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Persistence and adherence to rivastigmine in patients with dementia: Results from a noninterventional, retrospective study using the National Health Insurance research database of Taiwan
Alzheimer’s & Dementia: Translational Research & Clinical Interventions - (2018) 1-6 1 2 Featured Article 3 4 5Q1 6 7 8 9 10 11 a,b,c c d e f 12Q6 g,h i j k j, 13 14 a Graduate Institute of Clinical Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan 15 b Department of Cardiovascular Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan 16 c Clinical Informatics & Medical Statistics Research Center, College of Medicine, Chang Gung University, Taoyuan, Taiwan 17 d Cognition and Aging Center, Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan 18 e Department of Neurology, National Taiwan University Hospital, College of Medicine, Taipei, Taiwan 19 f Department of Neurology, Shuang Ho Hospital, College of Medicine, Taipei Medical University, New Taipei, Taiwan 20 g Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan 21 h Faculty of Medicine, National Yang-Ming University Schools of Medicine, Taipei, Taiwan 22 i Department of Neurology, Changhua Christian Hospital, Changhua, Taiwan 23 j Department of Neurology, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Taoyuan, Taiwan 24 k Novartis (Taiwan) Co. Ltd., Taipei, Taiwan 25 26 27 28Q2 Abstract Objective: To assess adherence and persistence of patients treated with rivastigmine versus donepe29 zil using data from Taiwan National Health Insurance Research Database. 30 Methods: Patients diagnosed with dementia in National Health Insurance Research Database from 31 January 2011 to December 2012 were eligible. Persistence was calculated as time (in consecutive 32 days) from first prescription date of rivastigmine/donepezil until discontinuation/medication 33 switch/end of available data, whichever occurred first. Adherence was calculated as proportion of 34 days covered and medication possession ratio. 35 Results: Of 385,097 patients, 10,531 were first-time users of rivastigmine (oral: n 5 3439; patch: 36 n 5 868) or donepezil (n 5 6224). Majority of patients persisted on rivastigmine 4.5 and 6 mg for 37 38 429 and 468 days, respectively, versus 443 and 441 days for patients receiving 5 and 10 mg donepezil 39 once daily, respectively. Persistence duration of patients who switched dose during titration to stable 40 dose was observed to be dose dependent. Patients who initially received 1.5 mg oral rivastigmine 41 required a shorter time to reach a stable dose compared with those who initiated treatment at a higher 42 dose of rivastigmine (3 mg [P ,.0001] and 4.5 mg [P 5.013]). Patients at a stable dose of 4.5 or 6 mg 43 rivastigmine were observed to persist longer than those at a lower dose of rivastigmine and donepezil. 44 No significant difference was observed between oral rivastigmine and donepezil groups in proportion 45 of days covered (P 5 .195) and medication possession ratio (P 5 .079). 46 Discussion: Although results indicate significant difference in persistence between rivastigmine and 47 donepezil groups, clinical significance remains to be determined. 48 49 Ó 2018 Published by Elsevier Inc. on behalf of the Alzheimer’s Association. This is an open access 50 article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 51 Keywords: National Health Insurance Research Database; Rivastigmine; Donepezil; Adherence; Persistence 52 53 54
Persistence and adherence to rivastigmine in patients with dementia: Results from a noninterventional, retrospective study using the National Health Insurance research database of Taiwan Chee-Jen Chang , Tse Chih Chou , Chiung-Chih Chang , Ta-Fu Chen , Chaur-Jong Hu , Jong-Ling Fuh , Wenfu Wang , Chiung-Mei Chen , Winco Hsu , Chin-Chang Huang *
Conflict of interest: The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.
*Corresponding author. Tel.: 1886-3-3281200 # 8420, 8418; Fax: 18863-3287226. E-mail address: [email protected]
https://doi.org/10.1016/j.trci.2018.06.013 2352-8737/Ó 2018 Published by Elsevier Inc. on behalf of the Alzheimer’s Association. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). FLA 5.5.0 DTD TRCI176_proof 13 July 2018 7:33 pm ce
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1. Introduction Dementia is a major health concern worldwide, and dementia of Alzheimer’s type accounts for an estimated 60%–80% of the cases. The age-adjusted prevalence of all-cause dementia in a nationwide survey conducted in Taiwan was 8.04% [1]. In Taiwan, the projected number of people with dementia (aged 65 years) is 0.15 million, and this number is expected to reach 0.21 million by 2020 [2]. Current treatment options for Alzheimer’s disease (AD) available in Taiwan include cholinesterase inhibitors (ChEIs), such as rivastigmine, donepezil, and galantamine, or the N-methyl-D-aspartate receptor antagonist, memantine [3]. Poor adherence and persistence to medication is a major challenge in treating patients, particularly those with chronic diseases [4]. Adherence and persistence to ChEIs is critical in patients with dementia to stabilize or improve cognitive function [5,6]. Adherence to ChEI therapy can also improve activities of daily living and may lessen behavioral disturbances that accompany AD [7]. However, the cognitive decline associated with disease progression leads to suboptimal treatment compliance in patients with AD. Older patients are particularly susceptible to treatment noncompliance [5,7,8]. Persistence to ChEI therapy has been reported to be affected by several other factors such as choice of drug, polypharmacy, increased risk of drug interactions, ease of administration, and reimbursement status of the drug [8–10]. Hence, this study aimed to assess adherence and persistence to rivastigmine versus donepezil using data from the Taiwan National Health Insurance Research Database. 2. Methods 2.1. Data source In March 1995, a government-administered, insurancebased, national health-care system, that is, a single-payer National Health Insurance program, was launched in Taiwan. The database of this program contains registration files and original claims data for reimbursement. Large computerized de-identified data were derived from this system by the National Health Insurance Administration, Taiwan, and Ministry of Health and Welfare, Taiwan, and maintained by the Health and Welfare Data Center (HWDC), Taiwan. These data are provided to scientists in Taiwan for research purposes. The National Health Insurance Research Database collects and releases data annually [11]. The index date for the present study was defined as the first prescription of rivastigmine or donepezil. 2.2. Study population The study population comprised patients with data available in the National Health Insurance Research Database from January 1, 2010 to December 31, 2012. Because the
index date was defined as the first prescription of rivastigmine (oral/transdermal patch) or donepezil, patients were required to have been continuously enrolled for a minimum of 1 year before the index date and at least 9 months after the index date. Thus, data were collected for subjects diagnosed with mild cognitive impairment or AD or Parkinson’s disease dementia or dementia with Lewy bodies and prescribed with rivastigmine (oral/transdermal patch) or oral donepezil in 2011 and/or 2012. Patients on any other ChEI or memantine during the preindex period and/or during the study period were excluded from the study. 2.3. Treatment Patients were prescribed 5-cm2 rivastigmine patch, oral rivastigmine twice daily, or donepezil once daily. 2.4. Study design This was an observational, retrospective database study of a population-based cohort to assess the adherence and persistence of rivastigmine versus donepezil. Adherence to treatment was measured as proportion of days covered (PDC) and medication possession ratio (MPR). For each index treatment, PDC and MPR were presented as a point estimate and as intervals of 20% (0%–19%, 20%–39%, 40%–59%, 60%–79%, and 80%) and were provided for all patients and in those with at least two claims for the index therapy. Patients with PDC and MPR .80% were considered adherent, and those with PDC and MPR ,80% as nonadherent. The methodology for calculating medication adherence is described in Supplementary Figure 1. Persistence to index therapy was calculated based on treatment practice patterns, that is, based on the time (in consecutive days) from index therapy initiation until discontinuation, medication switch, or end of available data, whichever occurred first. 2.5. Statistical analysis Descriptive statistics, such as mean, median, standard deviation (SD), and percentiles, were summarized for continuous variables. Frequencies and proportions were derived for ordinal and nominal variables. Groups were compared for baseline characteristics and outcome measures using both parametric and nonparametric approaches such as the 2-sample t test and analysis of variance test for continuous variables and the chi-squared test and Fisher’s exact test for categorical variables. In particular, analysis of variance was used for comparing the differences in PDC and MPR among oral rivastigmine, oral donepezil, and rivastigmine patch. SAS, version 9.4, was used for data management and statistical analysis; all tests were two-sided, and a P value , .05 for a type-I error was considered statistically significant.
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3. Results A total of 385,097 patients were registered in the database between January 2010 and December 2012; 10,531 patients were first-time users of rivastigmine or donepezil. Of them, 3439 were treated with oral rivastigmine (mean age 6 SD: 77.14 6 7.93 years), 868 with 5-cm2 rivastigmine patch (mean age 6 SD: 77.73 6 7.48 years), and 6224 with donepezil (mean age 6 SD: 77.79 6 7.95 years) (Fig. 1). Baseline characteristics of the study population are presented in Table 1. Overall, the persistence duration in patients treated with oral rivastigmine, rivastigmine patch 5 cm2, and donepezil was 447 6 296, 375 6 262, and 481 6 287 days, respectively (Supplementary Table 1). The persistence duration for donepezil was statistically significant compared with oral rivastigmine (P 5 .001). Overall, 72.06% of patients receiving 1.5 mg oral rivastigmine and 34.69% of patients receiving 3 mg oral rivastigmine at the index date were switched to higher doses (4.5 and 6 mg rivastigmine) to achieve a stable dose. Majority of patients achieved optimal treatment outcome at 3 mg (64.02%) or 4.5 mg (91.22%) oral rivastigmine. In the donepezil group, 29.02% of patients receiving 5 mg donepezil at the index date were switched to 10 mg donepezil to achieve a stable dose. Overall, 70.98% and 98.68% of patients were stable at 5 and 10 mg/day donepezil, respectively (Table 2).
3
date had a persistence duration of 584 6 263 and 458 6 282 days, respectively (Fig. 2). 3.2. Persistence duration of patients who switched dose during titration to stable dose Patients in this study were found to initiate treatment with ChEIs at different doses. In this subgroup analysis, the persistence duration of patients receiving oral rivastigmine and donepezil was observed to be dose dependent. Patients who initially received 1.5 mg oral rivastigmine required a shorter time (72 6 83 days) to reach a stable dose compared with those who initiated treatment at a higher dose of rivastigmine (3 mg, 126 6 152 days [P , .0001] and 4.5 mg, 124 6 154 days [P 5 .013]). The average time to reach a maintenance dose of 3, 4.5, and 6 mg rivastigmine after initial treatment with 1.5 mg rivastigmine was 62 6 90, 76 6 76, and 149 6 89 days, respectively. For patients treated with donepezil, the persistence duration until dose adjustment was 174 6 153 and 184 6 204 days for donepezil 5 and 10 mg, respectively. 3.3. Persistence duration from stable dose to treatment discontinuation or end of available data Patients at a stable dose of 4.5 or 6 mg rivastigmine were observed to persist longer than those at a lower dose of rivastigmine and donepezil (Fig. 3).
3.1. Persistence duration from initiation to discontinuation of the medication or end of available data
3.4. PDC and MPR
Unlike donepezil, the persistence duration of oral rivastigmine was longer at higher doses. Patients treated with 6 mg oral rivastigmine and 10 mg donepezil at the index
Patients receiving oral rivastigmine had the highest PDC and MPR and had a significantly higher PDC compared with those receiving rivastigmine patch (P , .001). Patients
2010–2012 Diagnosis of Alzheimer’s disease (AD), mild cognitive impairment, Parkinson’s disease dementia, dementia with Lewy bodies (N=385097) Inclusion criteria: Ever used rivastigmine or donepezil between 2010–2012 (n=32799)
First-time use of rivastigmine or donepezil during Jan 2011–Dec 2012 (n=10531)
Oral rivastigmine (n=3439)
Exclusion criteria: 1. Prescribed with rivastigmine or donepezil without AD diagnosis (n=7267) 2. Ever used rivastigmine or donepezil during 2010 (n=14473) 3. Ever used memantine (n=53) 4. Ever used galantamine (n=151) 5. Diagnosis of vascular dementia within 3 months before index date (n=324)
Rivastigmine patch (n=868)
Oral donepezil (n=6224)
Fig. 1. Patient disposition.
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Table 1 Baseline characteristics Characteristics N Age, years Gender Female Male
Rivastigmine patch (5 cm2)
Oral rivastigmine
Donepezil
868 77.73 (7.48)
3439 77.14 (7.93)
6224 77.79 (7.95)
2048 (59.55) 1391 (40.45)
3894 (62.56) 2330 (37.44)
515 (59.33) 353 (40.67)
NOTE. Values are presented as mean (standard deviation) unless otherwise stated.
receiving donepezil had a significantly higher PDC compared with those receiving rivastigmine patch (P 5 .001), whereas no significant difference was observed between the oral rivastigmine and donepezil groups (P 5 .195). A similar pattern was observed for MPR in the oral rivastigmine group compared with the rivastigmine patch group (P , .001), in the rivastigmine patch group compared with the donepezil group (P 5 .001), and in the oral rivastigmine group compared with the donepezil group (P 5 .079) (Table 3).
4. Discussion The results of this study suggest that patients with dementia receiving a stable dose of 4.5 or 6 mg rivastigmine continued treatment for more days and were more likely to remain on therapy for a longer duration. Majority of patients receiving stable dose achieved optimal treatment outcome at higher doses of rivastigmine and donepezil. On the other hand, while similar pattern was reported when the persistence duration of oral rivastigmine was observed from the index date until discontinuation of the medication or end of available data, patients receiving donepezil 5 mg reported longer persistence duration than those receiving donepezil 10 mg. This indicates that patients receiving higher doses of rivastigmine may achieve better treatment outcomes with regard to slowing cognitive decline. Although, the reasons for discontinuation were not recorded, it may include the following: lack of efficacy;
lack of safety and tolerability e.g., patients experiencing more cholinergic side effects such as nausea and vomiting; and cognitive decline of 2 points on the Mini–Mental State Examination (MMSE) scale, which may pose a challenge in reapplication of the drugs. Per the reimbursement criteria in Taiwan, patients have to be reevaluated for treatment response every year and are required to stop the treatment following a cognitive decline of 2 points on the MMSE scale or 1 point on the clinical dementia rating scale compared with the previous treatment year. In Taiwan, the 5-cm2 rivastigmine patch was reimbursed since March 2011, whereas the 10- and 15-cm2 rivastigmine patches were not available in the timeframe during which this study was conducted. Considering that titration is critical in optimizing the disease treatment outcome, the study simply presents the analysis results of the 5-cm2 rivastigmine patch but does not compare it with oral rivastigmine and donepezil, for which the titration doses were available. The results from an observational administrative health database study (N 5 5622) in patients aged 65 years who received a new prescription of an oral ChEI between February and May 2006 showed that the 1-year persistence of treatment with donepezil and rivastigmine was 45.9% (95% confidence interval [CI]: 43%–48.8%) and 40.2% (95% CI: 37.3%–43.1%), respectively. The average periods of rivastigmine and donepezil therapies were 272 and 287 days, respectively [9]. Results from a 12-month retrospective analysis of longitudinal research databases of patients (aged 65 years) with newly diagnosed AD and a filled prescription for rivastigmine or donepezil between January 1, 1999 and December 31, 2002 showed that the persistence durations of rivastigmine and donepezil were 234 days (median: 312) and 235 days (median: 315), respectively [12]. An analysis of the administrative health-care database in Quebec, Canada (N 5 28,405) showed that in patients aged 50 years and new users of oral ChEIs from 1997 to 2006, treatment adherence to donepezil (n 5 19,031) and rivastigmine (n 5 3791) was 94.5% (95% CI: 94.1%–95.0%) and 99.2% (95% CI: 97.8%–100.6%), respectively [13]. Clinical trials and open-label extension studies have reported the long-term treatment benefits of ChEIs in patients
Table 2 Dose titration up to stable dose
Dose at index date (mg) Oral rivastigmine 1.5 3 4.5 6 Donepezil 5 10
No. of patients who switched dose/total no. of patients
Dose at stable dose period (oral rivastigmine) (mg)
Donepezil (mg)
1.5
3
4.5
6
5
10
1736/2409 249/692 28/319 0/15
673 (27.94%) 9 (1.3%) 6 (1.88%) 0 (0%)
716 (29.72%) 443 (64.02%) 6 (1.88%) 0 (0%)
980 (40.68%) 192 (27.75%) 291 (91.22%) 0 (0%)
40 (1.66%) 48 (6.94%) 16 (5.02%) 15 (100%)
-
-
1146/3949 30/2275
-
-
-
-
2803 (70.98%) 30 (1.32%)
1146 (29.02%) 2245 (98.68%)
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C.-J. Chang et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions - (2018) 1-6 Table 3 Comparison of PDC and MPR for AD medications
900 800
Average no. of days
600
PDC MPR
500 400
Q5
Oral rivastigmine
Rivastigmine patch 5 cm2
Donepezil
0.9227 6 0.1429 0.9404 6 0.1385
0.8956 6 0.1692 0.9074 6 0.1687
0.9166 6 0.1467 0.9332 6 0.1438
700
Abbreviations: AD, Alzheimer’s disease; MPR, medication possession ratio; PDC, proportion of days covered; SD, standard deviation. NOTE. All values are mean 6 SD unless specified. NOTE. n 5 9468; 1063 samples are excluded from the analysis due to only one record of therapy initiation but without following medication.
300 200 100 0 Rivastigmine 1.5 mg (n=2173)
Rivastigmine 3 mg (n=592)
Rivastigmine 4.5 mg (n=288)
Rivastigmine 6 mg (n=15)
Donepezil 5 mg (n=3626)
Donepezil 10 mg (n=1993)
Fig. 2. Persistence duration from initiation to discontinuation of the medication or end of available data (grouped by initiation dose).
with AD [14–17]. Doody et al. reported a rapid decline in cognition and function when a 6-week placebo washout was given to patients who had been receiving donepezil [18]. A study examining the effect of persistent treatment with anti-dementia drugs reported less decline on multiple cognitive, functional, and global outcome measures with persistent drug treatment [19]. Maintaining ChEI therapy may provide a greater chance of slowing/delaying symptomatic disease progression and delaying nursing home placement [20,21]. Therefore, as long as ChEI treatment is tolerated and patients benefit, the treatment gap should be monitored carefully [22,23]. The National Health Insurance reimbursement criteria for mild-to-moderate dementia include an MMSE score of 10–26 or a clinical dementia rating score of 1–2. Per the reimbursement criteria in Taiwan, patients can switch to other ChEIs within 3 months as a result of any side effect(s), and there is no need to resubmit for approval. However, it is imperative to record the reasons for switching medication to avoid frequent switching. Patients have to be reevaluated for treatment response every year, and the treatment should be stopped if MMSE scores decrease by 2 points or clinical dementia rating scores by 1 point compared with the previous treatment year. 800 700
Average no. of days
512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578
5
600 500 400 300 200 100
The major strength of this study is the use of nationwide population-based data which provides with a large sample size. However, there are certain limitations of this study. First, the reasons of discontinuation were not recorded which is important to understand the differences in the duration of the use of medications. In addition, the sample size of high dose of rivastigmine (6 mg) group is small; hence, generalizing the findings should be done with caution. Further research is needed to ascertain the findings from this study. 5. Conclusion Although the difference in persistence and adherence to treatment between patients on a stable dose of 4.5 or 6 mg rivastigmine twice daily and donepezil was statistically significant, the clinical significance is yet to be determined. Results from this study add onto the existing evidence of dose-dependent efficacy, that is, patients receiving rivastigmine should be titrated to the maximum possible dose before switching to another drug is considered. Acknowledgments The study was funded by Novartis (Taiwan) Co., Ltd. This study was based in part on data from the National Health Insurance Research Database provided by the Bureau of National Health Insurance, Department of Health, and managed by the HWDC. The interpretation and conclusions contained herein do not represent those of the National Health Insurance Administration, Department of Health, or National Health Research Institutes. The authors wish to thank Preetinder Kaur from Novartis Healthcare Pvt. Ltd., Hyderabad, India, for providing medical writing support for development of the manuscript. All authors reviewed the draft and provided critical comments and approved the final submitted version. Disclosures: Winco Hsu was employee of Novartis (Taiwan) Co., Ltd. at the time of conduct of the study.
0 Rivastigmine 1.5 mg (n=452)
Rivastigmine 3 mg (n=1065)
Rivastigmine 4.5 mg (n=1432)
Rivastigmine 6 mg (n=119)
Donepezil 5 mg (n=2510)
Donepezil 10 mg (n=3109)
Fig. 3. Persistence duration from stable dose to discontinuation of treatment or end of available data (grouped by prescription dose at stable stage).
Supplementary data Supplementary data related to this article can be found at https://doi.org/10.1016/j.trci.2018.06.013.
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RESEARCH IN CONTEXT
1. Systematic review: Based on the review of literature available on PubMed on adherence and persistence to cholinesterase inhibitors in patients with dementia, and to the best of our knowledge, this is the first study on adherence and persistence to rivastigmine in an Asian population. 2. Interpretation: We suggest that patients receiving rivastigmine should be titrated to the highest possible dose before switching to any other cholinesterase inhibitor or memantine; switching should only be encouraged when treatment response is considered insufficient at the maximum tolerated dose. 3. Future directions: Use of currently available cholinesterase inhibitors needs optimization until new therapies are introduced. Findings of this study will add on to the existing knowledge of dementia management, and the data can be extrapolated to other Asian countries.
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[8] Maxwell CJ, Stock K, Seitz D, Herrmann N. Persistence and adherence with dementia pharmacotherapy: relevance of patient, provider, and system factors. Can J Psychiatry 2014;59:624–31. [9] Herrmann N, Binder C, Dalziel W, Smyth S, Camacho F. Persistence with cholinesterase inhibitor therapy for dementia: an observational administrative health database study. Drugs Aging 2009; 26:403–7. [10] Massoud F. Persistence with cholinesterase inhibitor treatment in Alzheimer’s disease. Can J Neurol Sci 2013;40:623–4. [11] National Health Insurance Research Database. Available at: http:// nhird.nhri.org.tw/en/. Accessed January, 2017. [12] Suh C, Thomas SK, Valiyeva E, Arcona S, Vo L. Drug persistency of two cholinesterase inhibitors: rivastigmine versus donepezil in elderly patients with Alzheimer’s disease. Drugs Aging 2005; 22:695–707. [13] Blais L, Kettani FZ, Perreault S, Leroux JC, Forget A, Kergoat MJ. Adherence to cholinesterase inhibitors in patients with Alzheimer’s disease. J Am Geriatr Soc 2009;57:366–8. [14] De Rui M, Coin A, Granziera S, Girardi A, Catanzaro S, Manzato E, et al. Short- and long-term efficacy of cholinesterase inhibitors in older adults with Alzheimer’s disease and mixed dementia: results of a 21-month observational study. Panminerva Med 2014. Q3 [15] Seltzer B. Is long-term treatment of Alzheimer’s disease with cholinesterase inhibitor therapy justified? Drugs Aging 2007;24:881–90. [16] Farlow MR, Lilly ML, ENA713 B352 Study Group. Rivastigmine: an open-label, observational study of safety and effectiveness in treating patients with Alzheimer’s disease for up to 5 years. BMC Geriatr 2005; 5:3. [17] Courtney C, Farrell D, Gray R, Hills R, Lynch L, Sellwood E, et al., Bentham; AD2000 Collaborative Group. Long-term donepezil treatment in 565 patients with Alzheimer’s disease (AD2000): randomised double-blind trial. Lancet 2004;363:2105–15. [18] Doody RS, Geldmacher DS, Gordon B, Perdomo CA, Pratt RD. Openlabel, multicenter, phase 3 extension study of the safety and efficacy of donepezil in patients with Alzheimer disease. Arch Neurol 2001; 58:427–33. [19] Rountree SD, Chan W, Pavlik VN, Darby EJ, Siddiqui S, Doody RS. Persistent treatment with cholinesterase inhibitors and/or memantine slows clinical progression of Alzheimer disease. Alzheimers Res Ther 2009;1:7. [20] Lopez OL, Becker JT, Wahed AS, Saxton J, Sweet RA, Wolk DA, et al. Long-term effects of the concomitant use of memantine with cholinesterase inhibition in Alzheimer disease. J Neurol Neurosurg Psychiatry 2009;80:600–7. [21] Gillette-Guyonnet S, Andrieu S, Cortes F, Nourhashemi F, Cantet C, Ousset PJ, et al. Outcome of Alzheimer’s disease: potential impact of cholinesterase inhibitors. J Gerontol A Biol Sci 2006;61:516–20. [22] Johannsen P. Long-term cholinesterase inhibitor treatment of Alzheimer’s disease. CNS Drugs 2004;18:757–68. [23] National Institute for Health and Clinical Excellence: donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer’s disease (review of NICE technology appraisal guidance 111). Available at: https://www.nice.org.uk/guidance/ta217/documents/alzheimers-diseasedonepezil-galantamine-rivastigmine-and-memantine-review-finalappraisal-determination3, 2011. Accessed January, 2017. Q4
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Persistence and adherence to rivastigmine in patients with dementia: Results from a noninterventional, retrospective study using the National Health Insurance research database of Taiwan Chee-Jen Chang , Tse Chih Chou , Chiung-Chih Chang , Ta-Fu Chen , Chaur-Jong Hu , Jong-Ling Fuh , Wenfu Wang , Chiung-Mei Chen , Winco Hsu , Chin-Chang Huang *
Conflict of interest: The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.
*Corresponding author. Tel.: 1886-3-3281200 # 8420, 8418; Fax: 18863-3287226. E-mail address: [email protected]
https://doi.org/10.1016/j.trci.2018.06.013 2352-8737/Ó 2018 Published by Elsevier Inc. on behalf of the Alzheimer’s Association. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). FLA 5.5.0 DTD TRCI176_proof 13 July 2018 7:33 pm ce
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1. Introduction Dementia is a major health concern worldwide, and dementia of Alzheimer’s type accounts for an estimated 60%–80% of the cases. The age-adjusted prevalence of all-cause dementia in a nationwide survey conducted in Taiwan was 8.04% [1]. In Taiwan, the projected number of people with dementia (aged 65 years) is 0.15 million, and this number is expected to reach 0.21 million by 2020 [2]. Current treatment options for Alzheimer’s disease (AD) available in Taiwan include cholinesterase inhibitors (ChEIs), such as rivastigmine, donepezil, and galantamine, or the N-methyl-D-aspartate receptor antagonist, memantine [3]. Poor adherence and persistence to medication is a major challenge in treating patients, particularly those with chronic diseases [4]. Adherence and persistence to ChEIs is critical in patients with dementia to stabilize or improve cognitive function [5,6]. Adherence to ChEI therapy can also improve activities of daily living and may lessen behavioral disturbances that accompany AD [7]. However, the cognitive decline associated with disease progression leads to suboptimal treatment compliance in patients with AD. Older patients are particularly susceptible to treatment noncompliance [5,7,8]. Persistence to ChEI therapy has been reported to be affected by several other factors such as choice of drug, polypharmacy, increased risk of drug interactions, ease of administration, and reimbursement status of the drug [8–10]. Hence, this study aimed to assess adherence and persistence to rivastigmine versus donepezil using data from the Taiwan National Health Insurance Research Database. 2. Methods 2.1. Data source In March 1995, a government-administered, insurancebased, national health-care system, that is, a single-payer National Health Insurance program, was launched in Taiwan. The database of this program contains registration files and original claims data for reimbursement. Large computerized de-identified data were derived from this system by the National Health Insurance Administration, Taiwan, and Ministry of Health and Welfare, Taiwan, and maintained by the Health and Welfare Data Center (HWDC), Taiwan. These data are provided to scientists in Taiwan for research purposes. The National Health Insurance Research Database collects and releases data annually [11]. The index date for the present study was defined as the first prescription of rivastigmine or donepezil. 2.2. Study population The study population comprised patients with data available in the National Health Insurance Research Database from January 1, 2010 to December 31, 2012. Because the
index date was defined as the first prescription of rivastigmine (oral/transdermal patch) or donepezil, patients were required to have been continuously enrolled for a minimum of 1 year before the index date and at least 9 months after the index date. Thus, data were collected for subjects diagnosed with mild cognitive impairment or AD or Parkinson’s disease dementia or dementia with Lewy bodies and prescribed with rivastigmine (oral/transdermal patch) or oral donepezil in 2011 and/or 2012. Patients on any other ChEI or memantine during the preindex period and/or during the study period were excluded from the study. 2.3. Treatment Patients were prescribed 5-cm2 rivastigmine patch, oral rivastigmine twice daily, or donepezil once daily. 2.4. Study design This was an observational, retrospective database study of a population-based cohort to assess the adherence and persistence of rivastigmine versus donepezil. Adherence to treatment was measured as proportion of days covered (PDC) and medication possession ratio (MPR). For each index treatment, PDC and MPR were presented as a point estimate and as intervals of 20% (0%–19%, 20%–39%, 40%–59%, 60%–79%, and 80%) and were provided for all patients and in those with at least two claims for the index therapy. Patients with PDC and MPR .80% were considered adherent, and those with PDC and MPR ,80% as nonadherent. The methodology for calculating medication adherence is described in Supplementary Figure 1. Persistence to index therapy was calculated based on treatment practice patterns, that is, based on the time (in consecutive days) from index therapy initiation until discontinuation, medication switch, or end of available data, whichever occurred first. 2.5. Statistical analysis Descriptive statistics, such as mean, median, standard deviation (SD), and percentiles, were summarized for continuous variables. Frequencies and proportions were derived for ordinal and nominal variables. Groups were compared for baseline characteristics and outcome measures using both parametric and nonparametric approaches such as the 2-sample t test and analysis of variance test for continuous variables and the chi-squared test and Fisher’s exact test for categorical variables. In particular, analysis of variance was used for comparing the differences in PDC and MPR among oral rivastigmine, oral donepezil, and rivastigmine patch. SAS, version 9.4, was used for data management and statistical analysis; all tests were two-sided, and a P value , .05 for a type-I error was considered statistically significant.
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3. Results A total of 385,097 patients were registered in the database between January 2010 and December 2012; 10,531 patients were first-time users of rivastigmine or donepezil. Of them, 3439 were treated with oral rivastigmine (mean age 6 SD: 77.14 6 7.93 years), 868 with 5-cm2 rivastigmine patch (mean age 6 SD: 77.73 6 7.48 years), and 6224 with donepezil (mean age 6 SD: 77.79 6 7.95 years) (Fig. 1). Baseline characteristics of the study population are presented in Table 1. Overall, the persistence duration in patients treated with oral rivastigmine, rivastigmine patch 5 cm2, and donepezil was 447 6 296, 375 6 262, and 481 6 287 days, respectively (Supplementary Table 1). The persistence duration for donepezil was statistically significant compared with oral rivastigmine (P 5 .001). Overall, 72.06% of patients receiving 1.5 mg oral rivastigmine and 34.69% of patients receiving 3 mg oral rivastigmine at the index date were switched to higher doses (4.5 and 6 mg rivastigmine) to achieve a stable dose. Majority of patients achieved optimal treatment outcome at 3 mg (64.02%) or 4.5 mg (91.22%) oral rivastigmine. In the donepezil group, 29.02% of patients receiving 5 mg donepezil at the index date were switched to 10 mg donepezil to achieve a stable dose. Overall, 70.98% and 98.68% of patients were stable at 5 and 10 mg/day donepezil, respectively (Table 2).
3
date had a persistence duration of 584 6 263 and 458 6 282 days, respectively (Fig. 2). 3.2. Persistence duration of patients who switched dose during titration to stable dose Patients in this study were found to initiate treatment with ChEIs at different doses. In this subgroup analysis, the persistence duration of patients receiving oral rivastigmine and donepezil was observed to be dose dependent. Patients who initially received 1.5 mg oral rivastigmine required a shorter time (72 6 83 days) to reach a stable dose compared with those who initiated treatment at a higher dose of rivastigmine (3 mg, 126 6 152 days [P , .0001] and 4.5 mg, 124 6 154 days [P 5 .013]). The average time to reach a maintenance dose of 3, 4.5, and 6 mg rivastigmine after initial treatment with 1.5 mg rivastigmine was 62 6 90, 76 6 76, and 149 6 89 days, respectively. For patients treated with donepezil, the persistence duration until dose adjustment was 174 6 153 and 184 6 204 days for donepezil 5 and 10 mg, respectively. 3.3. Persistence duration from stable dose to treatment discontinuation or end of available data Patients at a stable dose of 4.5 or 6 mg rivastigmine were observed to persist longer than those at a lower dose of rivastigmine and donepezil (Fig. 3).
3.1. Persistence duration from initiation to discontinuation of the medication or end of available data
3.4. PDC and MPR
Unlike donepezil, the persistence duration of oral rivastigmine was longer at higher doses. Patients treated with 6 mg oral rivastigmine and 10 mg donepezil at the index
Patients receiving oral rivastigmine had the highest PDC and MPR and had a significantly higher PDC compared with those receiving rivastigmine patch (P , .001). Patients
2010–2012 Diagnosis of Alzheimer’s disease (AD), mild cognitive impairment, Parkinson’s disease dementia, dementia with Lewy bodies (N=385097) Inclusion criteria: Ever used rivastigmine or donepezil between 2010–2012 (n=32799)
First-time use of rivastigmine or donepezil during Jan 2011–Dec 2012 (n=10531)
Oral rivastigmine (n=3439)
Exclusion criteria: 1. Prescribed with rivastigmine or donepezil without AD diagnosis (n=7267) 2. Ever used rivastigmine or donepezil during 2010 (n=14473) 3. Ever used memantine (n=53) 4. Ever used galantamine (n=151) 5. Diagnosis of vascular dementia within 3 months before index date (n=324)
Rivastigmine patch (n=868)
Oral donepezil (n=6224)
Fig. 1. Patient disposition.
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Table 1 Baseline characteristics Characteristics N Age, years Gender Female Male
Rivastigmine patch (5 cm2)
Oral rivastigmine
Donepezil
868 77.73 (7.48)
3439 77.14 (7.93)
6224 77.79 (7.95)
2048 (59.55) 1391 (40.45)
3894 (62.56) 2330 (37.44)
515 (59.33) 353 (40.67)
NOTE. Values are presented as mean (standard deviation) unless otherwise stated.
receiving donepezil had a significantly higher PDC compared with those receiving rivastigmine patch (P 5 .001), whereas no significant difference was observed between the oral rivastigmine and donepezil groups (P 5 .195). A similar pattern was observed for MPR in the oral rivastigmine group compared with the rivastigmine patch group (P , .001), in the rivastigmine patch group compared with the donepezil group (P 5 .001), and in the oral rivastigmine group compared with the donepezil group (P 5 .079) (Table 3).
4. Discussion The results of this study suggest that patients with dementia receiving a stable dose of 4.5 or 6 mg rivastigmine continued treatment for more days and were more likely to remain on therapy for a longer duration. Majority of patients receiving stable dose achieved optimal treatment outcome at higher doses of rivastigmine and donepezil. On the other hand, while similar pattern was reported when the persistence duration of oral rivastigmine was observed from the index date until discontinuation of the medication or end of available data, patients receiving donepezil 5 mg reported longer persistence duration than those receiving donepezil 10 mg. This indicates that patients receiving higher doses of rivastigmine may achieve better treatment outcomes with regard to slowing cognitive decline. Although, the reasons for discontinuation were not recorded, it may include the following: lack of efficacy;
lack of safety and tolerability e.g., patients experiencing more cholinergic side effects such as nausea and vomiting; and cognitive decline of 2 points on the Mini–Mental State Examination (MMSE) scale, which may pose a challenge in reapplication of the drugs. Per the reimbursement criteria in Taiwan, patients have to be reevaluated for treatment response every year and are required to stop the treatment following a cognitive decline of 2 points on the MMSE scale or 1 point on the clinical dementia rating scale compared with the previous treatment year. In Taiwan, the 5-cm2 rivastigmine patch was reimbursed since March 2011, whereas the 10- and 15-cm2 rivastigmine patches were not available in the timeframe during which this study was conducted. Considering that titration is critical in optimizing the disease treatment outcome, the study simply presents the analysis results of the 5-cm2 rivastigmine patch but does not compare it with oral rivastigmine and donepezil, for which the titration doses were available. The results from an observational administrative health database study (N 5 5622) in patients aged 65 years who received a new prescription of an oral ChEI between February and May 2006 showed that the 1-year persistence of treatment with donepezil and rivastigmine was 45.9% (95% confidence interval [CI]: 43%–48.8%) and 40.2% (95% CI: 37.3%–43.1%), respectively. The average periods of rivastigmine and donepezil therapies were 272 and 287 days, respectively [9]. Results from a 12-month retrospective analysis of longitudinal research databases of patients (aged 65 years) with newly diagnosed AD and a filled prescription for rivastigmine or donepezil between January 1, 1999 and December 31, 2002 showed that the persistence durations of rivastigmine and donepezil were 234 days (median: 312) and 235 days (median: 315), respectively [12]. An analysis of the administrative health-care database in Quebec, Canada (N 5 28,405) showed that in patients aged 50 years and new users of oral ChEIs from 1997 to 2006, treatment adherence to donepezil (n 5 19,031) and rivastigmine (n 5 3791) was 94.5% (95% CI: 94.1%–95.0%) and 99.2% (95% CI: 97.8%–100.6%), respectively [13]. Clinical trials and open-label extension studies have reported the long-term treatment benefits of ChEIs in patients
Table 2 Dose titration up to stable dose
Dose at index date (mg) Oral rivastigmine 1.5 3 4.5 6 Donepezil 5 10
No. of patients who switched dose/total no. of patients
Dose at stable dose period (oral rivastigmine) (mg)
Donepezil (mg)
1.5
3
4.5
6
5
10
1736/2409 249/692 28/319 0/15
673 (27.94%) 9 (1.3%) 6 (1.88%) 0 (0%)
716 (29.72%) 443 (64.02%) 6 (1.88%) 0 (0%)
980 (40.68%) 192 (27.75%) 291 (91.22%) 0 (0%)
40 (1.66%) 48 (6.94%) 16 (5.02%) 15 (100%)
-
-
1146/3949 30/2275
-
-
-
-
2803 (70.98%) 30 (1.32%)
1146 (29.02%) 2245 (98.68%)
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C.-J. Chang et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions - (2018) 1-6 Table 3 Comparison of PDC and MPR for AD medications
900 800
Average no. of days
600
PDC MPR
500 400
Q5
Oral rivastigmine
Rivastigmine patch 5 cm2
Donepezil
0.9227 6 0.1429 0.9404 6 0.1385
0.8956 6 0.1692 0.9074 6 0.1687
0.9166 6 0.1467 0.9332 6 0.1438
700
Abbreviations: AD, Alzheimer’s disease; MPR, medication possession ratio; PDC, proportion of days covered; SD, standard deviation. NOTE. All values are mean 6 SD unless specified. NOTE. n 5 9468; 1063 samples are excluded from the analysis due to only one record of therapy initiation but without following medication.
300 200 100 0 Rivastigmine 1.5 mg (n=2173)
Rivastigmine 3 mg (n=592)
Rivastigmine 4.5 mg (n=288)
Rivastigmine 6 mg (n=15)
Donepezil 5 mg (n=3626)
Donepezil 10 mg (n=1993)
Fig. 2. Persistence duration from initiation to discontinuation of the medication or end of available data (grouped by initiation dose).
with AD [14–17]. Doody et al. reported a rapid decline in cognition and function when a 6-week placebo washout was given to patients who had been receiving donepezil [18]. A study examining the effect of persistent treatment with anti-dementia drugs reported less decline on multiple cognitive, functional, and global outcome measures with persistent drug treatment [19]. Maintaining ChEI therapy may provide a greater chance of slowing/delaying symptomatic disease progression and delaying nursing home placement [20,21]. Therefore, as long as ChEI treatment is tolerated and patients benefit, the treatment gap should be monitored carefully [22,23]. The National Health Insurance reimbursement criteria for mild-to-moderate dementia include an MMSE score of 10–26 or a clinical dementia rating score of 1–2. Per the reimbursement criteria in Taiwan, patients can switch to other ChEIs within 3 months as a result of any side effect(s), and there is no need to resubmit for approval. However, it is imperative to record the reasons for switching medication to avoid frequent switching. Patients have to be reevaluated for treatment response every year, and the treatment should be stopped if MMSE scores decrease by 2 points or clinical dementia rating scores by 1 point compared with the previous treatment year. 800 700
Average no. of days
512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578
5
600 500 400 300 200 100
The major strength of this study is the use of nationwide population-based data which provides with a large sample size. However, there are certain limitations of this study. First, the reasons of discontinuation were not recorded which is important to understand the differences in the duration of the use of medications. In addition, the sample size of high dose of rivastigmine (6 mg) group is small; hence, generalizing the findings should be done with caution. Further research is needed to ascertain the findings from this study. 5. Conclusion Although the difference in persistence and adherence to treatment between patients on a stable dose of 4.5 or 6 mg rivastigmine twice daily and donepezil was statistically significant, the clinical significance is yet to be determined. Results from this study add onto the existing evidence of dose-dependent efficacy, that is, patients receiving rivastigmine should be titrated to the maximum possible dose before switching to another drug is considered. Acknowledgments The study was funded by Novartis (Taiwan) Co., Ltd. This study was based in part on data from the National Health Insurance Research Database provided by the Bureau of National Health Insurance, Department of Health, and managed by the HWDC. The interpretation and conclusions contained herein do not represent those of the National Health Insurance Administration, Department of Health, or National Health Research Institutes. The authors wish to thank Preetinder Kaur from Novartis Healthcare Pvt. Ltd., Hyderabad, India, for providing medical writing support for development of the manuscript. All authors reviewed the draft and provided critical comments and approved the final submitted version. Disclosures: Winco Hsu was employee of Novartis (Taiwan) Co., Ltd. at the time of conduct of the study.
0 Rivastigmine 1.5 mg (n=452)
Rivastigmine 3 mg (n=1065)
Rivastigmine 4.5 mg (n=1432)
Rivastigmine 6 mg (n=119)
Donepezil 5 mg (n=2510)
Donepezil 10 mg (n=3109)
Fig. 3. Persistence duration from stable dose to discontinuation of treatment or end of available data (grouped by prescription dose at stable stage).
Supplementary data Supplementary data related to this article can be found at https://doi.org/10.1016/j.trci.2018.06.013.
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RESEARCH IN CONTEXT
1. Systematic review: Based on the review of literature available on PubMed on adherence and persistence to cholinesterase inhibitors in patients with dementia, and to the best of our knowledge, this is the first study on adherence and persistence to rivastigmine in an Asian population. 2. Interpretation: We suggest that patients receiving rivastigmine should be titrated to the highest possible dose before switching to any other cholinesterase inhibitor or memantine; switching should only be encouraged when treatment response is considered insufficient at the maximum tolerated dose. 3. Future directions: Use of currently available cholinesterase inhibitors needs optimization until new therapies are introduced. Findings of this study will add on to the existing knowledge of dementia management, and the data can be extrapolated to other Asian countries.
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