Analysis of Adherence, Persistence, and Surgery Among Endometriosis Patients Treated with Leuprolide Acetate Plus Norethindrone Acetate Add-Back Therapy

BACKGROUND: Endometriosis affects over 10 million women in the United States. Depot leuprolide acetate (LA), a gonadotropin-releasing hormone agonist, has been used extensively for the treatment of women with endometriosis but is associated with hypoestrogenic symptoms and bone mineral density loss. The concomitant use of add-back therapies, specifically norethindrone acetate (NETA), can alleviate these adverse effects. OBJECTIVE: To compare adherence to and persistence with LA treatment and time to endometriosis-related surgery among women treated with LA plus NETA and women treated with LA plus other add-back therapies or LA only. METHODS: This retrospective analysis was conducted using Truven Health MarketScan Commercial Claims and Encounters Database. Women with a diagnosis of endometriosis (ICD-9-CM code 617.xx) who initiated LA (index date) in 2005-2011 were selected for inclusion. Additional requirements were 12 months of continuous enrollment pre- and post-index and no evidence of endometriosis-related surgeries pre-index or up to 30 days post-index; no pre-index use of estrogen or noncontraceptive hormones; and no diagnoses of uterine fibroids, malignant neoplasms, infertility, or pregnancy. Patients were characterized as using NETA; other add-back therapies (estrogens, progestins, or estrogen-progestin combinations); or no add-back therapy. Adherence to and persistence with LA were measured over the 6 months following the index date using outpatient medical and pharmacy claims. Patients were considered adherent if their proportion of days covered was greater than or equal to 0.80. Persistence was operationalized as time to discontinuation, defined as a continuous gap of > 60 days without LA on hand. Time to endometriosis-related surgery (laparotomy, laparoscopy, excision/ablation/fulguration, oophorectomy, and hysterectomy) was measured over the 12 months following the index date. Surgeries were identified from inpatient and outpatient medical claims using procedure codes. Outcomes were compared among cohorts using multivariable logistic and Cox proportional hazards regression models controlling for demographics and baseline clinical characteristics. RESULTS: The final sample included 3,114 women, with a mean age of 36.9 years. The majority of women used LA only with no add-back therapy (n = 1,963, 63.0%), while 15.1% (n = 470) used NETA, and 21.9% (N = 681) used other add-back therapies. During the 6-month follow-up, more patients in the LA plus NETA cohort were adherent to LA therapy compared with LA only (47.2% vs. 31.5%, P < 0.001), and fewer patients discontinued (37.9% vs. 59.6%, P < 0.001). Additionally, fewer patients underwent endometriosis-related surgery in the 12 months after LA initiation in the LA plus NETA cohort (12.6% vs. 16.9%, P = 0.021). In multivariable models, women who initiated LA plus NETA or LA plus other add-back therapies had a higher likelihood of being adherent to LA than LA only patients (OR = 1.91, 95% CI = 1.55-2.36 and OR = 1.95, 95% CI = 1.63-2.34) and lower likelihood of LA discontinuation (HR = 0.54, 95% CI = 0.46-0.63 and HR = 0.59, 95% CI = 0.52-0.68). NETA patients had a lower surgery rate in the 12-month post-index period compared with other add-back patients (HR = 0.68, 95% CI = 0.50-0.93) or LA only patients (HR = 0.69, 95% CI = 0.52-0.92). CONCLUSIONS: For women with endometriosis, treatment with LA and concomitant add-back therapies was associated with better adherence to and persistence with LA over the 6 months following initiation, compared with treatment with LA only. The increased adherence and persistence to LA may translate into decreased need for surgical intervention, although fewer endometriosis-related surgeries were only observed in the 12 months following LA initiation for patients using concomitant NETA add-back therapy. These results support an increased and earlier use of NETA add-back therapy among women who initiate LA.

RESULTS: The final sample included 3,114 women, with a mean age of 36.9 years. The majority of women used LA only with no add-back therapy (n = 1,963, 63.0%), while 15.1% (n = 470) used NETA, and 21.9% (N = 681) used other add-back therapies. During the 6-month follow-up, more patients in the LA plus NETA cohort were adherent to LA therapy compared with LA only (47.2% vs. 31.5%, P < 0.001), and fewer patients discontinued (37.9% vs. 59.6%, P < 0.001). Additionally, fewer patients underwent endometriosis-related surgery in the 12 months after LA initiation in the LA plus NETA cohort (12.6% vs. 16.9%, P = 0.021). In multivariable models, women who initiated LA plus NETA or LA plus other add-back therapies had

R E S E A R C H
• Depot leuprolide acetate (LA), a gonadotropin-releasing hormone agonist, has been used extensively for the treatment of women with endometriosis but is associated with menopausal symptoms (hot flashes, vaginal atrophy, and insomnia) and bone mineral density loss. • The tolerability of LA can be increased with concomitant use of add-back therapies, including norethindrone acetate (NETA).

What is already known about this subject
• This study evaluated adherence to and persistence with LA over the 6 months following initiation among women who initiated LA and used NETA; women who initiated LA and used other add-back therapies; or women who initiated LA only in a large commercial claims database. • Presence and time to endometriosis-related surgery in the 12 months following LA initiation was also compared among the 3 cohorts. • Women who initiated add-back therapy were more adherent and persistent to LA therapy, and those who used NETA had lower surgery rates.
better persistence and compliance to LA. 12 We undertook this retrospective study to extend this area of research by assessing adherence to and persistence with LA treatment among women treated with LA plus NETA; women treated with LA only; and women treated with LA in combination with other hormonal add-back therapies using data reflecting real-world use in more recent years, more clearly defined add-back cohorts, and measurement of adherence and persistence to LA over the initial 6-month period of therapy where use of add-back therapy is not currently mandated per label. 19 An additional objective was to compare time to endometriosis-related surgery among these cohorts of women to determine the potential effect of add-back therapy on surgery rates.

■■ Methods Data Source
We used data from the Truven Health MarketScan Commercial Claims and Encounters (Commercial) Database from 2004 to 2012. The database contains the pooled health care utilization records of approximately 39.5 million privately insured individuals in the United States. 23 All study data were de-identified and complied with all aspects of the Health Insurance Portability and Accountability Act (HIPAA) and therefore were exempted from institutional review board approval.

Patient Selection
Adult women (aged 18-49 years) with at least 1 claim (outpatient pharmacy or medical) for LA between January 1, 2005, and December 31, 2011, were identified using National Drug Code (NDC) numbers or the Healthcare Common Procedure Coding System (HCPCS) code J1950 for injection, leuprolide acetate (for depot suspension), per 3.75 mg (a separate HCPCS code for the 11.25 mg dose administered every 3 months does not exist). The index date was the first use of LA. Women were required to have at least 1 nondiagnostic medical claim with an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis of endometriosis (617.x) in any position in the 12 months pre-index or up to 60 days postindex. Additionally, patients had to be continuously enrolled with medical and pharmacy benefits for 12 months pre-index (pre-index period) and post-index (follow-up period). Patients were excluded from the study sample if their claims records had codes indicating the following (see Appendix A, available in online article): • LA claims in the pre-index period.
• Estrogen or noncontraceptive estrogen/progestin combinations claims in the first 11 months of the pre-index period. • Eligard, Viadur, nondepot LA formulations (e.g., subcutaneous or powder compounding forms), depot LA formulations with a strength of > 11.25 mg or strength of 7.5 mg, or medical claim for 1 mg or 7.5 mg of LA during the study period because these are not indicated for endometriosis treatment. • Pregnancy-assisting medications during the study period. E ndometriosis, characterized by the presence of extrauterine endometrial-like tissue, is a complex gynecological disease that affects over 10 million women in the United States. [1][2][3] Endometriosis affects at least 6%-10% of reproductiveaged women and is present in approximately 38% of women with infertility and approximately 87% of women with chronic pelvic pain. 4 Endometriosis can be managed surgically and/or pharmacologically. 5 Surgical interventions are characterized by high recurrence rates, morbidity, and complication risks, making this approach a formidable challenge. 6 Endometriosis recurrence rates of up to 50% have been reported in the 5 years following laparoscopic surgery, 7,8 and many patients undergo multiple surgeries. 9,10 Current mainstays of noninvasive pharmacologic therapy are oral contraceptives, nonsteroidal antiinflammatory drugs (NSAIDs), progestogens, androgens, and gonadotropin-releasing hormone agonists (GnRHa). 11 GnRHa, such as leuprolide acetate (LA), have been used extensively for the treatment of endometriosis, and the microsphere depot formulation of LA administered once a month or once every 3 months provides a more tolerable option than earlier formulations. 12 While 3 to 6 months of treatment with GnRHa has been proven efficacious in improving endometriosis-related symptoms, its long-term use is restricted because of several side effects that include hypoestrogenic symptoms, such as hot flashes, headache, and vaginitis, and associated bone mineral density (BMD) loss. 7,13 These side effects may be associated with decreased persistence with therapy. 12 Concomitant use of add-back therapy along with GnRHa has been found to improve compliance. 14 Multiple add-back regimens including estrogen, progestins, and norethindrone acetate (NETA) have been demonstrated to prevent BMD loss, without altering the clinical effectiveness of GnRHa. [15][16][17] In comparison to GnRHa therapy alone, the beneficial impact of adding add-back therapy to GnRHa therapy in reducing the occurrence of osteoporosis and symptoms of postmenopausal syndrome was confirmed in a recently published meta-analysis. 18 NETA, a progestin, is approved by the U.S. Food and Drug Administration (FDA) as add-back therapy to be co-administered with LA for up to 12 months. 19 In clinical trials that assessed the safety and efficacy of LA along with NETA alone or in combination with low-dose conjugated estrogens, the combination of LA plus add-back therapies provided extended pain relief and BMD preservation. [15][16][17] Similar clinical results regarding reduction in LA-associated BMD loss were reported when LA was given in combination with other addback agents such as sodium etidronate and low-dose norethindrone and etidronate alone. 20,21 Despite higher GnRHa treatment compliance and persistence and a reduced adverse event profile associated with addback therapy, fewer than 1 in 3 patients treated with GnRHa are estimated to use concomitant add-back therapy. 12 All other patients were included in the LA only cohort.

Outcome Measures
The 3 study outcomes measured were adherence to index LA therapy, persistence with index LA therapy, and surgery incidence following LA initiation. LA adherence and persistence were calculated using outpatient medical and pharmacy claims. For outpatient medical claims for LA, an estimated duration of prescription supply was adopted from a previous study as follows: 30 days for HCPCS J1950 if the paid amount on the claim was less than $1,000 and 90 days if the paid amount was $1,000 or more because a separate HCPCS code for the 11.25 mg dose administered every 3 months does not exist. 12 Adherence was measured using proportion of days covered (PDC), which is defined as the ratio of the total days during follow-up with LA "on hand" to the number of days in the evaluation period. 24 Patients with PDC ≥ 0.80 were considered adherent to LA. 24,25 Persistence was measured using the LA discontinuation rate. Discontinuation was defined as a gap of at least 60 days after the runout of the previous LA claim based on service dates and days supply/estimated duration of prescription supply. Time to discontinuation was also measured. The third study outcome was endometriosis-related surgery, defined as at least 1 medi-cal claim with an ICD-9-CM procedure or Current Procedural Terminology (CPT) code for a laparoscopy, laparotomy, other excision/ablation/fulguration, oophorectomy, or hysterectomy during the follow-up period (Appendix A) with an endometriosis diagnosis code on the same day. The presence of and time to first endometriosis-related surgery were described. Adherence and persistence were evaluated during the first 6 months following LA initiation because this is the recommended length of treatment. 26 Treatment beyond 6 months necessitates the addition of add-back therapy, according to the FDA. 26 Endometriosis-related surgery was measured over the full follow-up period (12 months). The follow-up period is relevant because another previously published analysis measured other LA treatment outcomes, including pelvic pain and BMD, over a 12-month period. 15

Covariates
To account for the multidimensional nature of factors that could affect treatment adherence/persistence, several covariates were captured including demographic and clinical characteristics. 27 Baseline demographic characteristics, including age, U.S Census Bureau geographic region, type of residence (urban/ rural) and health insurance plan type, were assessed on the index date. Baseline clinical characteristics, including the Deyo Charlson Comorbidity Index (CCI), 28 and comorbid conditions based on the presence of ICD-9-CM diagnosis and CPT procedure codes, and medication use based on NDC numbers and HCPCS codes were assessed during the 12-month pre-index period (Appendix A). Because of the nature of information recorded in claims databases, over-the-counter medication use could not be captured.

Statistical Analysis
All study variables for each study cohort, including demographic and clinical characteristics, medication use, and outcomes, were analyzed descriptively. Categorical variables were compared between cohorts using chi-square tests, whereas continuous variables were compared using t-tests. Multivariable analyses were conducted to compare adherence to and persistence with LA and surgery following LA initiation among the 3 cohorts. The odds of having a PDC ≥ 0.80 at 6 months postindex were modeled using logistic regression with the addback therapy cohort (NETA, other, or none) as the independent variable. Cox proportional hazards models were employed to estimate time to LA discontinuation over 6 months post-index and time to endometriosis-related surgery over 12 months post-index with the add-back therapy cohort (NETA, other, or none) as the independent variable. Models controlled for age, insurance plan type, region, urbanicity, CCI, pre-index period anxiety diagnosis, pre-index period depression diagnosis, preindex period opioid prescription, NSAID prescription, and antidepressant prescription. A P value of < 0.05 was considered statistically significant.

Patient Sample Selection Flowchart
Female patients with at least 1 medical or pharmacy claim for LA between January 1, 2005, and December 31, 2011 (first is index date) N = 57,811 Patients with a diagnosis of endometriosis in any position on at least 1 inpatient facility or nondiagnostic inpatient professional or outpatient claim in the 12 months before index date or within 60 days after index date n = 28,841 Patients aged 18-49 years at index date n = 27,744 Patients with continuous enrollment and pharmacy data availability 12 months before index date n = 15,059 Patients with no evidence of LA in the 12 months before index date n = 14,071 Patients with no evidence of estrogen or noncontraceptive estrogen/progestin combination use in the 12 months before index date a n = 13,621 Patients with no evidence of endometriosis-related surgery in the 12 months before index date or within 30 days after index date b n=5,453 Patients without any nondiagnostic claims with a diagnosis of uterine fibroids in any position in the 12 months before index date n = 5,409 Patients with continuous enrollment and pharmacy data availability 12 months after index date n = 4,098 Patients with no claims for Eligard, Viadur, or other forms of LA during 12 months before and after index date c n = 4,004 Patients without any nondiagnostic claims with a diagnosis of malignant neoplasm of female genitourinary organs or infertility in any position in the 12 months before index date and without any nondiagnostic claims with a pregnancyrelated diagnosis in any position or claim with a pregnancy-related procedure code or infertility-related medication in the 12 months before and after index date n = 3,114 There were 202 patients who met the NETA definition but had at least 1 claim for other add-back therapy in the 30 days before the index date or in the 45 days after the last LA claim so were included in the other add-back cohort. Complete patient attrition is described in Figure 1.

Baseline Demographics, Clinical Characteristics, and Medication Use
Demographic and pre-index period clinical characteristics are presented in Tables 1 and 2  add-back therapy cohort and the LA only cohort (P < 0.03). Opioids (50.4%-55.5%), NSAIDs (36.6%-40.2%), hormonal contraceptives (22.8%-64.2%), and antidepressants (27.5%-33.2%) were the most commonly used medications in the preperiod. Opioid and antidepressant use were significantly more prevalent in the LA plus NETA add-back cohort compared with the LA only cohort (P < 0.05). The proportion of patients with a claim for hormonal contraceptive was also significantly lower in the LA plus NETA cohort, compared with the LA plus other add-back cohort (P < 0.001), since hormonal contraceptives use in the 30 days before index was considered in the other addback category.

Unadjusted Results
Unadjusted results are presented descriptively in Table 3 and Figure 2A and 2B. Over the 6-month post-index period during which LA adherence was measured, women treated with LA plus NETA add-back therapy had significantly (P < 0.  Figure 2A; approximately 10% restarted LA after discontinuing within the 6 months following the index date. Compared with the LA plus NETA add-back therapy cohort, a significantly higher proportion of patients underwent endometriosis-related surgery in the LA only cohort (12.6% vs. 16.9%, P = 0.021) during the 12-month follow-up period. Hysterectomy was the most common procedure performed (11.7% of entire study population), while laparotomy (0.8% of the entire study population) was rare. Among those who had surgery, patients in the LA plus NETA add-back therapy cohort had significantly longer average time to surgery compared with those in the LA only cohort (mean = 185 days [SD 86.4] vs. mean = 139 days [SD 94.9], P = 0.001). Figure 2B presents unadjusted time to surgery. The proportion of patients who had surgery over the 12-month follow-up period was significantly lower for women who were adherent to LA over the first 6 months compared with those who were not adherent (LA plus NETA add-back: 8.6% vs. 16  Analysis of Adherence, Persistence, and Surgery Among Endometriosis Patients Treated with Leuprolide Acetate Plus Norethindrone Acetate Add-Back Therapy (hazard ratio [HR] = 0.538, 95% CI = 0.459-0.631, P < 0.001), as did patients initiating LA plus other add-back therapies (HR = 0.590, 95% CI = 0.516-0.675, P < 0.001). There were no significant differences in adherence or persistence when comparing the LA plus NETA cohort with the LA plus other addback cohort. However, LA plus NETA add-back therapy was associated with decreased hazards of surgery compared with those with LA plus other add-back therapies (HR = 0.681, 95% CI = 0.496-0.934, P = 0.017) and those treated with LA only (HR = 0.693, 95% CI = 0.523-0.917, P = 0.010).

■■ Discussion
In a commercially insured population, women with endometriosis treated with LA plus NETA were more likely to be adherent to and persistent with LA for 6 months, compared with patients treated with LA only, and were less likely to have surgery within 12 months, compared with women treated with LA plus other add-back therapies or LA only. trend was observed for women who were persistent compared with those who were nonpersistent to LA over 6 months (LA plus NETA add-back: 9.6% vs. 17.4%, P = 0.013; LA plus other add-back: 11.3% vs. 25.2%, P < 0.001; LA only: 11.2% vs. 20.8%, P < 0.001). Figure 3   antiproliferative effects and to reduce BMD losses and vasomotor symptoms, such as hot flashes, commonly encountered by women treated with GnRHa. 32 The combination of LA and NETA may alleviate the side effects of LA only, resulting in patients staying on the medication for longer periods of time.

Adjusted Results
Although the reduction in number and size of endometriotic lesions was only shown for LA monotherapy, 26,33 one could speculate that LA's benefit would be likewise present for LA plus add-back therapy, potentially leading to a reduced need for, or a delay in, endometriosis-related surgery. Reducing the need for surgery is expected to be associated with economic savings, given the considerable costs of endometriosis-related surgeries together with rates of complications associated with those procedures. 34 This analysis used a large commercial insurance database to describe improved adherence and reduced surgery rates associated with the use of LA and add-back therapy in a database with sufficient sample size and longitudinality to yield robust comparisons. Additionally, the definition of study cohorts produced a clean cohort of patients using LA plus NETA without any other add-back therapies for comparison with LA only patients. The methods employed in this study were influenced by a previous study comparing LA adherence and persistence by Fuldeore et al (2010). 12 This previous analysis was conducted with MarketScan data from 2002 to 2004. Similar to our analysis, the index date was initiation of LA. Evidence of claims for add-back therapy (estrogen, progestin, or There is also an indication that women who are adherent and persistent to LA have lower rates of surgery. This is currently being explored further in a separate analysis. A recently published meta-analysis confirmed the beneficial effects of adding add-back therapies to GnRHa therapy for endometriosis because add-back therapies reduce the occurrence of osteoporosis and postmenopausal syndrome symptoms compared with GnRHa therapy alone. 18 Use of add-back therapies with a GnRHa, such as LA, is also known to enhance persistence and adherence of LA treatment in patients. 12,15 Better improvement in the quality of life measures for a longer period of time were also reported in women treated with GnRHa plus add-back therapies, compared with GnRHa or oral contraceptive treatments alone. 29,30 Since the NETA cohort and other add-back cohort had similar levels of LA adherence and persistence, the difference in surgery risk between the 2 add-back cohorts may be due to use of estrogens by some women in the other addback cohort. Estrogen use can negate the effects of LA therapy because estrogen stimulates the growth of endometrial tissue. 31,32 It is important to note that the other add-back cohort is heterogeneous with respective to add-back therapy composition. Therefore, results for that cohort should be interpreted cautiously because individual types of add-back therapy (estrogens, progestins, or combinations thereof) may have different associations with adherence, persistence, and surgery.
Among the add-back therapies, the hormonal profile of NETA has been shown to exhibit strong endometrial  Analysis of Adherence, Persistence, and Surgery Among Endometriosis Patients Treated with Leuprolide Acetate Plus Norethindrone Acetate Add-Back Therapy norethindrone) was measured in the 7 days before the index date through 45 days after. Persistence and compliance (measured as medication possession ratio [MPR]) were evaluated over 12 months and found to be better among women with evidence of add-back therapy. 12 Our analysis varied in several ways. First, the data used in this analysis are reflective of current utilization patterns, compared with the data used in the Fuldeore et al. analysis. 12 Second, we evaluated adherence and persistence over a 6-month period, which is consistent with LA prescribing information for initial endometriosis management. Patients using LA for periods longer than 6 months should be concurrently using add-back therapy per the drug label. We conducted a sensitivity analysis where we measured these outcomes over the 12 months following LA initiation (data not shown), which yielded results similar to the previous analysis of LA and addback therapy conducted by Fuldeore et al. 12 Over a 12-month period, we found an average PDC of 0. 42 12 Regarding LA persistence, we found that patients treated with LA plus NETA persisted on therapy for an average of 5.3 months over the 12-month period, compared with 5.0 months for patients treated with LA plus other add-back therapy and 3.9 for patients treated with LA only. Fuldeore et al. reported times on therapy of 5.8 months, 4.6-5.8 months, and 4.2 months, respectively. 12 Third, women with endometriosis-related surgery were excluded from our analysis because they may experience effects related to the surgical intervention in combination with LA effects during the follow-up period. Women who underwent surgery within 30 days of initiating LA were also excluded because LA may be used as preparation for surgery rather than as a treatment on its own. Fourth, we employed multivariable models for adherence controlling for demographic and clinical characteristics because previous research has shown that LA adherence is affected by age, while the Fuldeore et al. analysis only modeled persistence in a descriptive manner that did not account for baseline differences between patients. 12

Limitations
There are limitations to our analysis that merit consideration. First, this study was limited to information contained in an  Analysis of Adherence, Persistence, and Surgery Among Endometriosis Patients Treated with Leuprolide Acetate Plus Norethindrone Acetate Add-Back Therapy administrative claims database. Over-the-counter medications are not captured, since they do not generate insurance claims. Symptoms of endometriosis and comorbid conditions may not be captured correctly if the diagnoses were not recorded by health care providers for reimbursement. Another limitation of the current study is that health care claims databases are not designed primarily to capture adverse events (AEs). 35,36 Thus, certain AEs associated with using LA or undergoing laparoscopy may not be collected if the AE did not result in a diagnosis or procedure on a health care claim. Nonetheless, it must be anticipated that a similar safety profile to that seen in LA's drug labels applies to the study population. Most frequent AEs observed among endometriosis patients are hot flashes, headache, vaginitis, depression/emotional lability, general pain, nausea/vomiting, weight gain or loss, decreased libido, dizziness, acne, and impact on bone health, 26 whereas AEs related to undergoing laparoscopy include vascular, intestinal, urinary tract, and nerve injuries. [37][38][39][40][41][42] Second, we used the dose defined as per the label and paid amount to estimate day supply for assigning days supply for LA medical claims because doses are not available on medical claims. Third, ICD-9-CM codes do not contain information on endometriosis stage, which may influence treatment choices and outcomes. Endometriosis stage may have differed between the 3 cohorts and could have affected physicians' prescribing patterns.
Fourth, this study design was observational; therefore, causal inference should be drawn cautiously. Physicianprescribing patterns and preferences for pharmacotherapy versus surgical treatments, as well as patient preferences could not be captured. Just as differences in endometriosis stage could have biased the study findings, the inability to adjust for physician and patient preferences may have resulted in uncontrolled confounding. Future research using patient and/or physician surveys should be conducted to assess patient and physician preferences and their relationship with surgery rates.
Finally, the analyses were limited to women with commercial insurance, so the results may not be generalizable to women insured through other mechanisms, such as Medicaid, or the uninsured, all of which warrant further research.

■■ Conclusions
This study shows that for women with endometriosis, treatment with LA and concomitant add-back therapy was associated with better adherence to and persistence with LA over the 6 months following initiation compared with treatment with LA only. For women treated with LA along with NETA, the odds of being adherent to LA were 91% higher compared with those treated with LA only. Women treated with LA plus NETA also had 46% lower probability of discontinuing LA over 6 months. There were no significant differences in adherence and persistence between women treated with NETA versus other add-back therapies. However, NETA add-back use was associated with lower risk of endometriosis-related surgery than other add-back therapies. Women treated with LA plus NETA had a 31% lower probability of surgery compared with women treated with LA only and a 32% lower probability of surgery compared with women treated with other therapies. The increased adherence and persistence to LA may translate into decreased need for surgical intervention. These results support increased and earlier use of NETA add-back therapy among women with endometriosis who initiate LA.