Cost Effectiveness of Fremanezumab in Episodic and Chronic Migraine Patients from a Japanese Healthcare Perspective.

BACKGROUND AND OBJECTIVES: Fremanezumab is an effective treatment for episodic (EM) and chronic migraine (CM) patients in Japan, but its cost effectiveness remains unknown. The objective of this study was to determine the cost effectiveness of fremanezumab compared with standard of care (SOC) in previously treated EM and CM patients from a Japanese healthcare perspective. METHODS: Estimated regression models were implemented in a probabilistic Markov model to inform effectiveness and health-related quality-of-life data for fremanezumab and SOC. The model was further populated with data from the literature. The adjusted Japanese healthcare perspective included productivity losses. The main model outcomes were quality-adjusted life-years (QALYs), costs (2022 Japanese Yen [¥]), and incremental outcomes including the incremental cost-effectiveness ratio (ICER). Analyses were performed separately for the EM and CM patients and combined. Costs and effects were discounted at an annual rate of 2.0%. RESULTS: The mean QALYs over a 25-year time horizon for the EM and CM populations combined were 13.03 for SOC and 13.15 for fremanezumab. The associated costs were ¥27,550,292 for SOC and ¥28,371,048 for fremanezumab. QALYs were higher and costs lower for EM patients compared with CM patients for both fremanezumab and SOC. The deterministic ICERs of fremanezumab versus SOC were ¥6,334,861 for EM, ¥7,393,824 for CM, and ¥6,530,398 for EM and CM combined. Indirect costs and choice of mean migraine days model distribution had a substantial impact on the ICER. CONCLUSION: Using fremanezumab in a heterogeneous mixture of Japanese EM and CM patients resulted in a reduction of monthly migraine days and thus more QALYs compared with SOC. The cost effectiveness of fremanezumab versus SOC in EM and CM patients resulted in an ICER of ¥6,530,398, from an adjusted Japanese public healthcare perspective.

Fremanezumab is an effective treatment for episodic and chronic migraine patients in Japan, but it is unknown how the costs relate to the health benefits. The current research determined the relation between costs and effects of fremanezumab compared with the current standard of care in Japanese clinical practice, to see if the costs are justified by the health benefits. A model was used to inform the treatment effect of fremanezumab and standard of care. Data on costs, the frequency in which health care was used, and impairment of work due to migraine were also included in the model and obtained from the literature. The main outcomes were the number of years that patients were alive while taking their quality of life into account, costs, and the difference in these outcomes between patients who were treated with fremanezumab and those receiving standard of care. Subsequently, it was estimated how costs and effects related to one another and whether the costs were justified by the health benefits. The outcomes showed that patients treated with fremanezumab had a better quality of life compared with those receiving standard of care, while the costs associated with fremanezumab were higher. Compared with standard of care, the health benefits of treating patients with fremanezumab were justified by the costs within an acceptable range. Taking the absence from work due to illness into account had a substantial impact on the model outcomes.

Validation and comparison of the coding algorithms to identify people with migraine using Japanese claims data.

Purpose: The study aimed to validate and compare coding algorithms for identifying people with migraine within the Japanese claims database. Methods: This study used the administrative claim database provided by DeSC Healthcare, Inc., that was linked to the results of an online survey administered to adult users of the health app "kencom®." The ability of the 12 algorithms to detect migraines using diagnostic records alone or with prescription records was evaluated based on sensitivity, specificity, positive predictive values (PPVs), and negative predictive values (NPVs). We used a migraine diagnosis judged based on respondents' self-reported symptoms according to the diagnostic criteria of the International Classification of Headache Disorders, version 3 (ICHD-3), as true. Results: Of the 21,480 individuals, 691 had migraine according to the ICHD-3 criteria. The 12 algorithms had a sensitivity of 5.4-8.8%, specificity of 98.8-99.6%, PPVs of 19.2-32.5%, and NPVs of 96.9-97.0%. Algorithm 9 (migraine diagnostic records more than once AND at least one prescription record for migraine prophylaxis or triptans in the same month as diagnosis) produced the highest PPV, whereas Algorithm 2 (at least one diagnostic record of migraine or tension-type headache) had the highest sensitivity. Similar trends were observed when using the ID-Migraine or 4-item migraine screener, instead of the ICHD-3 criteria, for case ascertainment. Conclusion: Strict algorithms, such as Algorithm 9, yielded a higher PPV but a lower sensitivity, and such algorithms may be suitable for studies estimating the relative risk. Conversely, algorithms based on a single diagnostic record, such as Algorithm 2, had a higher sensitivity and may be suitable for studies estimating the prevalence/incidence of disease. Our findings will help select a desirable algorithm for migraine studies using a Japanese claim database.

Modeling Monthly Migraine-Day Distributions Using Longitudinal Regression Models and Linking Quality of Life to Inform Cost-Effectiveness Analysis: A Case Study of Fremanezumab in Japanese-Korean Migraine Patients.

BACKGROUND AND OBJECTIVES: As regression approaches have been used more recently to model the effectiveness and health-related quality of life (HRQOL) of novel migraine treatments, an example is provided for fremanezumab. The objective is to estimate the distribution of mean monthly migraine days (MMD) as a continuous variable and corresponding migraine-specific utility values as a function of the MMD, to inform health states in a cost-effectiveness model (CEM). METHODS: Three longitudinal regression models (zero-adjusted gamma [ZAGA], zero-inflated beta-binomial [ZIBB], and zero-inflated negative binomial [ZINBI]) were fitted to Japanese-Korean clinical trial data of episodic (EM) and chronic migraine (CM) patients treated with fremanezumab or placebo, to estimate MMD over a period of 12 months. The EQ-5D-5L and the migraine-specific quality-of-life (MSQ), mapped to the EQ-5D-3L, questionnaires were used to measure HRQOL. Migraine-specific utility values were estimated as a function of MMD using a linear mixed effects model. RESULTS: The ZIBB models fitted the data best in estimating the distribution of mean MMD over time. MSQ-derived values were more sensitive than the EQ-5D-5L values for the effect of the number of MMD on HRQOL, with higher values for less MMD and more time on treatment. CONCLUSIONS: Using longitudinal regression models to estimate MMD distributions and linking utility values as a function is an appropriate method to inform CEMs and capture inter-patient heterogeneity. The observed distribution shifts demonstrated fremanezumab's effect at reducing MMD for both EM and CM patients, while treatment effect on HRQOL was captured by MMD and time on treatment.

The current study provides an example of an approach that can be used to estimate the number of migraine days per month and the quality of life of migraine patients. The outcomes of this approach can give an impression of how well a patient reacts to a new migraine treatment called fremanezumab. In this study, different mathematical equations were used to measure the migraine days per month and quality of life over a period of 1 year. The data came from Japanese-Korean patients that participated in clinical trials. The patients reported the number of days that they had migraine and their quality of life was measured with two validated questionnaires. With the gathered data, the quality of life was calculated for the number of migraine days that a patient could have per month. Patients who had the fewest migraine days and were treated the longest with the new treatment reported the best quality of life. The investigated approach is an appropriate method to measure the impact of fremanezumab on the number of monthly migraine days and a patient's quality of life. The measurements of this approach can be linked to other parameters in an economic model to estimate the costs required to reach a certain level of treatment effect with this new migraine treatment.

The Assessment of the Diagnostic Delay in Japanese People with Parkinson's Disease Using a Web-based Survey of Patients and Physicians.

Objective Although diagnostic criteria of Parkinson's disease (PD) have been established, the details of the process by which patients notice symptoms, visit a physician, and receive a diagnosis of PD is unclear. We therefore explored factors influencing latency in diagnosing PD. Methods We performed an internet-based survey of patients with PD and their families as well as physicians treating patients with PD to identify any diagnostic latency and its determinants. Evaluated factors included motor and non-motor symptoms, the diagnosis history and symptoms, patients' feelings toward PD prior to the diagnosis, and physician-determined reasons for the diagnostic delay. Results Among the 186 eligible patient respondents (including 87 responses from family members of patients), 24% received a PD diagnosis >1 year after the onset of PD-related symptoms, 58.6% had mid- or late-stage PD at the diagnosis, and 29% of patients had initially thought their symptoms were common age-related phenomena. Tremor (42%) was the most frequent symptom that led patients to visit a medical institution, whereas gait disturbance (14%) was the least frequent. More patients diagnosed with early-stage PD than those diagnosed with mid- or late-stage PD consulted a neurologist at their first visit. Among the 331 eligible physicians, patients' misinterpretation of their symptoms as being age-related was deemed one of or the most common cause (s) of a diagnostic delay by 67% and 36%, respectively. Conclusion Patients' insufficient or misinterpreted information about PD may cause delays in accessing healthcare services, leading to diagnostic delay.

An association between cancer type and delirium incidence in Japanese elderly patients: A retrospective longitudinal study.

OBJECTIVE: There is not a known elevated prevalence of delirium in older adult cancer patients. However, it is unknown if the incidence of delirium varies by cancer type among older adult patients. Therefore, this study aimed to examine the association between the incidence of delirium and cancer type among older adult patients using a Japanese hospital-based administrative claims database. METHODS: A total of 76,868 patients over 65 years of age or older, first diagnosed with cancer on an initial date of hospitalization between April 2008 and December 2019, were included in this retrospective longitudinal study. Delirium was defined by the World Health Organization's International Statistical Classification of Diseases and Related Health Problems (ICD-10) codes or antipsychotic medication use. Cox proportional hazard models were performed to estimate the risk of delirium incidence according to 22 cancer types during the one-year hospitalization period. RESULTS: The incidence rates of delirium were 17.1% for men and 15.3% for women. Compared to gastric cancer, the risk of delirium was significantly higher for pancreatic cancer (HR: 1.26, 95% CI: 1.11-1.42 for men; HR: 1.27, 95% CI: 1.11-1.45 for women), leukemia (HR: 1.24, 95% CI: 1.09-1.41 for men; HR: 1.20, 95% CI: 1.03-1.41 for women), and oropharyngeal cancer (HR: 1.30, 95% CI: 1.10-1.54 for men; HR: 1.32; 95% CI: 1.02-1.72 for women) after adjusting for age, initial hospitalization year, antipsychotic medications, and surgery. CONCLUSIONS: As compared to gastric cancer, patients with pancreatic cancer, leukemia, oropharyngeal cancer were found to have a higher risk of developing delirium. Our study findings suggested that the risk of delirium incidence may vary by cancer type.

Prescribing Pattern of Hypnotic Medications in Patients Initiating Treatment at Japanese Hospitals: A Nationwide, Retrospective, Longitudinal, Observational Study Using a Claims Database.

BACKGROUND: Prolonged treatment of insomnia using benzodiazepine (BZD) receptor agonists, including BZD and non-BZD hypnotic drugs, can cause drug dependence, tolerance, abuse and other adverse events. These side effects are more common and/or severe in older adults taking different hypnotic drugs concomitantly. Therefore, a single prescription is limited to 30 daily doses for most BZD receptor agonists and restrictions apply to the prescription of more than three types of hypnotic drugs in Japan. Little is known, however, about the real-world prescribing pattern of hypnotic drugs in Japan. OBJECTIVE: We analysed prescribing patterns for hypnotic drugs in Japan to evaluate whether real-world use differs from guideline recommendations. METHODS: In this nationwide, retrospective, longitudinal, observational study, we analysed the types of hypnotic drugs prescribed, duration of medication and treatment setting in a subset of hospitals in Japan using a hospital-based administrative claims database (Medical Data Vision). Patients initiating treatment with hypnotic drugs between January 2012 and December 2016 were included in the analyses to assess the duration of medication and occurrence of co-prescription of a second and third hypnotic drug, within a year from prescription of the first hypnotic drugs. RESULTS: In 261,167 patients analysed, the first hypnotic drugs prescribed were BZDs (59.7%), non-BZDs (36.8%), a melatonin receptor agonist [MRA] (3.1%) and an orexin receptor antagonist [ORA] (0.4%). Benzodiazepine and non-BZD hypnotic drugs were mostly prescribed in inpatient settings (57.7% and 63.0%, respectively) and the MRA and ORA mostly in outpatient settings (62.6% and 65.4%, respectively). The departments that prescribed the most patients their first hypnotic drugs were internal medicine (23.6%), general surgery (11.8%), orthopaedic surgery (11.4%) and urology (5.3%). Of the total prescriptions of MRA and ORA as the first hypnotic drugs, 22.0% and 31.8% were in internal medicine, 4.4% each in general surgery, 6.0% and 4.5% in orthopaedic surgery, 9.7% and 4.4% in neurology, and 10.1% and 12.2% in psychiatry departments, respectively. Mean duration of medication was 1.13 months for non-BZDs, 1.15 months for BZDs, 1.29 months for the ORA and 1.83 months for the MRA. Overall, 5.3% (95% confidence interval 5.2-5.4) of patients were prescribed a second hypnotic drug; of these, 8.4% (95% confidence interval 8.0-8.9) were prescribed at least three hypnotic drugs within a year. Patients who were prescribed three or more hypnotic drugs received higher doses of the first drug than patients who received fewer hypnotic drugs. CONCLUSIONS: Benzodiazepine receptor agonists were the most common hypnotic drugs prescribed as the first drug to patients in Japan. Further education and awareness may be needed on the risk of complications and adverse events associated with these therapies. The duration of BZD receptor agonist use was shorter than for the MRA and ORA, in accordance with prescribing guidelines. Long-term use and co-prescribing of hypnotic drugs were also uncommon.

Effect of residual insomnia and use of hypnotics on relapse of depression: a retrospective cohort study using a health insurance claims database.

BACKGROUND: Residual insomnia is associated with a risk of depression recurrence. METHODS: In this retrospective, longitudinal cohort study, the recurrence pattern of depression in patients with or without residual insomnia was assessed using a health insurance claims database. Patients who were diagnosed with major depressive disorder and prescribed antidepressants, between January 2006 and June 2017 in Japan, were enrolled in the study. Residual insomnia was defined by a prescription of hypnotics, and recurrence of depression by prescription of antidepressants. Main outcomes included time to recurrence and the 1-year recurrence rate. Factors associated with recurrence of depression were assessed by multivariate analyses. The effect of residual insomnia on the frequency of recurrence was assessed by Chi-square test. RESULTS: Of the 30,381 patients analyzed, there were 4,166 and 26,215 patients with or without residual insomnia, respectively. Time to recurrence in patients with residual insomnia was significantly shorter compared with those without residual insomnia (p <0.001), with a 1-year recurrence rate (95% CI) of 43.4% (41.9-45.0) and 7.4% (7.1-7.7), respectively. The frequency of recurrence was significantly higher in patients with residual insomnia than in those without (p <0.0001). A higher risk of depression recurrence (odds ratio 9.98, 95% CI 9.22-10.81) was found for residual insomnia compared with other significant factors. LIMITATIONS: The diagnosis stated in the receipt data may not accurately reflect the patient's condition, and medication adherence was unknown but assumed. CONCLUSIONS: Residual insomnia is a significant risk factor for depression recurrence in Japanese patients.

Patterns of hypnotic prescribing for residual insomnia and recurrence of major depressive disorder: a retrospective cohort study using a Japanese health insurance claims database.

BACKGROUND: Major depressive disorder (MDD) is highly prevalent in Japan and frequently accompanied by insomnia that may persist even with MDD remission. Hypnotics are used for the pharmacological treatment of insomnia, but their influence on MDD recurrence or residual insomnia following MDD remission is unclear. This retrospective, longitudinal, cohort study utilized a large Japanese health insurance claims database to investigate patterns of hypnotic prescriptions among patients with MDD, and the influence of hypnotic prescription pattern on MDD recurrence. METHODS: Eligible patients (20-56 years) were those registered in the Japan Medical Data Center database between 1 January 2005 and 31 December 2018, and prescribed antidepressant and hypnotic therapy after being diagnosed with MDD. Patients who had ceased antidepressant therapy for > 180 days were followed for 1 year to evaluate depression recurrence, as assessed using Kaplan-Meier estimates. Logistic regression modelling was used to analyze the effect of hypnotic prescription pattern on MDD recurrence. RESULTS: Of the 179,174 patients diagnosed with MDD who initiated antidepressant treatment between 1 January 2006 and 30 June 2017, complete prescription information was available for 2946 eligible patients who had been prescribed hypnotics. More patients were prescribed hypnotic monotherapy (70.8%) than combination therapy (29.2%). The most prescribed therapies were benzodiazepine monotherapy (26.2%), non-benzodiazepine monotherapy (28.9%), and combination therapy with two drugs (21.1%). Among patients prescribed multiple hypnotics, concomitant prescriptions for anxiolytics, antipsychotics, mood stabilizers and sedative antidepressants were more common. The 1-year recurrence rate for MDD was approximately 20%, irrespective of hypnotic mono- versus combination therapy or class of hypnotic therapy. Being a spouse (odds ratio [OR], 1.44; 95% confidence interval [CI], 1.03-2.02) or other family member (OR, 1.46, 95% CI, 0.99-2.16) of the insured individual, or being prescribed a sedative antidepressant (OR, 1.50, 95% CI, 1.24-1.82) conferred higher odds of MDD recurrence within 1 year of completing antidepressant therapy. CONCLUSIONS: Benzodiazepines are the most prescribed hypnotic among Japanese patients with MDD, though combination hypnotic therapy is routinely prescribed. Hypnotic prescription pattern does not appear to influence real-world MDD recurrence, though hypnotics should be appropriately prescribed given class differences in efficacy and safety.

Assessment of current clinical practices for major depression in Japan using a web-based questionnaire.

PURPOSE: To investigate the current clinical practice of Japanese physicians in the diagnosis and management of major depression (major depressive disorder [MDD]). PATIENTS AND METHODS: Japanese physicians specializing in psychiatry or psychosomatic medicine in the medical database of Nihon Ultmarc Inc. (Chuo-Ku, Tokyo, Japan), who had treated ≥30 patients with MDD in the past month were invited to complete a web-based questionnaire from January 15 to 29, 2018. The questionnaire was comprised of 28 questions pertaining to the physician's background, the criteria and tools used to diagnose MDD during physician-patient consultation, and actual and preferred duration of physician-patient consultation. Responses were given as single answer numerical values or as multiple-choice answers. RESULTS: From the 518 physicians invited to participate, 340 completed questionnaires were analyzed. Respondents were predominantly male (90%), hospital based (73%), affiliated with the Department of Psychiatry (95%), and members of the Japanese Society of Psychiatry and Neurology (87%). The majority of physicians (84%) agreed that "improvement of cognitive dysfunction caused by major depression is an important factor for patients to return to work" was the most challenging aspect of MDD diagnosis and management. Moreover, 83% of physicians conducted psychological assessments using a cognition evaluation test with most of their patients at the time of MDD diagnosis; the most commonly used tool was the Hasegawa Dementia Scale-Revised. Both hospital-based physicians and general practitioners would prefer to have longer consultations with their patients. CONCLUSION: Physicians acknowledge the importance of the assessment and management of cognitive dysfunction in patients with MDD. However, most physicians would prefer to have longer consultation times with their patients for the diagnosis of MDD. In the future, it may be useful to introduce digital tools (eg, THINC-it®) for the initial screening of cognitive dysfunction.

Training effect and fatigue in polypyrrole-based artificial muscles.

Artificial muscles based on an electrochemomechanical strain (ECMS) in conducting polymers, namely polypyrrole (PPy) film, have been studied from viewpoints of training, fatigue and aging by repeat cycles under tensile loads. ECMS was approximately 2% in a saline solution, resulting from both insertion and exclusion of Na(+) with solvated water molecules as well in the film. Transient responses of ECMS and current induced by voltage stimuli were measured under tensile stresses up to 5 MPa to see the training effect, fatigue and aging of the film. At higher stresses the film showed larger creeping, which resulted from realignment or conformation change, slipping and breaking of polymer chains. After the experience of large stresses, the training effect in ECMS was appreciably observed as an increase of the strain. Without stress the conductivity of the film was stable (no fatigue) upon an electrochemical cycle; however, under high tensile stresses the conductivity decreased remarkably (fatigue and aging). It is to be noted that straightened polymer chains can be easily oxidized and degraded due to lower pi-electron energy. The conversion efficiency from electrical to mechanical energy in this system was found to be less than 0.03%.

Work behaviors of artificial muscle based on cation driven polypyrrole.

A soft actuator mimicking natural muscles (artificial muscle) has been developed using a flexible conducting polymer of polypyrrole films, which were driven by electrical stimulus in a saline solution. The work characteristics were studied under various load stresses and found to behave like natural muscles. The artificial muscles shrunk and stiffened by the positive electrical stimulus by 2-3% at the maximum force of 5 MPa, and relaxed by application of negative voltages. At larger load stresses, the artificial muscle shrunk slowly as natural muscles do. The driving current also lasted longer at larger loads, indicating that the muscle sensed the magnitude of the load stress. During contraction of the muscle, the conversion efficiency from the electrical input and mechanical output energies was estimated to be around 0.06%. The maximum volumetric work was approximately estimated to be 100 kJ m(-3). These figures are unexpectedly small compared with those of natural muscles.

Tubular linear actuators using conducting polymer, polypyrrole.

Conducting polymers show an electrochemomechanical deformation (ECMD), which is able to be utilized as soft actuators. A tubular linear actuator of polypyrrole film is fabricated and the characteristics are examined. The film was electrochemically prepared on an acryl resin rod in an aqueous electrolyte solution of pyrrole and dodecylbenzensulfonic acid (DBS), followed by removing the rod. The actuations of tubular polypyrrole film due to ECMD in various conditions have been examined to clarify the mechanism. It has been found that the tubular actuator elongates upon reduction with the strain of 7%, which is more than twice of that observed in a rectangular film. The facts indicate that cations play the role of dopants instead of large DBS anion and the tubular structure gives the better performance for large strain.