What is happening with not recommended drugs for dementia in Argentina? Prescription patterns and direct costs analysis

Dementia is an age-associated syndrome most commonly due to Alzheimer's disease (AD) and/or cerebrovascular disease. Calcium has an important role in regulating brain functions. Calcium ions link membrane excitation to subsequent intracellular molecular responses. Age-associated changes in calcium homoeostasis have possible repercussions on higher cortical functions. Nimodipine is an isopropyl calcium channel blocker which readily crosses the blood-brain barrier. Its primary action is to reduce the number of open calcium channels in cell membranes, thus restricting influx of calcium ions into cells. The usefulness of nimodipine in patients with Alzheimer's disease and vascular dementia and unspecified dementia is still controversial. In spite of the uncertainties about its efficacy in dementia, nimodipine is currently frequently prescribed for cognitive impairment and dementia in several continental European countries. To assess the clinical efficacy of nimodipine for the manifestations of dementia, in unclassified disease and in the major subtypes - Alzheimer's disease, cerebrovascular disease, and mixed Alzheimer's and cerebrovascular disease. The Cochrane Dementia and Cognitive Improvement Group's Specialized Register - which contains reports of trials from all major medical databases and many trial databases - was last searched on 3 August 2001 using the term 'nimodipin*'. All unconfounded, double-blind, randomized trials in which treatment with nimodipine was administered for more than a day and compared with placebo in patients with dementia, of unclassified type or attributable to Alzheimer's disease, cerebrovascular disease, or mixed Alzheimer's and cerebrovascular disease. Data were extracted independently by the reviewers and the odds ratio (95%CI) or the average difference (95%CI) were estimated. Both intention-to-treat and on-treatment results were extracted. Fourteen trials were included which tested two treatment regimes, 90 and 180 mg/day of nimodipine for 12 and 24 weeks. Two trials included only patients with Alzheimer's disease (AD), 9 trials included only patients with cerebrovascular dementia (CVD), and three trials included patients with AD, CVD and mixed disease. Available outcome data from 9 trials (2492 patients) cover the domains of cognitive function, activities of daily living, global clinical state, safety and tolerability. By pooling available data from all trials, whatever the diagnosis of the patients included, this review found benefit associated with nimodipine (90 mg/day at 12 weeks) compared with placebo on the SCAG scale ( WMD -7.59, 95% CI -9.87 to -5.31, P<0.00001) on clinical global impression (WMD -0.87, 95% CI -1.07 to -0.67, P<0.00001) and cognitive function (SMD 0.61, 95% CI 0.42 to 0.81, P<0.00001) but not on scales assessing activities of daily living. When the AD trials and the VD trials were pooled separately similar significant results were found for the 90mg/day dose of nimodipine at 12 weeks. Drop-out rates were low in the trials, affecting similar proportions of treatment and placebo groups. Nimodipine is well tolerated with a low rate of adverse effects similar to that associated with placebo. There were slightly more adverse cerebrovascular events, and adverse events due to blood problems, associated with placebo than with nimodipine, and adverse autonomic events were slightly more common with nimodipine than with placebo. Nimodipine can be of some benefit in the treatment of patients with features of dementia due to unclassified disease or to Alzheimer's disease, cerebrovascular disease, or mixed Alzheimer's and cerebrovascular disease. It appears to be well tolerated with few side effects. Data were not available from several trials, a total of more than 500 patients. A meta-analysis of individual patient data from all trials is desirable. Dementia is a chronic disorder and the short-term benefits of nimodipine demonstrated in the trials reviewed do not justify its use as a long-term anti-dementia drug. New research must focus on longer term outcomes.

In 2015, there were 47 million people with dementia worldwide.1 The overall number of people with dementia is projected to reach 132 million in 2050, 51% of whom will be from Asian countries.1 Japan has the highest prevalence of dementia among the OECD countries, where 2% of inhabitants (5 million) are living with dementia. There are significant unmet needs regarding the effectiveness of antidementia drug use in real‐world settings. Populations in settings of clinical trials on antidementia drugs generally deviate from those in clinical practice settings (eg, exclusion of people aged ≥85 years).2 It remains controversial whether the desirable consequences of antidementia drug use outweigh its undesirable consequences.2 Such controversy regarding benefit‐risk balance has resulted in inconsistencies in the strength of recommendations on the use of antidementia drugs among clinical practice guidelines. Some guidelines leave the choice of whether to use antidementia drugs to clinicians,3 whereas the Japanese guideline strongly recommends that clinicians use antidementia drugs in the treatment of Alzheimer's disease.4 The recommendations in guidelines might impact on the prescribing practices of antidementia drugs. Therefore, this study aimed to examine the prevalence of antidementia drug use in Japan. We used a nationwide claims database, the National Database of Health Insurance Claim Information and Specified Medical Checkups, which covers almost all claims in Japan. The database included information on clinical and procedural characteristics. The local institutional review board approved the study protocol. We identified all prescriptions for antidementia drugs (donepezil, galantamine, memantine, and rivastigmine) between April 2015 and March 2016. The number of prevalent users was counted using the patient identification numbers (called “ID0”). The annual prevalence of antidementia drug use was then calculated by dividing the number of prevalent users by the number of inhabitants. The annual quantity of antidementia drugs consumed (expressed in milligrams) was calculated for each drug, and converted into a defined daily dose. In addition, the quantity of antidementia drugs consumed was converted into a defined daily dose per 1000 inhabitants per day (DID). There were 1 733 916 prevalent users of antidementia drugs (Table 1). The annual prevalence of antidementia drug use was 1.4% among all inhabitants and 5.1% among those aged ≥65 years, with a peak of 17.0% among those aged ≥85 years. Users aged ≥85 years consumed 46.8% of the total quantity of antidementia drugs prescribed. The DID showed that 13 in 100 inhabitants aged ≥85 years received a maintenance dose of an antidementia drug every day. Similar findings were observed in both sexes. Table 1 Annual prevalence and quantity of antidementia drugs consumed Sex‐Age Group, Years No. of Inhabitants No. of Patients with Prescriptions for Antidementia Drugs Prevalence of Antidementia Drug Users, % Annual Quantity of Antidementia Drugs Consumed, DDD DDD per 1000 Inhabitants per Day, DID Total 125 640 987 1 733 916 1.4 498 098 242 10.8 0‐64 92 175 546 20 612 0.0 6 090 721 0.2 65‐69 9 643 867 43 471 0.5 12 898 213 3.7 70‐74 7 695 811 108 155 1.4 31 555 992 11.2 75‐79 6 276 856 261 408 4.2 75 939 321 33.1 80‐84 4 961 420 468 350 9.4 138 323 340 76.2 ≥85 4 887 487 831 920 17.0 233 290 655 130.4 Men 61 013 327 566 595 0.9 160 706 002 7.2 0‐64 46 527 858 10 659 0.0 3 020 046 0.2 65‐69 4 659 662 20 723 0.4 5 949 790 3.5 70‐74 3 582 440 47 323 1.3 13 565 524 10.3 75‐79 2 787 417 105 273 3.8 30 455 166 29.9 80‐84 1 994 326 164 276 8.2 48 021 079 65.8 ≥85 1 461 624 218 341 14.9 59 694 397 111.6 Women 64 627 660 1 167 321 1.8 337 392 240 14.3 0‐64 45 647 688 9953 0.0 3 070 675 0.2 65‐69 4 984 205 22 748 0.5 6 948 423 3.8 70‐74 4 113 371 60 832 1.5 17 990 468 11.9 75‐79 3 489 439 156 135 4.5 45 484 155 35.6 80‐84 2 967 094 304 074 10.2 90 302 261 83.2 ≥85 3 425 863 613 579 17.9 173 596 258 138.4 DDD, defined daily dose; DID, defined daily dose per 1000 inhabitants. To our knowledge, this is the first study to establish the prevalence of antidementia drug use in Japan. The prevalence of antidementia drug use among inhabitants aged ≥85 years seems to be incredibly high, compared to that reported in a nationwide study in Germany which yielded an annual prevalence of 18% even among people with dementia aged ≥85 years.5 However, clinical trials of antidementia drugs have mainly focused on people with dementia aged <85 years. Our findings suggest that the significant gap between what is known and what is done needs addressing. Until more clinical trials focusing on the oldest‐old population become available, the strength of recommendation on the use of antidementia drugs in guidelines will be weak or limited to the population younger than 85 years because of the serious indirectness and potentially increased risks of adverse drug reactions associated with aging. The main limitation of this study is that our database did not cover approximately 5% of inhabitants aged ≥65 years. Nevertheless, our study provides evidence on the minimum prevalence of antidementia drug use in Japan. CONFLICT OF INTEREST During the past 3 years, YO received personal fees from Merck & Co., Inc., Janssen Pharmaceuticals, Inc., Medical Technology Association, Cando Inc., and the Japan Medical Data Center. He has also received research grants from the Japan Agency for Medical Research and Development; Ministry of Health, Labour and Welfare; Japan Society for the Promotion of Science; Institute for Health Economics and Policy; and Mental Health and Morita Therapy. NS received personal fees from Daiichi Sankyo Co., Ltd., outside the submitted work.