed for sofosbuvir. METHODS: Our price-volume model is based on the following parameters: I) total patients candidate to the treatment; II) patients actually treated; III) treatment full cost per patient; IV) estimated nationwide budget impact in the absence of any price-volume intervention; V) price-halving population (PHP), which is the main model parameter. Treated patients ranged from 30,000 to 100,000. The full nominal yearly cost per patient was set at 10,000 €. RESULTS: In 9 price-volume simulations (testing three values of PHP at 25,000 or 50,0000 or 100,000 patients), the total national expenditure varied from 204 to 721 million €. In the least expensive scenario (PHP = 25,000 patients), the expenditure ranged from 204 to 338 million € while the average treatment cost per year was 3,382 €. At more than 100,000 treated patients, the treatment cost reduced to 626 €. On the other hand, the scenarios based on PHP = 50,000 and PHP = 100,000 patients were very unlikely to be acceptable for national health systems. CONCLUSIONS: Our study offered a pattern of different scenarios among which some national health systems in Europe could select the "true" decision on PCSK9 inhibitors. This decision is expected to be made over the next few months.

Targeted Treatments for Pulmonary Arterial Hypertension: Interpreting Outcomes by Network Meta-analysis.

BACKGROUND: No meta-analysis for indirect comparisons has been conducted to study the effectiveness of treatments for pulmonary arterial hypertension (PAH). METHODS: Our search covered the literature up to December 2014. The following five classes of agents indicated for PAH were evaluated: 1) oral endothelin receptor antagonists (ERAs); 2) oral phosphodiesterase type 5 inhibitors (PDE-5Is); 3) prostanoids administered by oral, intravenous, subcutaneous or inhalatory route; 4) selective non-prostanoid prostacyclin receptor (IP receptor) agonists (sPRAs); 5) soluble guanylate cyclase stimulators (sGCSs). Our methodology was based on standard models of Bayesian network meta-analysis. The end-point of our analysis was clinical worsening. Odds ratio was the outcome measure along with 95% credible intervals. RESULTS: Our search identified 17 randomised controlled trials (4,465 patients). There were 15 head-to-head comparisons (five direct, 10 indirect). As expected, nearly all values of odds ratio estimated for the direct comparisons versus placebo favoured the treatment arm at levels of statistical significance. More interestingly, none of the 10 head-to-head indirect comparisons between active agents showed any statistically significant difference. CONCLUSION: Our results indicate that these five classes of agents for PAH are more effective than placebo and show no significant difference in effectiveness from one another. In this context, choosing the treatment for an individual patient is a quite difficult task.

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.

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.

The safety of bevacizumab and ranibizumab in clinical studies.

In comparing the safety of ranibizumab versus bevacizumab in age-related macular degeneration, the meta-analyses published thus far have given conflicting results, particularly about the risk of venous thrombotic events and ocular inflammation. From the comparison of the design and the findings of these meta-analysis, we tried to identify the potential explanations to account for these discrepancies. We separately evaluated the incidence of ocular inflammation with the two agents between randomized studies and non-randomized studies. While no increase in risk was found in randomized studies, non-randomized studies showed an increase in risk for bevacizumab versus ranibizumab. One interpretation of these findings is that bevacizumab itself does not represent any increase in risk of ocular inflammation and/or cardiovascular events under the rigorous conditions of a randomized study, but this agent can be at the origin of an increase in risk when administered in the "real world"; this setting could in fact leave space for less strictly controlled preparation of aliquots for intravitreal injection.

Anti-reabsorptive agents in women with osteoporosis: determining statistical equivalence according to evidence-based methods.

BACKGROUND: In the present study, we undertook an equivalence analysis on the effectiveness of the main anti-reabsorptive agents indicated for women with osteoporosis. METHODS: Our methodology was a combination of meta-analysis (both pair-wise meta-analysis and network meta-analysis) and equivalence testing. The end-point was the incidence on new vertebral fractures. The anti-reabsorptive agents examined included alendronate, zoledronate, ibandronate, risedronate, and denosumab. RESULTS: Our analysis involved nine randomized trials. Ten head-to-head indirect comparisons were examined through network meta-analysis and the respective values of RR were estimated. The 95 % confidence intervals for RR remained within the interval of a relative ±40 % variation for all comparisons that involved alendronate, risedronate, ibandronate, and denosumab. In contrast, the comparisons involving zoledronate satisfied a post hoc margin up to ±67 %. CONCLUSION: Our results confirm that most of these anti-reabsorptive drugs (namely, alendronate, risedronate, ibandronate, and denosumab) are equivalent according to reasonable equivalence margins.