Health-Related Quality of Life Improvements in Moderate to Very Severe Chronic Obstructive Pulmonary Disease Patients on Nebulized Glycopyrrolate: Evidence from the GOLDEN Studies.

Background: Symptoms of chronic obstructive pulmonary disease (COPD) may diminish patients' health-related quality of life (HRQoL). We report effects of Longhala™ Magnair™ (glycopyrrolate) Inhalation Solution, a drug/device combination of the long-acting antimuscarinic glycopyrrolate administered using the eFlow® closed system (eFlow CS) nebulizer, on HRQoL from the Glycopyrrolate for Obstructive Lung Disease Via Electronic Nebulizer (GOLDEN) clinical studies. Methods: Data consisted of a pooled analysis of 2 phase 3, 12-week efficacy studies (GOLDEN-3 and -4) of glycopyrrolate/eFlow CS (25 or 50 mcg twice daily [BID]) versus placebo, and a 48-week, open-label safety study (GOLDEN-5) of glycopyrrolate/eFlow CS 50 mcg BID versus tiotropium 18 mcg once daily in patients with moderate to very severe COPD. Change from baseline in HRQoL was measured via the St George's Respiratory Questionnaire (SGRQ). Results are provided as mean changes in SGRQ Total score and as response analysis (≥4-point improvement [responder], no change, and ≥4-point worsening in Total score) using analysis of covariance or logistic regression, as applicable. Results: Atotal of 1293 patients were evaluated from GOLDEN-3 and -4 and 1086 from GOLDEN-5. Glycopyrrolate/eFlow CS significantly improved SGRQ Total and component scores. The percentage of SGRQ responders in pooled GOLDEN-3/4 was 46.8% for glycopyrrolate/eFlow CS 25 mcg, 41.7% for glycopyrrolate/eFlow CS 50 mcg, and 34.5% for placebo. SGRQ Total and component score improvements were similar between glycopyrrolate/eFlow CS and tiotropium in GOLDEN-5. Conclusions: The drug/device combination of glycopyrrolate/eFlow CS significantly improved HRQoL, as measured by the SGRQ, offering a potential maintenance treatment option in patients with moderate to very severe COPD. ClinicalTrials.gov: NCT02347761, NCT02347774, NCT02276222.

Long-term health-related quality-of-life and symptom response profiles with arformoterol in COPD: results from a 52-week trial.

Background: Symptom severity is the largest factor in determining subjective health in COPD. Symptoms (eg, chronic cough, dyspnea) are associated with decreased health-related quality of life (HRQoL). We evaluated the impact of arformoterol on HRQoL in COPD patients, measured by St George's Respiratory Questionnaire (SGRQ). Post hoc growth mixture model (GMM) analysis examined symptom response profiles. Methods: We examined data from a randomized, double-blind, parallel-group, 12-month safety trial of twice-daily nebulized arformoterol 15 µg (n=420) versus placebo (n=421). COPD severity was assessed by Global Initiative for Chronic Obstructive Lung Disease (GOLD) status. GMM analysis identified previously unknown patient subgroups and examined the heterogeneity in response to SGRQ Symptoms scores. Results: SGRQ Total score improved by 4.24 points with arformoterol and 2.02 points with placebo (P=0.006). Significantly greater improvements occurred for arformoterol versus placebo in SGRQ Symptoms (6.34 vs 4.25, P=0.031) and Impacts (3.91 vs 0.97, P=0.001) scores, but not in Activity score (3.57 vs 1.75, P=0.057). GMM identified responders and nonresponders based on the SGRQ Symptoms score. End-of-study mean difference in SGRQ Symptoms scores between these latent classes was 20.7 points (P<0.001; 95% confidence interval: 17.6-23.9). Compared with nonresponders, responders were more likely current smokers (55.52% vs 44.02%, P=0.0021) and had more severe COPD (forced expiratory volume in 1 second [FEV1]: 1.16 vs 1.23 L, P=0.0419), more exacerbations (0.96 vs 0.69, P=0.0018), and worse mean SGRQ Total (59.81 vs 40.57, P<0.0001), Clinical COPD Questionnaire (3.29 vs 2.05, P<0.0001), and Modified Medical Research Council Dyspnea Scale (3.13 vs 2.75, P<0.0001) scores. Arformoterol-receiving responders exhibited significantly greater improvements in FEV1 (0.09 vs 0.008, P=0.03) and fewer hospitalizations (0.13 vs 0.24, P=0.02) than those receiving placebo. Conclusion: In this study, arformoterol treatment significantly improved HRQoL reflected by SGRQ. For the analysis performed on these data, arformoterol may be particularly effective in improving lung function and reducing hospitalizations among patients who are unable to quit smoking or present with more severe symptoms.

Exacerbations, health services utilization, and costs in commercially-insured COPD patients treated with nebulized long-acting ß2-agonists.

OBJECTIVE: This retrospective cohort study compared exacerbations, health services utilization, and costs among chronic obstructive pulmonary disease (COPD) patients who received nebulized arformoterol or nebulized formoterol therapy. METHODS: Using PharMetrics Plus health plan claims, 417 nebulized long-acting ß2-agonist (LABA) users meeting the study inclusion criteria were identified: had ≥2 fills of nebulized arformoterol or nebulized formoterol from January 1, 2009, to December 31, 2011, adhered to using their index drug ≥60% of the days during 1 year post-index, were ≥35 years old and continuously enrolled 180 days pre- and 1 year post-index, and did not use a nebulized LABA or have an asthma diagnosis during the pre-index period. Descriptive and multivariate analyses were performed. RESULTS: A total of 274 nebulized arformoterol users and 143 nebulized formoterol users were identified with comparable demographic characteristics. However, significant differences were observed between the two groups in some clinical characteristics at index including comorbidities and use of antibiotics. At 1 year post-index, a lower proportion of nebulized arformoterol users had ≥1 exacerbation compared to nebulized formoterol users (70.4% vs 80.4%; p = 0.028). Among patients with ≥1 hospital admission, COPD-related costs per inpatient stay were significantly lower for nebulized arformoterol users than nebulized formoterol users (median = $9542 vs $14,025; p = 0.009). After controlling for confounders, nebulized arformoterol users had 19% marginally lower risk of exacerbations than nebulized formoterol users (hazard ratio = 0.81, 95% confidence interval = 0.64-1.03; p < 0.084) and 14.4% marginally lower COPD-related total costs at 1 year post-index (p = 0.062), primarily related to fewer hospital readmissions (7.6% vs 12.2%) and lower average costs per readmission stay (median = $7392 vs $18 081; p = 0.006). CONCLUSIONS: This study suggests that the choice of nebulized LABA may influence COPD-related exacerbation occurrence and costs. Future studies with larger and more closely matched nebulized arformoterol and nebulized formoterol users are needed to confirm these findings.

The economic burden of pleural effusions in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors.

OBJECTIVE: Tyrosine kinase inhibitors (TKI), the standard of care for patients with chronic myeloid leukemia (CML) patients, may in some cases lead to the development of pleural effusion (PE). The purpose of this study is to compare healthcare resource utilization and costs associated with PE among CML patients treated with a TKI therapy. METHODS: Two large retrospective claims databases (1999-2009) were combined to identify adult CML patients who received ≥1 TKI prescription before the index date, which was defined as 30 days before the first PE diagnosis for patients with PE and a randomly selected date for PE-free patients. Patients were followed for 6 months after the index date. PE and PE-free patients were matched on a 1:1 ratio. PE-related resource utilization and costs (measured in 2009 US dollars) were estimated for PE patients. All-cause and CML-related resource utilization and costs were compared between PE and PE-free patients. Multivariate regression models were used to control for confounding factors. RESULTS: The study included 186 matched pairs. PE-free and PE patients were on average 65.4 and 63.6 years old and 39.8% and 48.9% were female, respectively. PE patients had a significantly higher number of inpatient (IP) days, IP admissions, outpatient (OP) visits and emergency room (ER) visits than PE-free patients (all p < 0.01). All-cause medical services costs were $88,526 and $30,434 for PE and PE-free patients, respectively. After adjusting for confounding factors, the PE-related total medical costs were $47,288 (p < 0.01), which was mostly accounted for by higher IP (difference: $34,123, p < 0.01) and OP (difference: $9563, p < 0.05) costs. PE patients also incurred higher CML-related medical costs compared to PE-free patients (difference: $39,599; p < 0.01). CONCLUSION: PE presents a substantial economic burden for CML patients treated with TKI.

Comparative efficacy of nilotinib and dasatinib in newly diagnosed chronic myeloid leukemia: a matching-adjusted indirect comparison of randomized trials.

OBJECTIVE: Nilotinib and dasatinib have not been directly compared in a randomized trial for the treatment of newly diagnosed chronic myeloid leukemia in the chronic phase (CML-CP). The purpose of this study was to indirectly compare rates of major molecular response (MMR), progression-free survival (PFS) and overall survival by month 12 with nilotinib and dasatinib treatment of newly diagnosed CML-CP. METHODS: Individual patient data from a randomized trial of nilotinib vs. imatinib (ENESTnd) and published summary data from a separate randomized trial of dasatinib vs. imatinib (DASISION) were utilized. A matching-adjusted indirect comparison was conducted by weighting individual patients treated with nilotinib to match baseline characteristics reported for dasatinib-treated patients, including age, gender, ECOG performance status and hematology lab values. After matching, efficacy outcomes were compared for patients treated with nilotinib 300 mg twice daily vs. dasatinib 100 mg once daily. Patients randomized to imatinib 400 mg once daily in each trial were used to assess the adequacy of the matching. RESULTS: Before matching, patients randomized to nilotinib in ENESTnd (n = 273) were older, with a lower median platelet count and more favorable performance status compared to patients randomized to dasatinib in DASISION (n = 259). After matching, all baseline characteristics were balanced across treatment groups. Matched patients treated with nilotinib vs. dasatinib experienced significantly higher rates of MMR (56.8 vs. 45.9%, p = 0.014) and overall survival (99.5 vs. 97.3%, p = 0.046) and numerically higher rates of PFS (98.8 vs. 96.5%). Matched imatinib arms showed no statistically significant or clinically meaningful differences in these outcomes. LIMITATIONS: Baseline measures unavailable in one or both trials could not be matched. Adverse event rates were not formally compared across trials due to differences in reporting. CONCLUSION: Nilotinib was associated with significantly higher rates of MMR and overall survival compared with dasatinib by month 12 in the treatment of newly diagnosed CML-CP.

Retrospective real-world comparison of medical visits, costs, and adherence between nilotinib and dasatinib in chronic myeloid leukemia.

OBJECTIVE: To compare healthcare resource utilization, costs, and treatment adherence associated with dasatinib versus nilotinib treatment as second-line therapies in chronic myeloid leukemia (CML) patients. METHODS: Two large retrospective claims databases (01/1999-06/2009) were combined to identify CML patients (ICD-9 code 205.1x) who received one or more prescriptions of dasatinib or nilotinib. Studied patients had continuous enrollment ≥ 1 month prior to and after the index date, defined as the first prescription for dasatinib or nilotinib. Patients were followed for up to 6 months from the index date to the earliest of the termination of healthcare plan enrollment or end of data availability. Patients with bone marrow or stem cell transplant during the study period were excluded. Poisson regression models were used to compare healthcare resource utilization between the two groups. Results were reported as incidence rate ratios (IRR). Healthcare cost differences were estimated for each cost component using generalized linear models or two-part models. Treatment adherence was measured by the proportion of days covered (PDC) and compared using generalized linear models. Multivariate regressions were used to control for potential confounding factors. RESULTS: A total of 521 CML patients receiving second-line tyrosine kinase inhibitors (TKI) (452 dasatinib and 69 nilotinib) were studied. During the study period, dasatinib patients were estimated to have more than twice as many inpatient days (IRR = 2.44; p < 0.001) and nearly double the number of inpatient admissions (IRR = 1.99; p = 0.047) compared to nilotinib patients. Over the follow-up period, dasatinib patients incurred $8828 more in total medical service costs (p < 0.001); cost differences were mainly driven by an adjusted inpatient cost difference of $8520 (p = 0.003). Dasatinib patients were less adherent, with a PDC value approximately 13% lower compared to nilotinib patients (p = 0.009). CONCLUSIONS: Among CML patients treated with second-line TKIs, nilotinib patients were more adherent and experienced lower healthcare resource utilization, resulting in medical service cost savings compared to dasatinib patients.

Budgetary impact of treatment with adjuvant imatinib for 1 year following surgical resection of Kit-positive localized gastrointestinal stromal tumors.

BACKGROUND: Imatinib mesylate, an orally administered kinase inhibitor that targets the Kit (CD117) protein, currently has 10 approved indications including treatment of chronic myelogenous leukemia and metastatic gastrointestinal stromal tumors (GIST). Treatment with adjuvant imatinib following surgical resection of localized Kit-positive GIST, the most recent FDA-approved indication (December 2008), has been shown to significantly improve recurrence-free survival (RFS) compared with surgical resection alone. Although adjuvant imatinib has proven effective in clinical trials, it is important to consider the economic impact to health plans of introducing imatinib in accordance with its new labeled indication. OBJECTIVE: To evaluate the budgetary impact over a 3-year time horizon of treating patients with localized Kit-positive GIST with 1 year of adjuvant imatinib following surgical resection. METHODS: A Markov model was developed to predict patients' transitions across health states defined by initial treatment (surgical resection followed by adjuvant imatinib 400 milligrams [mg] daily versus surgical resection alone), recurrence, and progression. Treatments for a first recurrence were (a) imatinib 400 mg daily for recurrences following resection only or after completion of 1 year of treatment with imatinib 400 mg daily and (b) imatinib 800 mg daily for recurrence during active treatment with imatinib 400 mg daily. Treatments for further progression were imatinib 800 mg daily, sunitinib, or best supportive care (BSC) following imatinib 400 mg per day, and sunitinib or BSC following imatinib 800 mg daily. Recurrence rates were derived from the American College of Surgeons Oncology Group (ACOSOG) Z9001 clinical trial, which compared 1 year of adjuvant imatinib following surgical resection with surgical resection only. The total number of patients with localized and surgically resected GIST (incidence rate of 0.36 per 100,000) was estimated from epidemiologic studies of GIST. Uptake of treatment with imatinib was estimated from unpublished data from qualitative market research funded by the study sponsor. The uptake rate assumptions reflected both (a) the percentage of patients with Kitpositive disease and (b) the percentage of clinically eligible patients who would use imatinib. Costs were estimated by combining unit costs from published sources with expected resource utilization based on the clinical trial publication and National Comprehensive Cancer Network guidelines on the treatment of patients with GIST. To obtain estimates of the budgetary impact, we compared estimated health care costs with versus without adjuvant imatinib, where health care costs with imatinib reflected the costs of treatment minus cost offsets associated with delayed or avoided recurrence or progression. All "with" scenarios assumed no additional uses other than surgically resected localized Kit-positive GIST (i.e., no change in off-label use of imatinib). The budgetary impact was estimated for the first 3 years after the introduction of adjuvant imatinib in accordance with its new labeled indication in a hypothetical plan population of 10 million persons. Results were calculated both as total budgetary impact and as per member per month (PMPM) cost in 2009 dollars. Sensitivity analyses were performed to test the robustness of model results to changes in parameter estimates. RESULTS: The model predicted 36 incident resected GIST cases per year in a health plan of 10 million members. The estimated counts of cases treated with adjuvant imatinib were 10.8, 16.2, and 21.6 in the first, second, and third years after introduction, respectively, with the annual increases attributable to changes in the proportion of patients with resected GIST assumed to use imatinib (30% in year 1, rising to 45% in year 2 and 60% in year 3). The model predicted that treatment of these cases with imatinib will increase pharmacy costs by an additional $505,144 in the first year, $757,717 in the second year, and $1,010,289 in the third year. Increased resource use associated with monitoring patients during and after treatment with adjuvant imatinib would cost an additional $21,564, $38,145, and $56,605 in the first, second, and third years, respectively. Recurrence would be avoided or delayed in 7 patients over the 3-year period. Avoided or delayed recurrences would result in cost offsets of $61,583 in the first year, $156,702 in the second year, and $233,849 in the third year. The net budgetary impact was estimated to be $465,126 in the first year (less than $0.01 PMPM), $639,159 in the second year ($0.01 PMPM), and $833,044 in the third year ($0.01 PMPM). Results of sensitivity analyses indicated that the budgetary impact in the third year is most sensitive to changes in the price of adjuvant imatinib and recurrence rates. CONCLUSIONS: The model predicted that the introduction of adjuvant imatinib for treatment of surgically resected, localized, Kit-positive GIST will lead to a net budgetary impact of $0.01 PMPM in the third year after introduction assuming change in use only in accordance with the new labeled indication. Approximately 11.7%-21.9% of the cost of adjuvant imatinib is offset by the reduction in costs associated with GIST recurrence.