1 Pharmacy Outcomes Research Group, Kaiser Permanente California, Oakland.
3 Department of Research & Evaluation, Kaiser Permanente Southern California, Pasadena.
J Manag Care Spec Pharm. 2017 Apr;23(4):503-512. doi: 10.18553/jmcp.2017.23.4.503.
Examining drug exposure is essential to pharmacovigilance, especially for bisphosphonate (BP) therapy.
To examine differences in 4 measures of oral BP exposure: treatment discontinuation, adherence, persistence, and nonpersistence.
Among women aged ≥ 50 years who initiated oral BP therapy during 2002-2007 with at least 3 years of health plan membership follow-up, discontinuation was defined by evidence of no further treatment during the study observation period. Among those with at least 2 filled BP prescriptions during the study period, adherence was calculated for each year of follow-up using the (modified) proportion of days covered (mPDC) metric that allows for stockpiling of prescription/refills overlap ≤ 30 days supply. Persistence was quantified by treatment duration, allowing a gap of up to 60 days between prescription/refill days covered. Nonpersistence was quantified by the periods without drugs outside this allowable gap. Multivariable logistic regression was used to compare age and race groups and the relationships of early adherence (adherence during the first year) with subsequent adherence.
Among 48,390 women initiating oral BP therapy and followed for 3 years, 26.7% discontinued in year 1, and 14.7% of the remaining 35,456 women discontinued in year 2. Discontinuation rates were slightly higher (29.4%, P < 0.001) for women aged ≥ 75 years and somewhat lower (21.1%, P < 0.001) for Asian women. During the first year, 60.4% of the women achieved an mPDC of ≥ 75%, with demographic differences in adherence similar to that seen for treatment discontinuation. Over the 3 years, the median mPDC levels for BP therapy were 86%, 84%, and 85% in years 1, 2, and 3, respectively, for those receiving treatment. Cumulative persistence was 2.3 years (median, IQR = 1.0-3.0) overall and slightly greater for Asian versus white women and lower for older women. There were 18,174 (42.9%) women with at least 1 period of nonpersistence during 3 years follow-up in excess of the 60-day allowable gap between prescription/refills (median cumulative nonpersistence = 0.65, IQR = 0.30-1.25 years). Women with mPDC ≥ 75% during the first year had a 12-fold and 6-fold increased odds of mPDC ≥ 75% during year 2 and year 3, respectively.
BP discontinuation rates are highest for women during the first year. Among those continuing treatment in subsequent years, adherence rates were relatively stable. Persistence and adherence varied slightly by age and was somewhat higher in Asians, contributing to differences in cumulative BP exposure. We also found evidence that optimal adherence in the first year was highly predictive of optimal adherence in the subsequent 1-2 years. Hence, subgroups of patients receiving oral BP drugs may require different levels of support and monitoring to maximize treatment benefit, especially based on early patterns of use.
This study was supported by grants from the Kaiser Permanente Northern California Community Benefit Program and the National Institutes of Health, 1R01AG047230-01A1. The opinions expressed in this publication are solely the responsibility of the authors and do not represent the official views of Kaiser Permanente or the National Institutes of Health. Hui, Yi, and Chandra have received past research funding from Amgen not related to the current study. Adams has received research funding from Amgen, Merck, and Otsuka not related to the current study. Niu has received research funding from Bristol-Myers Squibb not related to the current study. Ettinger has received past legal fees in litigation involving Fosamax. Lo has received past research funding from Amgen and current research funding from Sanofi not related to the current study. The data from this study were presented at the Academy of Managed Care Pharmacy Annual Meeting; April 19-22, 2016; San Francisco, California. Study concept and design were contributed primarily by Hui and Lo, along with Adams, Niu, Yi, and Ettinger. Hui took the lead in data collection, along with Chandra, and data interpretation was performed by Niu, Yi, and Lo, along with the other authors. The manuscript was written by Hui, Adams, and Lo, along with Niu, Yi, and Ettinger, and revised by Ettinger, Hui, Lo, and Niu, along with the other authors.
检查药物暴露情况对于药物警戒至关重要，尤其是对于双膦酸盐 (BP) 治疗。
研究 4 种口服 BP 暴露指标的差异：治疗中断、依从性、持续性和非持续性。
在 2002-2007 年期间，年龄≥50 岁的女性开始接受口服 BP 治疗，且至少有 3 年的健康计划成员随访，通过研究观察期内无进一步治疗的证据来定义中断。对于在研究期间至少有 2 次 BP 处方的患者，根据 (改良) 比例天数覆盖度 (mPDC) 指标计算每个随访年的依从性，该指标允许处方/续方重叠不超过 30 天供应量。通过治疗持续时间来量化持续性，允许处方/续方覆盖度的时间间隔不超过 60 天。通过允许在这个可接受的间隔之外没有药物的时间段来量化非持续性。采用多变量逻辑回归比较年龄和种族组，并比较早期依从性（第一年的依从性）与随后的依从性之间的关系。
在 48390 名开始接受口服 BP 治疗并随访 3 年的女性中，有 26.7%的患者在第 1 年中断治疗，而在其余 35456 名患者中，有 14.7%的患者在第 2 年中断治疗。年龄≥75 岁的女性中断率略高（29.4%，P<0.001），而亚裔女性的中断率略低（21.1%，P<0.001）。在第一年，60.4%的女性达到了 mPDC≥75%，与治疗中断相似，在依从性方面存在人口统计学差异。在 3 年的随访中，接受治疗的患者的 mPDC 水平中位数分别为第 1 年 86%、第 2 年 84%和第 3 年 85%。总体累积持续性为 2.3 年（中位数，IQR=1.0-3.0），亚裔女性的持续性略高，而老年女性的持续性略低。在 3 年的随访中有 18174 名（42.9%）女性出现超过处方/续方 60 天允许间隔的非持续性期，超过 60 天（中位数累积非持续性=0.65，IQR=0.30-1.25 年）。在第一年 mPDC≥75%的女性中，mPDC 在第二年和第三年分别达到≥75%的可能性是 mPDC<75%的女性的 12 倍和 6 倍。
女性在第一年中断治疗的可能性最高。在随后几年继续治疗的患者中，依从性相对稳定。持续性和依从性在年龄上略有差异，且在亚裔中略高，这导致了累积 BP 暴露的差异。我们还发现，第一年的最佳依从性高度预测了后续 1-2 年的最佳依从性。因此，接受口服 BP 药物的患者亚组可能需要不同程度的支持和监测，以最大限度地提高治疗效果，特别是基于早期的使用模式。
本研究得到 Kaiser Permanente Northern California 社区福利计划和美国国立卫生研究院的资助，1R01AG047230-01A1。本出版物中表达的观点仅为作者的责任，并不代表 Kaiser Permanente 或美国国立卫生研究院的官方观点。Hui、Yi 和 Chandra 曾因与当前研究无关的 Amgen 获得过研究资金。Adams 曾因与当前研究无关的 Amgen、Merck 和 Otsuka 获得过研究资金。Niu 曾因与当前研究无关的 Bristol-Myers Squibb 获得过研究资金。Ettinger 曾因与 Fosamax 有关的法律诉讼而获得过法律费用。Lo 曾因与当前研究无关的 Amgen 和 Sanofi 获得过研究资金。本研究的数据在 2016 年 4 月 19-22 日举行的美国管理式医疗药房协会年会上进行了介绍。研究的概念和设计主要由 Hui 和 Lo 以及 Adams、Niu、Yi 和 Ettinger 提出。Hui 与 Chandra 一起主导了数据收集，数据解释由 Niu、Yi 和 Lo 以及其他作者共同完成。手稿由 Hui、Adams 和 Lo 以及 Niu、Yi 和 Ettinger 共同撰写，并由 Ettinger、Hui、Lo 和 Niu 以及其他作者共同修订。
