Is adjunctive pharmacotherapy in attention-deficit/hyperactivity disorder cost-effective in Canada: a cost-effectiveness assessment of guanfacine extended-release as an adjunctive therapy to a long-acting stimulant for the treatment of ADHD.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder in children, with worldwide prevalence of ADHD varying from 5.9 to 7.1 %, depending on the reporter. In case of inadequate response to stimulants, combination therapy of stimulants and an adjunctive medication may improve the control of ADHD symptoms, reduce the dose-limiting adverse events, and help control comorbidities. To date, the only medication to be used for adjunctive therapy to psychostimulants is guanfacine extended release (GXR). The aim of this study was to assess the economic impact of GXR as an adjunct therapy with long-acting stimulants (GXR + stimulant) compared to long-acting stimulant monotherapy (stimulant alone) in the treatment of children and adolescents with ADHD in Canada. METHOD: A Markov model was developed using health states defined based on the clinician-reported Clinical Global Impression-Severity (CGI-S) score (normal, mild, moderate, severe). Transition probabilities were calculated based on patient-level data from a published study. Long-acting stimulants available in Canada were considered in the base-case model: amphetamine mixed salts, methylphenidate HCl formulations, and lisdexamfetamine dimesylate. Analyses were conducted from a Canadian Ministry of Health (MoH; Ontario) and a societal perspective over a 1-year time horizon with weekly cycles. RESULTS: Over a 1-year time horizon, GXR + stimulant was associated with 0.655 quality-adjusted life year (QALY), compared to 0.627 QALY with stimulant alone, for a gain of 0.028 QALY. From a MoH perspective, GXR+ stimulant and stimulant alone were associated with total costs of $CA1,617 and $CA949, respectively (difference of $CA668), which resulted in an incremental cost-effectiveness ratio (ICER) of $CA23,720/QALY. From a societal perspective, GXR + stimulant and stimulant alone were associated with total costs of $CA3,915 and $CA3,582, respectively (difference of $CA334), which resulted in an ICER of $CA11,845/QALY. Probabilistic sensitivity analysis (PSA) of GXR + stimulant showed that it remains a cost-effective strategy in 100 % of the simulations from both perspectives in numerous PSA and one-way sensitivity analyses, relative to a willingness to pay threshold of $50,000/QALY. CONCLUSIONS: This economic evaluation demonstrates that GXR + stimulant is cost-effective compared to stimulant alone in the treatment of children and adolescents with ADHD in Canada.

Economic evaluation of arsenic trioxide for treatment of newly diagnosed acute promyelocytic leukaemia in Canada.

To assess, from a Canadian perspective, the economic impact of arsenic trioxide (ATO) + all-trans retinoic acid (ATRA) for treating newly diagnosed acute promyelocytic leukaemia (APL), the cost-effectiveness of ATO + ATRA compared to ATRA + idarubicin (IDA) was assessed over a lifetime horizon using a time-dependent Markov model. The model considers four health states: complete remission, treatment failure or relapse, post-failure, and death. Markov cycle length was 1 month for the first 48 months and 1 year thereafter. Efficacy outcomes in terms of event-free survival and overall survival were taken from a head-to-head clinical trial. Costs were associated with drug and administration, adverse events (AEs), treatment of relapses, follow-up visits, and productivity losses. Utilities and disutilities associated with health states and AEs were derived from the literature. Compared to ATRA + IDA, ATRA + ATO is associated with incremental cost-effectiveness ratios (ICERs) of $CAD50,193/quality-adjusted life years (QALY) and $CAD50,338/QALY from a Canadian Ministry of Health (MoH) and societal perspectives, respectively. Results of the one-way sensitivity analysis show that ICER varied from $CAD23,045 to $CAD60,759/QALY (MoH perspective) and from $CAD23,120 to $CAD60,905/QALY (societal perspective). ATO in the first-line therapy for patients with APL can be considered a more cost-effective strategy than standard treatment from a Canadian perspective.

Economic evaluation of arsenic trioxide compared to all-trans retinoic acid + conventional chemotherapy for treatment of relapsed acute promyelocytic leukemia in Canada.

OBJECTIVES: Acute promyelocytic leukemia (APL) is an uncommon type of acute leukemia characterized by high early mortality. Current first-line treatments include all-trans retinoic acid (ATRA), anthracyclines, and other conventional chemotherapies (CTs). Although APL is generally associated with a good prognosis, about 20% of patients who achieve remission subsequently relapse and are resistant to the previously administrated treatment. The objective of this study was to assess, from a Canadian perspective, the economic impact of arsenic trioxide (ATO) compared to ATRA+CT for treatment of patients with relapsed/refractory APL. METHODS: The cost-effectiveness of ATO compared to ATRA+CT for treating patients with relapsed/refractory APL was assessed over a lifetime horizon using a Markov model. The model considers five health states: induction, second remission, treatment failure or relapse, postfailure, and death. Markov cycle length was 1 month for the first 24 months and 1 yr thereafter. The model also takes into account the incidence of grade 3-4 adverse events reported in clinical trials. Analyses were conducted from a Canadian Ministry of Health (MoH) and a societal perspective. RESULTS: Compared to ATRA+CT, ATO was associated with incremental cost-effectiveness ratios of $ 20,551/quality-adjusted life year (QALY) from a MoH perspective and $ 22,219/QALY from a societal perspective. Results of the probabilistic sensitivity analysis indicated that ATO is a cost-effective strategy in 99.27% and 98.98% of the simulations from a MoH and a societal perspective, respectively. CONCLUSIONS: This economic evaluation demonstrates that ATO is a cost-effective strategy compared to ATRA+CT for treatment of patients with relapsed/refractory APL in Canada.

Cost-effectiveness of asenapine in the treatment of bipolar disorder in Canada.

BACKGROUND: Bipolar disorder (BPD) is prevalent and is associated with a significant economic burden. Asenapine, the first tetracyclic antipsychotic approved in Canada for the treatment of BPD, has shown a comparable efficacy profile to other atypical antipsychotics. In addition, it is associated with a favourable metabolic profile and minimal weight gain potential. This study aimed to assess the economic impact of asenapine compared to olanzapine in the treatment of BPD in Canada. METHODS: A decision tree combined with a Markov model was constructed to assess the cost-utility of asenapine compared with olanzapine. The decision tree takes into account the occurrence of extrapyramidal symptoms (EPS), the probability of switching to a different antipsychotic, and the probability of gaining weight. The Markov model takes into account long-term metabolic complications including diabetes, hypertension, coronary heart diseases (CHDs), and stroke. Analyses were conducted from both a Canadian Ministry of Health (MoH) and a societal perspective over a five-year time horizon with yearly cycles. RESULTS: In the treatment of BPD, asenapine is a dominant strategy over olanzapine from both a MoH and a societal perspective. In fact, asenapine is associated with lower costs and more quality-adjusted life years (QALYs). Results of the probabilistic sensitivity analysis indicated that asenapine remains a dominant strategy in 99.2% of the simulations, in both a MoH and a societal perspective, and this result is robust to the many deterministic sensitivity analyses performed. CONCLUSIONS: This economic evaluation demonstrates that asenapine is a cost-effective strategy compared to olanzapine in the treatment of BPD in Canada.

The Economic Impact of Treatment Sequencing in Chronic Lymphocytic Leukemia in Canada Using Venetoclax plus Obinutuzumab.

BACKGROUND: Bruton tyrosine kinase inhibitors (BTKis) represent an advancement in chronic lymphocytic leukemia; however, these agents are administered continuously until disease progression or unacceptable toxicity, raising concerns about their affordability. Venetoclax in combination with obinutuzumab (VO) is a fixed-duration (12-month) treatment, approved in Canada in 2020. This study estimated the total cumulative cost of different treatment sequences and evaluated the economic impact of introducing treatment sequences with/without VO, from a Canadian health care system perspective. METHODS: A 10-year partitioned survival model was developed, considering key clinical parameters and direct medical costs. Results were stratified by TP53 aberration. RESULTS: Treatment sequences starting with first-line (1L) VO resulted in lower 10-year cumulative costs compared to sequences starting with BTKis administered until disease progression, across both TP53 aberration subgroups. With a maximum of three lines of treatment over a 10-year period, cumulative costs were largely determined by the first two lines of treatment. When comparing sequences with the same 1L treatment, sequences with BTKis in second-line incurred greater costs compared to fixed-duration regimens. CONCLUSIONS: Overall, the economic impact of treating all patients with VO led to 10-year cumulative savings of CAD 169,341 and CAD 293,731 per patient, without and with TP53 aberration, respectively. These savings are mainly due to reductions in treatment costs associated with fixed treatment duration.

An interaction between L-prostaglandin D synthase and arrestin increases PGD2 production.

L-type prostaglandin synthase (L-PGDS) produces PGD(2), a lipid mediator involved in neuromodulation and inflammation. Here, we show that L-PGDS and arrestin-3 (Arr3) interact directly and can be co-immunoprecipitated endogenously from MG-63 osteoblasts. Perinuclear L-PGDS/Arr3 co-localization is observed in PGD(2)-producing MG-63 cells and is induced by the addition of the L-PGDS substrate or co-expression of COX-2 in HEK293 cells. Inhibition of L-PGDS activity in MG-63 cells triggers redistribution of Arr3 and L-PGDS to the cytoplasm. Perinuclear localization of L-PGDS is detected in wild-type mouse embryonic fibroblasts (MEFs) but is more diffused in MEFs-arr-2(-/-)-arr-3(-/-). Arrestin-3 promotes PGD(2) production by L-PGDS in vitro. IL-1ß-induced PGD(2) production is significantly lower in MEFs-arr-2(-/-)-arr-3(-/-) than in wild-type MEFs but can be rescued by expressing Arr2 or Arr3. A peptide corresponding to amino acids 86-100 of arrestin-3 derived from its L-PGDS binding domain stimulates L-PGDS-mediated PGD(2) production in vitro and in MG-63 cells. We report the first characterization of an interactor/modulator of a PGD(2) synthase and the identification of a new function for arrestin, which may open new opportunities for improving therapies for the treatment of inflammatory diseases.

Venetoclax in Combination with Azacitidine for the Treatment of Newly Diagnosed Acute Myeloid Leukemia: A Canadian Cost-Utility Analysis.

Treatment for acute myeloid leukemia (AML) typically involves intensive chemotherapy (IC); however, there is an unmet need for approximately 50% of AML patients who are deemed unfit or ineligible for IC. The purpose of this study was to evaluate, from a Canadian perspective, the economic impact of venetoclax in combination with azacitidine (Ven+Aza) for the treatment of patients with newly diagnosed AML who are 75 years or older or who have comorbidities that preclude using IC. A lifetime partitioned survival model was developed to assess the cost-effectiveness of Ven+Aza compared with Aza. Health states included event-free survival, progressive/relapsed disease, and death. Efficacy parameters were based on the VIALE-A trial. Analyses were conducted from Ministry of Health (MoH) and societal perspectives. Over a lifetime horizon, Ven+Aza was associated with a gain of 1.65 quality-adjusted life years (QALYs) compared with Aza. From an MoH perspective, Ven+Aza and Aza were associated with total costs of $204,305 and $82,333, respectively, resulting in an incremental cost-utility ratio of $73,841/QALY. Results were similar from a societal perspective. This economic evaluation demonstrates that, in comparison with Aza, Ven+Aza is a cost-effective strategy for the treatment of patients with newly diagnosed AML who are deemed unfit for IC.

The Economic Impact of Originator-to-Biosimilar Non-medical Switching in the Real-World Setting: A Systematic Literature Review.

INTRODUCTION: To save costs to the healthcare system, forced non-medical switch (NMS) policies that cut drug coverage for originator biologics and fund only less expensive biosimilars are being implemented. However, costs related to the impact of NMS on healthcare resource utilization (HCRU) must also be considered. This study aims to summarize the evidence on the economic impact of an originator-to-biosimilar NMS. METHODS: A systematic literature review (SLR) was conducted. Publications reporting on HCRU or costs associated with originator-to-biosimilar NMS in the real-world setting were searched in MEDLINE and EMBASE from January 2008 to February 2020. In addition to hand searching the reference lists of relevant publications and SLRs, key conference websites, PubMed, and various government sites were also searched for the 2 years preceding the search (2018-2020). RESULTS: A total of 1845 citations were identified, of which 49 were retained for data extraction. Most studies reporting on the HCRU associated with NMS reported on post-NMS HCRU alone without a comparison pre-NMS. However, four studies described a difference in HCRU (i.e., investigations pre- vs post-switch or between non-switchers vs switchers), all of which reported a relative increase in HCRU, including laboratory testing, imaging, medical visits, and hospitalizations, amongst patients who underwent an originator-to-biosimilar NMS. Most studies reporting on the costs associated with NMS reported significant savings following NMS on the basis of drug costs alone. However, four studies specifically reporting on the difference of costs following originator-to-biosimilar NMS all demonstrated an increase in HCRU-related costs associated with NMS (increase in HCRU-related costs of 4-37% or 148-2234 2020 Canadian dollars). CONCLUSION: Amongst the studies that reported on the difference in HCRU pre- vs post-switch or between non-switchers and switchers, all showed an increase in HCRU and related costs associated with NMS, suggesting that the expected overall savings due to less costly drug prices may be reduced as a result of an increase in HCRU and its associated costs post-switch. Nevertheless, more real-world studies that include NMS-related healthcare costs in addition to drug costs are needed.

Short-term efficacy of latanoprostene bunod for the treatment of open-angle glaucoma and ocular hypertension: a systematic literature review and a network meta-analysis.

BACKGROUND/AIMS: To assess the comparative efficacy of latanoprostene bunod (LBN), a novel prostaglandin analogue (PGA), to other medications for open-angle glaucoma and ocular hypertension on lowering intraocular pressure (IOP). METHODS: A systematic literature review adapted from the Li et al (Ophthalmology, 2016) study was conducted. Medline, Embase and PubMed were searched for randomised controlled trials published between 1 January 2014 and 19 March 2020. Studies had to report IOP reduction after 3 months for at least two different treatments among placebo, PGAs (bimatoprost 0.01%, bimatoprost 0.03%, latanoprost, LBN, tafluprost, unoprostone) or apraclonidine, betaxolol, brimonidine, brinzolamide, carteolol, dorzolamide, levobunolol, timolol, travoprost. A Bayesian network meta-analysis was performed to provide the relative effect in terms of mean difference (95% credible interval) of IOP reduction and ranking probabilities. Surface under the cumulative ranking curve (SUCRA) was generated. RESULTS: A total of 106 trials were included with data for 18 523 participants. LBN was significantly more effective than unoprostone (-3.45 (-4.77 to -2.12)). Although relative effect was not significative, compared with other PGAs, LBN numerically outperformed latanoprost (-0.70 (-1.83 to 0.43)) and tafluoprost (-0.41 (-1.87 to 1.07)), was similar to bimatoprost 0.01% (-0.02(-1.59 to 1.55)) and was slightly disadvantaged by bimatoprost 0.03% (-0.17 (-1.42 to 1.07)). LBN was significantly more efficient than the beta-blockers apraclonidine, betaxolol, brimonidine, brinzolamide, carteolol, dorzolamide and timolol. According to SUCRA, LBN was ranked second after bimatoprost 0.03%, followed by bimatoprost 0.01%. CONCLUSION: LBN was significantly more effective than the PGA unoprostone and most of the beta-blockers. Compared with the most widely used PGAs, LBN numerically outperformed latanoprost and travoprost and was similar to bimatoprost 0.01%.

Cost-effectiveness of asenapine in the treatment of schizophrenia in Canada.

OBJECTIVE: Asenapine is the first tetracyclic antipsychotic approved in Canada for the treatment of schizophrenia (SCZ). Asenapine has shown a comparable efficacy profile to other atypical antipsychotics and it is associated with a favourable metabolic profile and less weight gain. This study aimed to assess the economic impact of asenapine compared to other atypical antipsychotics in the treatment of SCZ in Canada. METHODS: A decision tree combined with a Markov model was constructed to assess the cost-utility of asenapine compared with other atypical antipsychotics. The decision tree takes into account the occurrence of extrapyramidal symptoms, the probability of switching to a different antipsychotic, and the probability of gaining weight. The Markov model takes into account long-term metabolic complications including diabetes, hypertension, coronary heart diseases, and stroke. In the base-case analysis, asenapine was compared to olanzapine. Asenapine was also compared with other atypical antipsychotics commonly used in Canada in alternative scenarios. Analyses were conducted from both Canadian Ministry of Health (MoH) and societal perspectives over a 5-year time horizon. RESULTS: In the treatment of SCZ, asenapine is a dominant strategy over olanzapine from both MoH and societal perspectives. Compared to quetiapine, asenapine is also a dominant strategy. Furthermore, asenapine has a favorable economic impact compared to ziprasidone and aripiprazole, as these antipsychotics are not cost-effective compared to asenapine from both MoH and societal perspectives. CONCLUSION: Despite the short time horizon, the lack of compliance data and the assumptions made, this economic evaluation demonstrates that asenapine is a cost-effective strategy compared to olanzapine and to most of the atypical antipsychotics frequently used in Canada.