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Originally published as JCO Early Release 10.1200/JCO.2007.11.5451 on January 7 2008 © 2008 American Society of Clinical Oncology. Adherence to Initial Adjuvant Anastrozole Therapy Among Women With Early-Stage Breast Cancer
From the Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; and AstraZeneca Pharmaceuticals, Wilmington, DE Corresponding author: Ann H. Partridge, MD, MPH, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; e-mail: ahpartridge{at}partners.org
Purpose Previous research evaluating adherence to tamoxifen therapy among women with early-stage breast cancer has revealed adherence estimates ranging from 25% to 96%. No previous studies have focused on adherence to adjuvant aromatase inhibitors. Methods We used longitudinal claims data from three large commercial health programs to estimate adherence with anastrozole therapy among women with early-stage breast cancer. Adherence was defined as the proportion of days that patients had medication available over the observation period (ie, days covered); women with fewer than 80% of days covered were defined as nonadherent. Results More than 12,000 women in the databases were found to have new anastrozole prescription claims during the period of study: 1,498 women were classified as having early-stage disease in one commercial health program (Plan A) data set, 1,899 women in another program (Plan B) data set, and 8,994 women in MarketScan, a commercial data set made up of several health programs. Mean adherence over the first 12 months of therapy ranged from 82% to 88% in the three data sets. Between 19% and 28% of women had fewer than 80% of days covered. For women with 36 months of continuous eligibility, the mean adherence decreased each year, ranging from 78% to 86% in year 1 to 62% to 79% in year 3 within the three data sets. Conclusion A substantial proportion of women with early-stage breast cancer may be suboptimally adherent to adjuvant anastrozole therapy. Future research should focus on the identification of patients at risk for nonadherence with oral hormonal therapy for breast cancer and the development of interventions to improve adherence.
Adherence has been increasingly recognized as an important problem in medical care, particularly for chronic oral medical therapies.1 Across diseases, adherence has been cited as the single most important modifiable factor that compromises treatment outcomes.2 There have been relatively few studies focusing on adherence to oral antineoplastic agents, particularly those examining patients outside of a clinical trial. Limited available evidence suggests that patient adherence to oral antineoplastic agents is quite variable, with reported adherence rates ranging from 20% to 100%.3 Among women with early-stage breast cancer, previous studies evaluating adherence to adjuvant tamoxifen therapy using varying methodology have revealed adherence estimates ranging from 25% to 96%.3-8 In 2001, the initial results of the Anastrozole, Tamoxifen Alone or in Combination trial revealed a statistically significant improvement in disease-free survival for postmenopausal women taking initial anastrozole compared with initial tamoxifen as adjuvant therapy for hormone receptor-positive early breast cancer.9 These findings lead to the subsequent United States Food and Drug Administration approval of anastrozole as adjuvant therapy for postmenopausal women with hormone receptor-positive early breast cancer, and widespread adoption of the practice of prescribing initial anastrozole therapy for many women with early breast cancer. Subsequent large trials have confirmed the role of adjuvant aromatase inhibitors in the management of postmenopausal women with hormone receptor-positive early-stage breast cancer.10-12 It is unclear whether similar patterns of nonadherence found with tamoxifen adjuvant therapy would be seen in women prescribed aromatase inhibitor therapy for prevention of disease recurrence. We sought to evaluate adherence to adjuvant endocrine therapy among women who were prescribed anastrozole as initial hormonal therapy for the treatment of early-stage breast cancer.
Setting We used longitudinal pharmacy, procedure, and medical claims data from three large national de-identified patient level databases to estimate adherence to initial adjuvant anastrozole therapy among women with early-breast cancer. Data from "Plan A" and "Plan B," two large commercial health plans that did not want to be identified in this report, as well as a nationally representative employer-based claims database (MarketScan), were used for this study. MarketScan includes 77 contributing employers and 12 contributing health plans, with 126 unique carriers, and eight Medicaid states. Because it represents employer-based claims throughout the country, MarketScan patient data overlaps to some degree with patient data from the other two health plans. We used all three data sets for comparative purposes, aiming to improve the validity and generalizability of our findings. Each data set captures retail pharmacy and mail order prescription transactions.
Study Participants
Definitions Persistency was defined as the percentage of patients continuing to fill prescriptions over time. Plan A study participants with 12-month MPRs of less than 80% were analyzed for assessment of complete therapy cessation during the first year and analysis of the average gap between consecutive refills. Study participants who had evidence of switching to another adjuvant endocrine therapy in the absence of disease progression were considered as adherent and persistent as long as they continued to fill prescriptions for endocrine therapy. Filled prescriptions through mail-order pharmacy were treated as 3 consecutive months of filled prescriptions. Institutional review board approval was not required for this research based on the guidelines provided by the United States Department of Health and Human Resources Office for Human Research Protections.21
Figure 1 depicts the women initiating endocrine therapy with anastrozole during the study period in the three data sets. When the staging algorithm was applied within each data set, the majority of patients initiating anastrozole therapy during the years under study (81%, or n = 1,948 women) were classified as having early-stage disease, 18% were classified as having indeterminate-stage disease, and 1% were classified as having late-stage disease in Plan A. In Plan B, 63% (n = 1,899) were classified as having early-stage disease, 35% were classified as having indeterminate-stage disease, and 2% were classified as having late-stage disease. Using MarketScan data, 74% of patients were classified as having early-stage breast cancer, 1% were classified as having advanced disease, and 25% were classified as having disease that was indeterminate. When considering only those participants who were determined to have early-stage breast cancer and a minimum of 12 months of follow-up information, 1,111 participants from Plan A, 1,587 participants from Plan B, and 4,434 participants from MarketScan were considered to be assessable for the primary analysis of 1-year adherence rates. Of these assessable study participants, 158 patients from Plan A, 360 patients from Plan B, and 481 patients from MarketScan had at least 36 months of follow-up information and were included in the long-term adherence analysis.
Table 1 lists characteristics of the study participants. Patients identified in the MarketScan data set were older than those in the other two programs, on average, and women in each data set were located geographically throughout the United States. Although the majority of patients used retail pharmacies, 16.7% to 48.5% filled a claim for at least one mail order endocrine therapy prescription during the period under consideration. Among patients initiating anastrozole therapy, 9.3% of patients in Plan A and 14.2% of those in Plan B had evidence of switching to another endocrine therapy during the study period, of which 58% and 60%, respectively, were changes to tamoxifen.
MPRs were calculated for patients from each data set. Early-stage breast cancer patients had filled prescriptions for endocrine therapy on average from 82% to 88% of days during their first year of therapy (Fig 2). Using the definition of adherence as an individual patient having 80% or greater MPR, 72% to 81% of patients were considered adherent to adjuvant endocrine therapy during the first year of therapy. Approximately one quarter of patients (range in the three data sets, 19% to 28%) had fewer than 80% of days covered during the first year of therapy and were considered nonadherent (Fig 3).
Long-Term Analysis For women with 36 months of continuous enrollment in the programs who remained eligible for analysis, the mean MPR declined over time from year 1 to year 3. (Fig 4). In year 1, the mean MPR for patients in Plan A was 86% and in year 3 it was found to be 79%. In Plan B, the mean MPR decreased from 78% in year 1 to 62% in year 3, and in MarketScan, the mean MPR decreased from 84% in year 1 to 72% in year 3. The proportion of eligible women who were considered nonadherent during the first 3 years of therapy also increased over time, ranging from 22% to 31% in year 1 up to 32% to 50% in year 3 in the three data sets (Fig 5).
Persistency Analysis To understand more fully the timing of nonadherence in the course of a woman's care, we evaluated patterns of prescription filling among patients considered nonadherent during the first year of endocrine therapy who had at least 16 months of enrollment in Plan A after their index anastrozole claim (n = 184). The mean 12-month MPR in this subset was 42%. Figure 6 shows the percentage of patients by month remaining persistent with endocrine therapy over the first year. If women in this subset did not have available filled prescriptions for endocrine therapy over a continuous 4-month period, they were considered as nonpersistent, likely having discontinued their endocrine therapy. The average gap in available medication between consecutive refills was 20 days, and most (82%) of these patients had no more than 30-day gaps in having available medication when they were persistent. However, 76% of these patients (13% of total in Plan A) were ultimately considered nonpersistent with oral endocrine therapy during the first 12 months, likely discontinuing therapy completely during this first year.
Adherence to medical treatment is a complex and multifaceted issue that can substantially alter the outcomes of therapy.22 Nonadherence can contribute greatly to the variability observed in a drug's therapeutic effect, with the potential for a clinician to attribute the patient's worsening condition to an absence of drug activity.16 Nonadherence has been associated with an increase in physician visits, higher hospitalization rates, and longer hospital stays.23-26 Suboptimal adherence can also compromise the patient-provider relationship, as misconceptions about the effects of a therapy on the part of either the patient or the provider in this setting may lead to a breakdown in communication and negatively affect the patient's views about care.20 In the setting of a formal clinical trial, nonadherence can lead to misleading results that may have tremendous implications for future patients.22,27-29
This study reveals that a substantial minority of patients are suboptimally adherent with the newest oral hormonal breast cancer treatments. There have been few previous studies regarding adherence to oral agents for the treatment of breast cancer. In a study of 26 breast cancer survivors, Waterhouse et al20 found that patient self-report and pill counts statistically significantly overestimated the degree to which patients adhered to their tamoxifen regimen, as compared with data recorded by an electronic pill cap that records the time of opening of the pill bottle, and ostensibly of taking medication (a microelectronic monitoring system device). Patients were monitored for approximately 3 months and classified as adherent if the measure of adherence indicated that In previous work using similar claims-based methodology in more than 2,000 women with early-stage breast cancer, rates of nonadherence to tamoxifen therapy were comparable to what we found in the present study.5 During the first year of therapy, an average of 87% of days were covered by filled prescriptions for tamoxifen, and 23% of women failed to achieve an optimal adherence threshold of 80% or greater of days covered. Additional follow-up showed that adherence to tamoxifen continued to decline over time, with approximately 50% of women demonstrating substantial nonadherence by year 4. Previous studies among select populations using self-report of tamoxifen persistence or discontinuation have found that approximately 15% to 35% of women discontinue tamoxifen prematurely at varying lengths of follow-up.4,6,7 Barron et al8 recently reported on tamoxifen persistence rates among a large cohort of women in Ireland initiating therapy using insurance claims-based methodology. They found that 22% of women had discontinued tamoxifen by the end of the first year, and by 3.5 years, 35% had discontinued therapy. Few studies of patients with cancer have evaluated the relationship between adherence levels and achievement of the treatment goal. In a retrospective analysis, Bonadonna and Valagussa27 found that breast cancer patients who received 85% or less of their prescribed adjuvant chemotherapy had shorter relapse-free and total survival times than those who received more complete treatment, and those who received less than 65% of planned therapy showed markedly inferior disease-free survival. It is unknown to what extent such results would apply to endocrine therapy of hormone-responsive disease. It is known, however, that a 5-year course of adjuvant tamoxifen is superior to treatment administered for 1 or 2 years.31,32 There seem to be benefits with aromatase inhibitor therapy that extends for 5 years, though it is uncertain to what extent suboptimal adherence to any endocrine therapy in the context of persistence (ie, not fully discontinuing the therapy) would impact on treatment outcome.9,12 Explanations for nonadherence in various medical settings have been difficult to determine.1,3,23 Previous studies have evaluated some factors associated with nonadherence with adjuvant tamoxifen therapy.5,6,8,33 These studies have suggested that sociodemographic factors, such as age and race/ethnicity, and treatment-related factors, including type of surgery, chemotherapy, and side effects, as well as beliefs about the benefits and risks of therapy, may be associated with adherence to tamoxifen. However, studies are inconsistent, and the methodology used in these studies and the present study, as well as the select populations evaluated, have significant limitations. At present, there is little definitive information available regarding why patients nonadhere to endocrine therapy or other anticancer therapies. This study focused on adherence to anastrozole because this was the only aromatase inhibitor approved for the treatment of early-stage breast cancer during the period under study. However, it is likely that adherence with other aromatase inhibitors is similar, given the preliminary evidence for similar experience of patients on these agents.34 This is the largest study of adherence to adjuvant endocrine therapy outside of a clinical trial and the first to consider aromatase inhibitor therapy. Our findings of suboptimal adherence among a substantial proportion of women in the so-called real world provide further evidence that adherence to oral antineoplastic agents in typical care settings is dramatically worse than that seen in clinical trials, and may translate into lower efficacy of therapy when compared with outcomes observed in clinical trials.3,35 Studies of adherence are often limited by difficulties in measurement, and there is no gold standard methodology. Pharmacy and insurance records can be used to assess adherence in large populations over extended periods of time, and patterns of ongoing prescription filling probably provide the most accurate estimate of actual medication use in large populations.13,16,36 The validity and generalizability of our findings are enhanced by the consistency seen across the three large national databases and the similarity of the findings to those in our previous study of tamoxifen. Nevertheless, the present study has a number of limitations. Claims-based data may result in systematic biases, particularly in terms of the inclusion of limited patient populations. This study evaluated the cohort of patients who initiated adjuvant anastrozole therapy in the available data sets. Although previous studies of adherence have focused on individuals on Medicare or Medicaid, older and indigent women, and those paying out of pocket would be a minority population in this study. Additionally, because actual clinical information was not available to identify stage of disease, a procedural and diagnostic algorithm was used which may have misclassified patients. It is reassuring, however, that the independent validation revealed complete concordance between the oncologists' review of early-stage disease and the algorithm classification. Further, the algorithm was designed to deliberately err on the side of indeterminate stage classification. Because only approximately 6% of women with breast cancer are determined to have advanced disease at initial presentation, it is likely that the majority of women in the indeterminate group represent women with early-stage disease.37 In this study, reasons for nonadherence, including severe side effects or adverse events, were not evaluated. In addition, claims databases fail to capture patients who are the most nonadherent (ie, those who never fill a single prescription). We applied the staging algorithm over the year(s) under consideration, and as a result may have excluded women who developed metastatic disease, which may have been associated with anastrozole nonadherence; these women would have been counted as having metastatic disease from the outset and would not be included in the analysis. If anything, these final two considerations would likely have artificially inflated the level of adherence and could lead to an underestimate of the magnitude of nonadherence in this population. Our findings that approximately one in four women with early-stage breast cancer may be suboptimally adherent to adjuvant anastrozole therapy during the first year of therapy, and that adherence declines over time, have important implications. Patients who are nonadherent to adjuvant endocrine therapy may be compromising their care. Oncologist and patient awareness of the problem of nonadherence, and communication regarding the importance of adherence to therapy, may improve health outcomes. Future research should focus on the identification of patients at risk for nonadherence and the development of interventions to improve and maintain adherence.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: Andrea LaFountain, AstraZeneca; Brooke S. Taylor, AstraZeneca; Aviva Asnis-Alibozek, AstraZeneca Leadership: N/A Consultant: Ann H. Partridge, AstraZeneca, Novartis; Eric Winer, AstraZeneca, Pfizer Stock: Andrea LaFountain, AstraZeneca; Aviva Asnis-Alibozek, AstraZeneca Honoraria: N/A Research Funds: Erica Mayer, AstraZeneca Testimony: N/A Other: N/A
Conception and design: Ann H. Partridge, Andrea LaFountain, Brooke S. Taylor, Aviva Asnis-Alibozek Financial support: Andrea LaFountain, Aviva Asnis-Alibozek Provision of study materials or patients: Aviva Asnis-Alibozek Collection and assembly of data: Andrea LaFountain, Brooke S. Taylor, Aviva Asnis-Alibozek Data analysis and interpretation: Ann H. Partridge, Andrea LaFountain, Erica Mayer, Brooke S. Taylor, Eric Winer, Aviva Asnis-Alibozek Manuscript writing: Ann H. Partridge, Andrea LaFountain, Erica Mayer, Brooke S. Taylor, Eric Winer, Aviva Asnis-Alibozek Final approval of manuscript: Ann H. Partridge, Andrea LaFountain, Erica Mayer, Brooke S. Taylor, Eric Winer, Aviva Asnis-Alibozek
published online ahead of print at www.jco.org on January 7, 2008. Presented as a poster at the 2006 San Antonio Breast Cancer Symposium, December 14-17, 2006, San Antonio, TX. An associated abstract was published in Breast Cancer Res Treat 100:S186, 2006 (suppl 1; abstr 4044). Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Coates AS, Keshaviah A, Thurlimann B, et al: Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: Update of Study BIG 1-98. J Clin Oncol 25: 486-492, 2007 13. Steiner JF, Koepsell TD, Fihn SD, et al: A general method of compliance assessment using centralized pharmacy records: Description and validation. Med Care 26: 814-823, 1988[Medline] 14. Gurwitz JH, Glynn RJ, Monane M, et al: Treatment for glaucoma: Adherence by the elderly. Am J Public Health 83: 711-716, 1993 15. Monane M, Bohn R, Gurwitz JH, et al: Noncompliance with congestive heart failure therapy in the elderly. Arch Intern Med 154: 433-437, 1994 16. Avorn J, Monette J, Lacour A, et al: Persistence of use of lipid-lowering medications: A cross-national study. JAMA 279: 1458-1462, 1998 17. 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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
80% days covered were defined as adherent, whereas patients with fewer than 80% of days covered were considered nonadherent. An 80% cutoff was chosen because it is a rate frequently cited in the literature as acceptable.
