Regorafenib versus Cabozantinib as a Second-Line Treatment for Advanced Hepatocellular Carcinoma: An Anchored Matching-Adjusted Indirect Comparison of Efficacy and Safety.

Introduction: The tyrosine kinase inhibitors regorafenib and cabozantinib remain the mainstay in second-line treatment of advanced hepatocellular carcinoma (HCC). There is currently no clear evidence of superiority in efficacy or safety to guide choice between the two treatments. Methods: We conducted an anchored matching-adjusted indirect comparison using individual patient data from the RESORCE trial of regorafenib and published aggregate data from the CELESTIAL trial of cabozantinib. Second-line HCC patients with prior sorafenib exposure of ≥3 months were included in the analyses. Hazard ratios (HRs) and restricted mean survival time (RMST) were estimated to quantify differences in overall survival (OS) and progression-free survival (PFS). Safety outcomes compared were rates of grade 3 or 4 adverse events (AEs), occurring in >10% of patients, and discontinuation or dose reduction due to treatment-related AEs. Results: After matching adjustment for differences in baseline patient characteristics, regorafenib showed a favorable OS (HR, 0.80; 95% CI: 0.54, 1.20) and ∼3-month-longer RMST over cabozantinib (RMST difference, 2.76 months; 95% CI: -1.03, 6.54), although not statistically significant. For PFS, there was no numerical difference in HR (HR, 1.00; 95% CI: 0.68, 1.49) and no clinically meaningful difference based on RMST analyses (RMST difference, -0.59 months; 95% CI: -1.83, 0.65). Regorafenib showed a significantly lower incidence of discontinuation (risk difference, -9.2%; 95% CI: -17.7%, -0.6%) and dose reductions (-15.2%; 95% CI: -29.0%, -1.5%) due to treatment-related AEs (any grade). Regorafenib was also associated with a lower incidence (not statistically significant) of grade 3 or 4 diarrhea (risk difference, -7.1%; 95% CI: -14.7%, 0.4%) and fatigue (-6.3%; 95% CI: -14.6%, 2.0%). Conclusion: This indirect treatment comparison suggests, relative to cabozantinib, that regorafenib could be associated with favorable OS (not statistically significant), lower rates of dose reductions and discontinuation due to treatment-related AEs, and lower rates of severe diarrhea and fatigue.

Front-line daratumumab-VTd versus standard-of-care in ASCT-eligible multiple myeloma: matching-adjusted indirect comparison.

Aim: To compare daratumumab plus standard-of-care (SoC; bortezomib/thalidomide/dexamethasone [VTd]) and VTd alone with other SoC for transplant-eligible newly diagnosed multiple myeloma. Patients & methods: We conducted an unanchored matching-adjusted indirect comparison of progression-free and overall survival (PFS/OS) with D-VTd/VTd versus bortezomib/lenalidomide/dexamethasone (VRd), bortezomib/cyclophosphamide/dexamethasone (VCd) and bortezomib/dexamethasone (Vd). Results: After matching adjustment, significant improvements in PFS were estimated for D-VTd versus VRd (hazard ratio [HR]: 0.47 [95% CI: 0.33-0.69]), VCd (HR: 0.35 [95% CI: 0.21-0.58]) and Vd (HR: 0.42 [95% CI: 0.28-0.63]). OS was significantly longer with D-VTd versus VRd (HR: 0.31 [95% CI: 0.16-0.57]), VCd (HR: 0.35 [95% CI: 0.14-0.86]) and Vd (HR: 0.38 [95% CI: 0.18-0.77]). No significant PFS/OS differences were seen for VTd versus other SoC. Conclusion: This analysis supports front-line daratumumab for transplant-eligible newly diagnosed multiple myeloma.

Comparative efficacy of brigatinib versus ceritinib and alectinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small cell lung cancer.

OBJECTIVE: Brigatinib, ceritinib, and alectinib are approved to treat crizotinib-refractory anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC), but no trial has compared them head-to-head. A matching-adjusted indirect comparison (MAIC) was conducted to estimate the relative efficacy of these agents in the crizotinib-refractory setting. METHODS: MAIC is a propensity score-type method that adjusts for differences in baseline characteristics between trials to estimate relative efficacy. Analyses were based on patient-level data from the ALTA trial for brigatinib and published summary-level trial data from ASCEND-1 and ASCEND-2 for ceritinib and NP28761 and NP28673 for alectinib. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared. RESULTS: After matching, all key baseline characteristics were balanced between trials. Compared with ceritinib, brigatinib was associated with longer PFS (ASCEND-1: median 15.7 vs 6.9 months, hazard ratio (HR) [95% confidence interval] = 0.38 [0.26-0.57]; ASCEND-2: median = 18.3 vs 7.2 months, HR = 0.33 [0.20-0.56]) and OS (ASCEND-1: not available; ASCEND-2: median 27.6 vs 14.9 months, HR = 0.33 [0.17-0.63]). Versus alectinib, brigatinib was associated with longer PFS (NP28761: median = 17.6 vs 8.2 months, HR = 0.56 [0.36-0.86]; NP28673: median = 17.6 vs 8.9 months, HR = 0.61 [0.40-0.93]); results for OS were inconclusive (NP28761: median = 27.6 vs 22.7 months, HR = 0.70 [0.42-1.16]; NP28673: median = 27.6 vs 26.0 months, HR = 0.66 [0.39-1.09]). ORR was similar. CONCLUSION: In crizotinib-refractory ALK + NSCLC patients, relative efficacy estimates suggest brigatinib may have prolonged PFS and OS vs ceritinib and prolonged PFS vs alectinib.

Financial impact of ivabradine on reducing heart failure penalties under the Hospital Readmission Reduction Program.

OBJECTIVE: The introduction of the Hospital Readmission Reduction Program (HRRP) has led to renewed interest in developing strategies to reduce 30 day readmissions among patients with heart failure (HF). In this study, a model was developed to investigate whether the addition of ivabradine to a standard-of-care (SoC) treatment regimen for patients with HF would reduce HRRP penalties incurred by a hypothetical hospital with excess 30 day readmissions. RESEARCH DESIGN: A model using a Monte Carlo simulation framework was developed. Model inputs included national hospital characteristics, hospital-specific characteristics, and the ivabradine treatment effect as quantified by a post hoc analysis of the Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIFT). RESULTS: The model computed an 83% reduction in HF readmission penalty payments in a hypothetical hospital with a readmission rate of 22.95% (excess readmission ratio = 1.056 over the national average readmission rate of 21.73%), translating into net savings of $44,016. A sensitivity analysis indicated that the readmission penalty is affected by the specific characteristics of the hospital, including the readmission rate, size of the ivabradine-eligible population, and ivabradine utilization. CONCLUSIONS: The results of this study indicate that the addition of ivabradine to an SoC treatment regimen for patients with HF may lead to a reduction in the penalties incurred by hospitals under the HRRP. This highlights the role ivabradine can play as part of a wider effort to optimize the care of patients with HF.

Budget Impact of Adding Ivabradine to Standard of Care in Patients with Chronic Systolic Heart Failure in the United States.

BACKGROUND: Heart failure (HF) costs $21 billion annually in direct health care costs, 80% of which is directly attributable to hospitalizations. The SHIFT clinical study demonstrated that ivabradine plus standard of care (SoC) reduced HF-related and all-cause hospitalizations compared with SoC alone. OBJECTIVE: To estimate the budget impact of ivabradine from a U.S. commercial payer perspective. METHODS: A budget impact model estimated the per-member-per month (PMPM) impact of introducing ivabradine to existing formularies by comparing a reference scenario (SoC) and a new drug scenario (ivabradine + SoC) in hypothetical 1 million-member commercial and Medicare Advantage plans. In both scenarios, U.S. claims data were used for the reference cumulative annual rates of hospitalizations (HF, non-HF cardiovascular [CV], and non-CV), and hospitalization rates were adjusted using SHIFT data. The model controlled for mortality risk using SHIFT and U.S. life table data, and hospitalization costs were obtained from U.S. claims data: HF-related = $37,507; non-HF CV = $28,951; and non-CV = $17,904. The annualized wholesale acquisition cost of ivabradine was $4,500, with baseline use for this new drug at 2%, increasing 2% per year. RESULTS: Based on the approved U.S. indication, approximately 2,000 commercially insured patients from a 1 million-member commercial plan were eligible to receive ivabradine. Ivabradine resulted in a PMPM cost savings of $0.01 and $0.04 in years 1 and 3 of the core model, respectively. After including the acquisition price for ivabradine, the model showed a decrease in total costs in the commercial ($991,256 and $474,499, respectively) and Medicare populations ($13,849,262 and $4,280,291, respectively) in year 1. This decrease was driven by ivabradine's reduction in hospitalization rates. For the core model, the estimated pharmacy-only PMPM in year 1 was $0.01 for the commercial population and $0.24 for the Medicare Advantage population. CONCLUSIONS: Adding ivabradine to SoC led to lower average annual treatment costs. The negative PMPM budget impact indicates that ivabradine is an affordable option for U.S. payers. DISCLOSURES: This study was funded by Amgen. Patel is employed by Amgen; Kielhorn was employed by Amgen at the time of the study but is no longer affiliated with Amgen. Borer, Böhm, Ford, and Komajda have received scientific support, consultative fees, and/or speakers honoraria from Servier and Amgen in connection with SHIFT, the trial underlying this analysis. Borer also has received consultative fees from Celladon, Pfizer, ARMGO, Cardiorentis, Novartis, and Takeda USA. Kansal, Dorman, Krotneva, and Zheng are employees of Evidera, which was hired to assist with this study. Tavazzi has received research grants and consultation fees from Servier in connection with this study and has had advisory board memberships with Boston Scientific, Servier, Cardiorentis, Medtronic, St. Jude Medical, and CVie Therapeutics. Study concept and design were contributed by Dorman and Keilhorn, along with the other authors. Tavazzi, Komajda, Ford, BÖhm, and Borer oversaw collection of the data. Tavazzi, Komajda, Ford, BÖhm, and Borer (along with Karl Swedberg) formed the Executive Committee of SHIFT, the trial underlying this analysis. The manuscript was written by Kansal, along with the other authors, and revised by Borer and Patel, with assistance from the other authors.

Cost-Effectiveness of Ivabradine for Heart Failure in the United States.

BACKGROUND: Ivabradine is a heart rate-lowering agent approved to reduce the risk of hospitalization for worsening heart failure. This study assessed the cost-effectiveness of adding ivabradine to background therapy in the United States from the perspective of a commercial or Medicare Advantage payer. METHODS AND RESULTS: A cost-effectiveness, cohort-based Markov model using a state transition approach tracked a cohort of heart failure patients with heart rate ≥70 beats per minute in sinus rhythm who were treated with ivabradine+background therapy or background therapy alone. Model inputs, including adjusted hazard ratios, rates of hospitalization and mortality, adverse events, and utility-regression equations, were derived from a large US claims database and SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial). In the commercial population, ivabradine+background therapy was associated with a cost savings of $8594 versus the cost of background therapy alone over a 10-year time horizon, primarily because of reduced hospitalization. Ivabradine was associated with an incremental benefit of 0.24 quality-adjusted life years over a 10-year time horizon. In the Medicare Advantage population, the incremental cost-effectiveness ratio for ivabradine was estimated to be $24 920/quality-adjusted life years. CONCLUSIONS: The cost-effectiveness model suggests that for a commercial population, the addition of ivabradine to background therapy was associated with cost savings and improved clinical outcomes. For a Medicare Advantage population, the analysis indicates that the clinical benefit of ivabradine can be achieved at a reasonable cost.

African Program for Onchocerciasis Control 1995-2010: Impact of Annual Ivermectin Mass Treatment on Off-Target Infectious Diseases.

Since its initiation in 1995, the African Program for Onchocerciasis Control (APOC) has had a substantial impact on the prevalence and burden of onchocerciasis through annual ivermectin mass treatment. Ivermectin is a broad-spectrum anti-parasitic agent that also has an impact on other co-endemic parasitic infections. In this study, we roughly assessed the additional impact of APOC activities on the burden of the most important off-target infections: soil-transmitted helminthiases (STH; ascariasis, trichuriasis, hookworm, and strongyloidiasis), lymphatic filariasis (LF), and scabies. Based on a literature review, we formulated assumptions about the impact of ivermectin treatment on the disease burden of these off-target infections. Using data on the number of ivermectin treatments in APOC regions and the latest estimates of the burden of disease, we then calculated the impact of APOC activities on off-target infections in terms of disability-adjusted life years (DALYs) averted. We conservatively estimated that between 1995 and 2010, annual ivermectin mass treatment has cumulatively averted about 500 thousand DALYs from co-endemic STH infections, LF, and scabies. This impact comprised approximately an additional 5.5% relative to the total burden averted from onchocerciasis (8.9 million DALYs) and indicates that the overall cost-effectiveness of APOC is even higher than previously reported.

Medication reconciliation at admission and discharge: a time and motion study.

BACKGROUND: Medication reconciliation at admission, transfer and discharge has been designated as a required hospital practice to reduce adverse drug events. However, implementation challenges have resulted in poor hospital adherence. The aim of this study was to assess the processes required to carry out medication reconciliation: the health professionals involved, the tasks and time devoted to medication reconciliation in general hospital settings. METHODS: A time-and-motion study design was used. Using a systematic sample of patients admitted and discharged from geriatric, medical and surgical units in two academic centers, health professionals involved in medication reconciliation were observed and timed. Descriptive statistics were used to summarize the number of professionals involved, tasks performed, and mean time devoted. RESULTS: Up to 3 professionals from 2 disciplines (medicine and pharmacy) were involved in the medication reconciliation process. Geriatric reconciliations took the most time to complete at admission (mean: 92.2 minutes (SD = 44.3)) and discharge (mean: 29.0 minutes (SD = 23.8)), followed by internal medicine at admission (mean: 46.2 minutes (SD = 21.1)) and 19.4 (SD = 11.7) minutes at discharge) and general surgery minutes at discharge (mean: 9.9 minutes (SD = 18.2)). Considerable differences in order, type and number of tasks performed were noted between and within units. Tasks independent of direct patient interaction took more than twice the time required to complete than tasks requiring patient interaction. CONCLUSION: Lack of coordination, specialized training and agreement on the roles and responsibilities of professionals are among the most probable reasons for work-flow inefficiencies, possibly variability in quality, and time required for the current medication reconciliation process. A better understanding of the admission processes in general surgery is required. Standardization and use of electronic tools could improve efficiency and hospital adherence.

Improved targeting of cancer care for older patients: a systematic review of the utility of comprehensive geriatric assessment.

A comprehensive geriatric assessment (CGA) provides clinicians with detailed information on a patient's physiological age and may aid in the treatment decision-making process. Conducting a CGA, however, is time-consuming, requiring extensive data collection and, in some cases, the involvement of multiple healthcare professionals. The CGA is also not specifically targeted towards assessing patients presenting with neoplastic pathologies. These limitations have precluded this tool's inclusion in routine oncologic practice involving seniors. In order to identify CGA domains most predictive of important cancer-specific outcomes, we conducted a systematic review (PROSPERO registration number CRD42012002476) using MEDLINE, CINAHL, EMBASE and CANCERLIT databases. Studies published in English or French between May 1997 and May 2012, in which a CGA was conducted in patients over the age of 65 initiating cancer treatment, were assessed for eligibility, of which 9 studies were selected for this review. As part of the inclusion criteria, all studies must have assessed, at minimum, the following domains: nutritional, cognitive and functional status, polypharmacy, comorbidities and the presence of geriatric syndromes. In predicting mortality, in at least one study or another, all of the aforementioned CGA domains were found to be significant. Most frequently, however, the following domains were reported for predicting mortality: nutritional status (HR=1.84-2.54), the presence of geriatric syndromes such as depression (HR=1.51-1.81), and functional status (HR=1.04-1.33). With regards to chemotherapy-related toxicity, similar findings were obtained where functional status (OR=1.71-2.47) and the presence of geriatric syndromes, such as impaired hearing (OR=1.67, 95% CI 1.04-2.69), had the most significant predictive value. Only one study reported on the incidence of post-operative complications for which severe comorbidity was found to be highly associated with experiencing severe complications (OR=5.62, 95% CI 2.18-14.50), while functional status was found to be significantly associated with experiencing any complication (OR=4.02, 95% CI 1.24-13.09).

Rates and predictors of consideration for adjuvant radiotherapy among high-risk breast cancer patients: a cohort study.

Radiotherapy (RT) after breast conserving surgery (BCS) represents the standard for local control of breast cancer (BC). However, variations in practice persist. We aimed to characterize the rate of RT consideration (or referral) after BCS and identify predictors in Quebec, Canada, where universal health insurance is in place. A historical prospective cohort study using the provincial hospital discharge and medical services databases was conducted. All women with incident, non-metastatic BC (stages I-III) undergoing BCS (1998-2005) were identified. Odds ratios (ORs) and 95 % confidence intervals (CIs) for RT consideration were estimated with a generalized estimating equations regression model, adjusting for clustering of patients within physicians. Of the 27,483 women selected, 90 % were considered for RT and 84 % subsequently received it. Relative to women 50-69 years old, younger and older women were less likely to be considered: ORs of 0.82 (95 % CI 0.73-0.93) and 0.10 (0.09-0.12), respectively. Emergency room visits and hospitalizations unrelated to BC were associated with decreased odds of RT consideration: 0.85 (0.76-0.94) and 0.83 (0.71-0.97). Women with regional BC considered for chemotherapy were more likely to be considered for RT: 3.41 (2.83-4.11). RT consideration odds increased by 7 % (OR of 1.07, 95 % CI 1.03-1.10) for every ten additional BCSs performed by the surgeon in the prior year. Social isolation, comorbidities, and greater distance to a referral center lowered the odds. Demographic and clinical patient-related risk factors, health service use, gaps in other aspects of BC management, and surgeon's experience predicted RT consideration.