Comparative efficacy, safety and durability of dolutegravir relative to common core agents in treatment-naïve patients infected with HIV-1: an update on a systematic review and network meta-analysis.

BACKGROUND: The objective of this study was to assess the durability of response of dolutegravir (DTG) as an antiretroviral core agent by comparing its efficacy and safety with other recommended or commonly used core agents up to 96-weeks (W96). METHODS: A previously published systematic review was updated to identify phase 3/4 randomised controlled trials (RCTs) of core agents in treatment-naïve HIV-1 patients. Efficacy [virologic suppression (VS), CD4+ cell change from baseline] and safety [adverse events [AEs], discontinuations, drug-related AEs [DRAEs]] were analysed at W96 using Bayesian network meta-analysis (NMA) adjusting for nucleoside/nucleotide reverse transcriptase inhibitors' (NRTIs') backbone. Subgroups of patients with VL > 100,000 copies/mL or CD4+ ≤ 200 cells/µL at baseline were analysed separately. RESULTS: The NMA included 20 studies reporting data at W96. A higher proportion of patients receiving DTG achieved VS compared to those on protease inhibitors [PI:Range:8.7%(CrI:3.1,16.0)-19.9%(10.8,30.5)], efavirenz [EFV:6.9%(1.3,10.8)] and cobicistat-boosted elvitegravir [EVG/c:8.2%(0.2,17.4)], and similar but numerically higher compared to rilpivirine [RPV:5.0%(- 2.8,12.5)], raltegravir [RAL:2.9%(- 1.6,7.7)] and bictegravir [BIC:2.7%(- 2.7,10.6)]. The probability that more patients on DTG would achieve VS at W96 compared to any other core agent was greater than 80%. A higher proportion of patients on DTG achieved VS compared to PI/rs [Range:33.1%(13.6,50.4)-45.3%(24.1,61.6)] and RAL [16.7%(3.3,31.2)] in patients with VL > 100,000 copies/mL at baseline, and similar VS was achieved in patients with CD4+ ≤ 200 cells/µL at baseline. DTG also achieved greater increase in CD4+ cells from baseline compared to EFV [32.6(10.7,54.7)], ritonavir-boosted darunavir [DRV/r:25.7(3.6,48.1)] and BIC [24.7(1.5,47.7)]. Patients receiving DTG had lower odds of discontinuing therapy by W96 compared to PI/rs, EFV, RAL and EVG/c. Patients on DTG had lower odds of experiencing an adverse event (AE) compared to patients on EFV [odds ratio:0.6(0.3,0.9)], ATV/r [0.4(0.3,0.6)] and LPV/r [0.3(0.2,0.5)]. For patients on DTG, the odds of experiencing a drug-related AE were lower than the odds for patients on EFV [0.3(0.2,0.4)], comparable to patients on RAL [1.1(0.8,1.4)] and higher than those on BIC [1.5(1.1,2.0)]. CONCLUSION: Un-boosted integrase inhibitors had better efficacy and similar safety compared to PI/rs at W96 in treatment-naïve patients with HIV-1, with DTG being among the most efficacious core agent, particularly in patients with baseline VL > 100,000 copies/mL or ≤ 200 CD4+ cells/µL, who can be difficult to treat.

Improving access to antiretrovirals in China: economic analyses of dolutegravir in HIV-1 patients.

BACKGROUND: The World Health Organisation recommended dolutegravir (DTG)-based antiretroviral therapy (ART) regimens are available but not reimbursed through the public reimbursement system in China. The objective of this analysis was to evaluate the cost-effectiveness of DTG (DTG + TDF/3TC) compared to efavirenz (EFV + TDF/3TC) in treatment-naive and ritonavir-boosted lopinavir (LPV/r + TDF/3TC) in first-line ART failure HIV-1-infected patients in China. METHODS: A dynamic Markov model comprising of 5 response states and 6 CD4+ count-based health states was used. Efficacy, estimated as probability of virologic suppression (HIV RNA < 50 copies/mL) at 48 weeks, was obtained from a published network meta-analysis for ART-naive patients and from the DAWNING study for patients failing first-line ART. Baseline cohort characteristics were informed using DTG phase 3 studies and the DAWNING study data, respectively. Health state utilities were derived from DTG phase 3 studies. A 5-year cost-effectiveness analyses was conducted using the societal perspective. Outcomes were quality-adjusted-life-years (QALYs), life-years (LYs), incremental cost per QALYs (ICER). RESULTS: The viral suppression rates for DTG + TDF/3TC were higher than EFV + TDF/3TC (75.3% vs 64.0%) in treatment-naive and LPV/r + TDF/3TC (74.8% vs 58.4%) in first-line ART failure patients. This resulted in higher QALYs for DTG + TDF/3TC in treatment-naive (4.232 vs 4.227) and first-line failure settings (4.224 vs 4.221). Total discounted cost for DTG + TDF/3TC patients (RMB 219.259 in treatment-naive and RMB 238,746 in first-line failures) were lower than comparators (EFV + TDF/3TC:RMB 221,605; LPV/r + TDF/3TC:RMB 244,364), thereby DTG dominated in both settings. Probabilistic sensitivity analyses indicated the probability of DTG + TDF/3TC being cost effective was 98.2% in treatment-naive setting and 100% in first-line failure setting at a willingness to pay threshold of RMB 100,000/QALY. CONCLUSIONS: With lower costs, higher response rates and higher QALYs, DTG + TDF/3TC can be considered as a cost-effective alternative for treatment naive and first-line failure patients in China.

Rescue medication use as a patient-reported outcome in COPD: a systematic review and regression analysis.

BACKGROUND: Reducing rescue medication use is a guideline-defined goal of asthma treatment, however, little is known about the validity of rescue medicine use as a marker of symptoms in chronic obstructive pulmonary disease (COPD). To improve patient outcomes, greater insight is needed into the relationship between rescue medication use and alternative COPD outcomes. METHODS: A systematic search of electronic databases (Embase®, MEDLINE® and Cochrane CENTRAL) was conducted from database start to 26 May, 2015. Studies of bronchodilator therapy with a duration of ≥24 weeks were included if they reported either mean change from baseline (CFB) in rescue medication use in puffs/day or % rescue-free days (%RFD), and at least one other COPD endpoint. Correlation and meta-regression analyses were undertaken to test the association between rescue medication use and other COPD outcomes using weighted means (weights proportional to the sample size of the treatment group) and unweighted means (equal weight for each treatment group). Each association was assessed at 6 months and study end. RESULTS: Forty-six studies involving 46,531 patients provided mean data from 145 treatment groups for evaluation. Changes in both measures of rescue medication use were correlated with changes in trough forced expiratory volume in one second ([FEV1]; Pearson correlation coefficients |r| ≥ 0.63; p < 0.0001) and with St George's Respiratory Questionnaire (SGRQ) score (|r| ≥ 0.70; p < 0.0001) at study end. Change in rescue medication use in puffs/day during the study correlated with annualized rates of moderate/severe exacerbations at 6 months and study end (both r = 0.66; p ≤ 0.0028). CFB in puffs/day was not well correlated with Transition Dyspnoea Index (TDI), but %RFD did correlate with TDI score at 6 months and study end (both r = 0.69; p < 0.0001). The values for CFB in puffs/day corresponding to the proposed minimal clinically important differences for trough FEV1 and SGRQ score were -1.3 and -0.6 puffs/day, respectively. A -1.0 puffs/day CFB in rescue use corresponded to a change of 0.26 events/patient-year in moderate/severe exacerbations. CONCLUSION: This analysis provides clear evidence of associations at a patient group level between rescue medication use and other clinically important COPD outcomes.

Characteristics, disease burden and costs of COPD patients in the two years following initiation of long-acting bronchodilators in UK primary care.

BACKGROUND: To assess the symptomatic and cost burden among patients initiating long-acting bronchodilator (LABD) therapy and impact of adherence on healthcare resource use and costs. METHODS: This retrospective cohort study identified patients with COPD who were newly prescribed a LABD (long-acting muscarinic antagonist [LAMA], long-acting beta2-agonist [LABA], a combination of LABA+LAMA or combination of LABA with inhaled corticosteroid [ICS]/LABA) between January 1, 2009 and November 30, 2013 from the UK Clinical Practice Research Datalink. Health care resource use, costs and symptom burden up to 24 months after treatment initiation were estimated. Adherence in the follow-up period was assessed using the medication possession ratio (MPR ≥ 80%). RESULTS: The cohort comprised 8283 LABD initiators (16% LABA, 81% LAMA and 3% LABA+LAMA) and 9246 LABA+ICS initiators with generally similar baseline characteristics; prior exacerbation rate was higher in the LABA+ICS cohort. Less than half the patients (LAMA:42%; LABA:34% and LABA+ICS:34%) were adherent to their index medication. Among adherent patients, the total annual per patient cost of COPD was £3008 for LAMA initiators, £2783 for LABA initiators and £3376 for LABA+ICS initiators; primarily due to general practitioner interactions. Among patients with a Medical Research Council dyspnea score recorded during 24 months follow-up, a substantial proportion of adherent patients (LAMA: 41%; LABA: 45%; LABA+ICS 44%) had clinically significant dyspnoea (MRC ≥ 3). CONCLUSION: Cost and symptomatic burden of COPD was high among patients initiating maintenance treatment, including patients adherent with their initial treatment. General practitioner interactions were the primary driver of costs. Further, real world studies are required to address unmet needs and optimize treatment pathways to improve COPD symptom burden and outcomes.

Cost-effectiveness of umeclidinium/vilanterol combination therapy compared to tiotropium monotherapy among symptomatic patients with chronic obstructive pulmonary disease in the UK.

BACKGROUND: The cost-effectiveness of umeclidinium bromide-vilanterol (UMEC/VI) versus tiotropium monotherapy in the UK was assessed using a UMEC/VI treatment-specific economic model based on a chronic obstructive pulmonary disease (COPD) disease-progression model. METHODS: The model was implemented as a linked-equation model to estimate COPD progression and associated health service costs, and its impact on quality-adjusted life years (QALYs) and survival. Statistical risk equations for clinical endpoints and resource use were derived from the ECLIPSE and TORCH studies, respectively. For the selected timeframe (1-40 years) and probabilistic analysis, model outputs included disaggregated costs, total costs, exacerbations, life-years and QALYs gained, and incremental cost-effectiveness ratios (ICERs). RESULTS: Random-effects meta-analysis of tiotropium comparator trials estimated treatment effect of UMEC/VI as 92.17 mL (95 % confidence interval: 61.52, 122.82) in forced expiratory volume in 1 s. With this benefit, UMEC/VI resulted in an estimated annual exacerbation reduction of 0.04 exacerbations/patient and 0.36 life years gained compared to tiotropium over patient lifetime. With an additional 0.18 QALYs/patient and an additional lifetime cost of £372/patient at price parity, the incremental cost effectiveness ratio (ICER) of UMEC/VI compared to tiotropium was £2088/QALY. This ICER increased to £17,541/QALY when price of UMEC/VI was increased to that of indacaterol plus tiotropium in separate inhalers. The ICER improved when model duration was reduced from patient lifetime to 1 or 5 years, or when treatment effect was assumed to last for 12 months following treatment initiation. CONCLUSION: UMEC/VI can be considered a cost-effective alternative to tiotropium at a certain price.

Resource Use and Costs up to Two Years Post Diagnosis Among Newly Diagnosed COPD Patients in the UK Primary Care Setting: A Retrospective Cohort Study.

The objective of this study was to estimate the annual resource use and costs before and after COPD diagnosis and compare it across stages of airflow obstruction and levels of dyspnoea in the UK primary care setting. A retrospective cohort of newly diagnosed COPD patients (1/1/2008-31/12/2009) was identified in the UK Clinical Practice Research Datalink (CPRD). Resource use did not include medication costs and comprised of exacerbations, all cause GP interactions, and non-COPD hospitalisations, which were estimated for up to 12 months before and 24 months after COPD diagnosis. It was further stratified using baseline characteristics, Medical Research Council (MRC) dyspnoea score, and stages of airflow limitation. COPD costs were estimated using NHS reference costs. The analysis included 7881 newly diagnosed COPD patients (mean age, 67.2 years; 45% females). In the 2 years follow-up, the cohort experienced moderate and severe exacerbations, non-COPD hospitalisations, and GP surgery visits at an annual rate of 0.51, 0.13, 0.47, and 12.85, respectively. All resource components showed an upward trend with increase airflow limitation and dyspnoea. GP interactions accounted for 58.5% of annual per patient COPD management costs, estimated to be £ 2047 during the observation period. The annual costs doubled from patients with low levels of dyspnoea (MRC = 1; £ 1473) to those with high levels of dyspnoea (MRC = 5; £ 3243). COPD management costs in the primary care setting continued to remain high up to 2 years following initial diagnosis. The cost burden increased with high levels of dyspnoea and airflow obstruction, suggesting that both measures can identify patients requiring increased monitoring.

Cost-effectiveness of infliximab for the treatment of active and progressive psoriatic arthritis.

BACKGROUND: Despite its proven efficacy, infliximab is often considered to be an expensive treatment for patients with psoriatic arthritis. OBJECTIVES: To estimate the cost-effectiveness of infliximab among patients with active and progressive psoriatic arthritis. METHODS: A decision analytic model was constructed to simulate disease progression in hypothetical cohorts of patients with psoriatic arthritis receiving infliximab maintenance treatment. The primary response measure was change in Health Assessment Questionnaire score from a baseline estimated from mixed treatment models drawn from published clinical trials. Palliative care, comprising nonbiologic disease-modifying antirheumatic drugs, was used as a comparator. The primary outcome was quality-adjusted life years. The dose of infliximab was estimated for a range of 60 to 80 kg per patient body weight. The costs and outcomes were discounted at 3.5% for a period of 40 years. Uncertainty around the results was explored with probabilistic sensitivity analysis. RESULTS: The mixed treatment comparison showed a significant reduction in Health Assessment Questionnaire score across all patients. The tumor necrosis factor α inhibitors were significantly superior to palliative care but comparable with one another. The incremental cost-effectiveness ratios for etanercept, adalimumab, and infliximab relative to palliative care were £17,327; £19,246; and £16,942 to £23,022, respectively, across all patients with psoriatic arthritis and £16,613; £18,170; and £15,788 to £21,736, respectively, in the subgroup with significant psoriasis. CONCLUSION: Infliximab represents a cost-effective treatment option well within the National Institute for Health and Clinical Excellence threshold relative to palliative care. In light of equivalent outcomes with other tumor necrosis factor α inhibitors, its position in the treatment pathway is likely to be governed by treatment costs.

Cost-effectiveness and budget impact of dolutegravir/lamivudine for treatment of human immunodeficiency virus (HIV-1) infection in the United States.

BACKGROUND: Dolutegravir(DTG)/lamivudine(3TC) is the first 2-drug regimen recommended as an initial treatment for people living with HIV (PLHIV). OBJECTIVE: To assess the cost-effectiveness and potential budget impact of DTG/3TC in the US healthcare setting. METHODS: A previously published hybrid decision-tree and Markov cohort state transition model was adapted to estimate the incremental costs and health outcome benefits over a patients' lifetime. DTG/3TC was compared with current standard of care in treatment naive and treatment experienced virologically suppressed PLHIV. Health states included in the model were based upon virologic response and CD4 cell count, with death as an absorbing state. Clinical data was informed by the Phase III GEMINI 1 and 2 clinical trials, a published network meta-analysis (NMA) in treatment-naive patients and the Phase III TANGO clinical trial in treatment experienced patients. Costs and utilities were informed by published data and discounted annually at a rate of 3%. A separate 5-year budget impact analysis was conducted assuming 5%-15% uptake in eligible treatment naive and 10%-30% uptake in eligible treatment experienced patients. RESULTS: In the treatment naive analyses based on GEMINI 1 and 2, DTG/3TC dominated, i.e., was less costly and more effective, than all comparators. DTG/3TC resulted in 0.083 incremental quality-adjusted life-years (QALYs) at a cost saving of $199,166 compared with the DTG + tenofovir disoproxil(TDF)/emtricitabine(FTC) comparator arm. The incremental QALY and cost savings for DTG/3TC compared with DTG/abacavir(ABC)/3TC, cobicistat-boosted darunavir(DRV/c)/tenofovir alafenamide(TAF)/FTC, and bictegravir (BIC)/TAF/FTC, based on NMA results were 0.465, 0.142, and 0.698, and $42,948, $122,846, and $44,962, respectively. In the analyses of treatment-experienced virologically suppressed patients based on TANGO, DTG/3TC offered slightly lower QALYs (-0.037) with an estimated savings of $78,730 when compared with continuation of TAF-based regimen (TBR). Sensitivity analyses demonstrated that these conclusions were relatively insensitive to alternative parameter estimates. The budget impact analysis estimated that by 5th year a total of 70,240 treatment naive patients and 1,340,480 treatment experienced patients could be eligible to be prescribed DTG/3TC. The estimated budget savings over 5 years ranged from $1.12b to $3.35b (corresponding to 27,512 to 82,536 on DTG/3TC by year 5) in the lowest and highest uptake scenarios, respectively. CONCLUSION: In conclusion, DTG/3TC with its comparable efficacy and lower drug acquisition costs, has the potential to offer significant cost savings to US healthcare payers for the initial treatment of treatment naive patients and as a treatment switching option for virologically suppressed patients. DISCLOSURES: This study was funded in full by ViiV healthcare, Brentford, UK. Medical writing to support this study was also funded in full by ViiV Healthcare, Brentford, UK. Butler, Hayward, and Jacob are employees of HEOR Ltd, the company performing this study funded by ViiV Healthcare. Anderson is an employee of GlaxoSmithKline and owns shares in the company. Punekar, Evitt, and Oglesby are employees of ViiV Healthcare and own stocks in GlaxoSmithKline.

Cost-effectiveness of scheduled maintenance treatment with infliximab for pediatric Crohn's disease.

BACKGROUND: Infliximab recently became the only biologic approved for use in pediatric patients with severe active Crohn's disease (CD). OBJECTIVES: To estimate the cost-effectiveness of scheduled maintenance treatment with infliximab compared with standard care in children suffering from severe active CD over 5 years from the UK National Health Service perspective. METHODS: A Markov model was constructed to simulate the progression of a hypothetical cohort of CD children through predefined health states on scheduled maintenance treatment with infliximab (5 mg/kg). The data to populate the model came from infliximab trials from Targan et al., ACCENT I, and REACH. The health states included in the model were remission, responding active disease, nonresponding active disease, surgery, postsurgery remission, postsurgery complications, and death. Standard care, comprising immunomodulators, and/or corticosteroids were used as a comparator. The primary outcome was quality-adjusted life-years (QALY) estimated using the EuroQol (EQ-5D) from a European CD population. To account for the weight-based dosing of infliximab, a baseline patient weight of 40 kg that increased by 5 kg/year up to 60 kg was used. The costs and outcomes were discounted at 3.5% over a period of 5 years. Probabilistic sensitivity analyses were performed by varying the infliximab efficacy estimates, costs, and utilities. RESULTS: The incremental cost-effectiveness ratio (ICER) for infliximab treatment was pound14,607 compared with standard care. The sensitivity analyses revealed the treatment effect of infliximab to be the most influential parameter with ICERs ranging from pound10,480 to pound37,017. Assuming a willingness to pay of pound30,000 per QALY, the probability of infliximab being cost-effective is 78.6%. CONCLUSION: Scheduled maintenance treatment with infliximab (5 mg/kg) is likely to be a cost-effective treatment in children suffering from severe active CD under an 8-week maintenance program.

Cost-Effectiveness of Dolutegravir as a First-Line Treatment Option in the HIV-1-Infected Treatment-Naive Patients in Russia.

OBJECTIVES: To evaluate the cost effectiveness of dolutegravir + abacavir/lamivudine (DTG + ABC/3TC) compared with raltegravir + abacavir/lamivudine (RAL + ABC/3TC) and ritonavir-boosted darunavir + abacavir/lamivudine (DRV/r + ABC/3TC) in HIV-1-infected treatment-naive patients in Russia. METHODS: A dynamic Markov model was developed with five response states and six CD4+-based health states. Efficacy estimated as probability of viral suppression (HIV RNA <50 copies/ml) at 48 weeks was obtained from a published network meta-analysis. Baseline cohort characteristics and health state utilities were informed using DTG phase 3 clinical trials. Health care resource use was obtained from literature and costed using published unit costs. Costs (presented in Russian rubles) included antiretroviral drug costs; HIV management costs such as routine care; costs of treating cardiovascular conditions, opportunistic infections, and drug-related adverse effects; and mortality costs. A patient lifetime analysis was conducted using the societal perspective. Outcomes were quality-adjusted life-years (QALYs), life-years, incremental cost per QALY ratio, and incremental cost per responder. RESULTS: The viral suppression rate among patients receiving DTG + ABC/3TC was 71.7% compared with 65.2% for RAL + ABC/3TC and 59.6% for DRV/r + ABC/3TC. The mean duration of response per patient was 116.6 months for DTG + ABC/3TC, 108.6 months for RAL + ABC/3TC, and 98.9 months for DRV/r + ABC/3TC. Total discounted costs for treatment over patient lifetime were RUB 2.89, 5.32, and 4.38 million for DTG + ABC/3TC, RAL + ABC/3TC, and DRV/r + ABC/3TC, respectively. Lifetime discounted QALYs were 12.73 for patients on DTG + ABC/3TC and 12.72 each for patients on RAL + ABC/3TC and DRV/r + ABC/3TC. DTG + ABC/3TC thus dominated the other two alternatives. CONCLUSIONS: With lower costs, higher response rates, and comparable QALYs, DTG + ABC/3TC can be considered as a cost-effective alternative.

Implications of chronic obstructive pulmonary disease (COPD) on patients' health status: a western view.

AIM: To assess and compare health status among chronic obstructive pulmonary disease (COPD) patients presenting for treatment in six countries and in two healthcare settings using a generic health status instrument. METHODS: A population based cross-sectional survey was conducted among 2703 patients and their physicians (1381 in primary and 1322 in specialty care) in five EU countries and the USA. Information was collected on demographic and clinical characteristics, exacerbations and health status estimated using EQ-5D. RESULTS: The mean EQ-5D score for COPD patients was similar between primary and specialty settings in all countries except Italy. Approximately, half of the patients indicated some impairment in health status on mobility, usual activities, pain/discomfort and anxiety/depression domains of EQ-5D. Approximately, 5% of patients in EU countries except UK had health status valued as worse than death based on valuations of the general population. Patients suffering from severe breathlessness, experiencing > or =3 exacerbations in the previous year, categorised as severe according to GOLD criteria, and experiencing day-time and night-time symptoms had significantly impaired health status. CONCLUSION: COPD patients classified as moderate/severe in clinical practice have worse health status compared to mild patients. This impairment is similar in primary and specialty setting across western countries.

Systematic review of the association between exercise tests and patient-reported outcomes in patients with chronic obstructive pulmonary disease.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is an increasingly common cause of death worldwide. Its cardinal symptoms include breathlessness and severely reduced exercise capacity. Several patient-reported outcome (PRO) measures are used to assess health-related quality of life (HRQoL), functional performance, and breathlessness in patients with COPD. Exercise testing is employed to measure functional performance objectively, which is generally believed to impact on overall HRQoL. However, the extent to which commonly used laboratory- and field-based exercise test results correlate with PROs has not been systematically assessed. MATERIALS AND METHODS: A search of Embase, MedLine, and the Cochrane Library identified primary publications in English that reported data on the correlations (Pearson's r or Spearman's ρ) between the outcomes of exercise tests and HRQoL and breathlessness PROs. Studies reporting on the following tests were included: 6-minute walk test (6MWT), 12MWT, incremental and endurance shuttle walk tests, incremental and endurance cycle ergometer tests, and treadmill tests. RESULTS: Of 3,205 articles screened, 28 were deemed eligible for inclusion. The most commonly reported HRQoL PRO measure was the St George's Respiratory Questionnaire (13 studies), and the most commonly reported breathlessness PRO measure was the Baseline Dyspnea Index (six studies). The St George's Respiratory Questionnaire appears to correlate very weakly to moderately with the 6MWT, and breathlessness PROs appear to be moderately to strongly associated with 6MWT outcomes. Across all studies, the 6MWT was the most commonly reported exercise test. Very few publications reporting associations between other exercise tests and PRO measures were found. CONCLUSION: This review found evidence to support the association of 6MWT outcomes with HRQoL and breathlessness PROs. There were limited data showing correlations with the outcomes of other exercise tests. Further work is required to examine the associations between these PROs and exercise test outcomes.

Non-persistence and non-adherence to long-acting COPD medication therapy: A retrospective cohort study based on a large German claims dataset.

OBJECTIVES: The main objectives of this study, based on a large cohort of German COPD patients, were to assess the level of non-persistence (NP) and non-adherence (NA) with long-acting COPD inhaler treatment and to describe factors that may be associated with NP and NA. METHODS: This was a retrospective cohort analysis based on claims data provided by a German statutory health insurance fund (years 2010-2012). NP was analyzed for treatment-naïve patients only; it was defined as a gap of >90 days in medication availability. With regard to NA, first the overall yearly medication possession ratio (MPR) was analyzed, NA was defined as MPR<80%. Secondly, adherence was explored only for the period in which a patient continued therapy with a long-acting COPD agent (no gap>90 days). RESULTS: 45,937 COPD patients who received at least one prescription of any long-acting COPD agent were identified (mean age 71.4 years; 45.2% female). Among these, 22,276 (42.4%) were classified as newly treated. The percentage of NP patients after 12 months was 65.3% on an overall patient level. Agent-specific NP rates were: 58.5% for LABA, 47.9% for LAMA, 78.0% for ICS, and 69.4% for single-device LABA/ICS combination treatment. The overall 12-month MPR across all agent classes on a patient level was 57.9% (70.0% of patients classified as non-adherent). During periods of general treatment continuation, the mean MPR/NA rates were 85.0%/30.1% (patient level across all agents), 89.3%/28.2% (LABA), 92.1%/16.2% (LAMA), 84.2%/43.8% (ICS) and 84.1%/42.8% (LABA/ICS combination). In the Cox regression analyses, several factors like female gender, higher CCI or lower number of specialist' visits were associated with earlier discontinuation of therapy. In comparison to LABA therapy, LAMA therapy was less likely to be associated with early NP, whereas patients who initiated ICS therapy or a single-device LABA/ICS combination therapy faced a higher NP risk. CONCLUSIONS: In German COPD patients, persistence and adherence with respect to long-acting bronchodilator therapy is poor. Approximately two thirds of patients fail to continue treatment after 12 months. In addition, about one third implement their treatment poorly during periods of general therapy continuation.

Bronchodilator reliever use and its association with the economic and humanistic burden of COPD: a propensity-matched study.

BACKGROUND AND AIMS: Short-acting bronchodilators are normally used as supplemental relief medication for breakthrough symptoms in COPD patients. The objective of this cross-sectional study was to assess if more frequent vs infrequent use of relief medication in maintenance-treated COPD patients, split by the severity dyspnea, was associated with an increase in the overall disease burden. METHODS: A population-based cross-sectional survey (Adelphi DSP) was conducted among patients with COPD in five European countries. Information was collected on demographic and clinical characteristics, reliever inhaler use, dyspnea (mMRC), health status (CAT, EQ-5D), sleep quality (JSEQ) and healthcare resource use including moderate-severe COPD exacerbations, physician visits, COPD medications and other COPD related resources. The humanistic and economic burden was compared between patients with infrequent reliever use (<1 occasion/week) and more frequent use (≥ 1 occasion/week). The association between increased reliever use and economic burden was also examined after matching patients based on propensity-scores balancing demographic and disease burden characteristics. RESULTS: Among the 1373 COPD patients prescribed a reliever inhaler, 29% reported using reliever medication ≥1 occasion/week. In the unmatched cohort, more frequent reliever use (n = 377) compared to infrequent use (n = 996) was linked to poorer health status (CAT: 25.7 vs 20.0; p < .0001; EQ-5D-3L: 0.63 vs 0.82; p < .0001) and poorer sleep quality (JSEQ: 8.6 vs 4.6 units; p < .0001). More frequent reliever use was also associated with higher annual rates of moderate/severe exacerbations (1.6 vs 1.0 events/year; p < .0001) and respiratory specialist visits (2.8 vs 2.2 events/year; p = .0001). In the propensity-score matched population, more frequent reliever use was also associated with significantly higher annual costs for COPD management (€5,034 vs €3,705, p = .0327) compared to patients with infrequent reliever use. CONCLUSION: In moderate-to-severe COPD, more frequent reliever use is associated with increased exacerbation risk and increased management costs.

Comparative efficacy of long-acting muscarinic antagonist monotherapies in COPD: a systematic review and network meta-analysis.

BACKGROUND: Randomized, controlled trials comparing long-acting muscarinic antagonist (LAMA) efficacy in COPD are limited. This network meta-analysis (NMA) assessed the relative efficacy of tiotropium 18 µg once-daily (OD) and newer agents (aclidinium 400 µg twice-daily, glycopyrronium 50 µg OD, and umeclidinium 62.5 µg OD). METHODS: A systematic literature review identified randomized, controlled trials of adult COPD patients receiving LAMAs. A NMA within a Bayesian framework examined change from baseline in trough forced expiratory volume in 1 second (FEV1), transitional dyspnea index focal score, St George's Respiratory Questionnaire score, and rescue medication use. RESULTS: Twenty-four studies (n=21,311) compared LAMAs with placebo/each other. Aclidinium, glycopyrronium, tiotropium, and umeclidinium, respectively, demonstrated favorable results versus placebo, for change from baseline (95% credible interval) in 12-week trough FEV1 (primary endpoint: 101.40 mL [77.06-125.60]; 117.20 mL [104.50-129.90]; 114.10 mL [103.10-125.20]; 136.70 mL [104.20-169.20]); 24-week trough FEV1 (128.10 mL [84.10-172.00]; 135.80 mL [123.10-148.30]; 106.40 mL [95.45-117.30]; 115.00 mL [74.51-155.30]); 24-week St George's Respiratory Questionnaire score (-4.60 [-6.76 to -2.54]; -3.14 [-3.83 to -2.45]; -2.43 [-2.92 to -1.93]; -4.69 [-7.05 to -2.31]); 24-week transitional dyspnea index score (1.00 [0.41-1.59]; 1.01 [0.79-1.22]; 0.82 [0.62-1.02]; 1.00 [0.49-1.51]); and 24-week rescue medication use (data not available; -0.41 puffs/day [-0.62 to -0.20]; -0.52 puffs/day [-0.74 to -0.30]; -0.30 puffs/day [-0.81 to 0.21]). For 12-week trough FEV1, differences in change from baseline (95% credible interval) were -12.8 mL (-39.39 to 13.93), aclidinium versus tiotropium; 3.08 mL (-7.58 to 13.69), glycopyrronium versus tiotropium; 22.58 mL (-11.58 to 56.97), umeclidinium versus tiotropium; 15.90 mL (-11.60 to 43.15), glycopyrronium versus aclidinium; 35.40 mL (-5.06 to 76.07), umeclidinium versus aclidinium; and 19.50 mL (-15.30 to 54.38), umeclidinium versus glycopyrronium. Limitations included inhaler-related factors and safety; longer-term outcomes were not considered. CONCLUSION: The new LAMAs studied had at least comparable efficacy to tiotropium, the established class standard. Choice should depend on physician's and patient's preference.

Systematic review of humanistic and economic burden of symptomatic chronic obstructive pulmonary disease.

BACKGROUND: An understanding of the humanistic and economic burden of individuals with symptomatic chronic obstructive pulmonary disease (COPD) is required to inform payers and healthcare professionals about the disease burden. OBJECTIVES: The aim of this systematic review was to identify and present humanistic [health-related quality of life (HRQoL)] and economic burdens of symptomatic COPD. METHODS: A comprehensive search of online databases (reimbursement or claims databases/other databases), abstracts from conference proceedings, published literature, clinical trials, medical records, health ministries, financial reports, registries, and other sources was conducted. Adult patients of any race or gender with symptomatic COPD were included. Humanistic and economic burdens included studies evaluating HRQoL and cost and resource use, respectively, associated with symptomatic COPD. RESULTS: Thirty-two studies reporting humanistic burden and 74 economic studies were identified. Symptomatic COPD led to impairment in the health state of patients, as assessed by HRQoL instruments. It was also associated with high economic burden across all countries. The overall, direct, and indirect costs per patient increased with an increase in symptoms, dyspnoea severity, and duration of disease. Across countries, the annual societal costs associated with symptomatic COPD were higher among patients with comorbidities. CONCLUSIONS: Symptomatic COPD is associated with a substantial economic burden. The HRQoL of patients with symptomatic COPD is, in general, low and influenced by dyspnoea.

Comparative efficacy of combination bronchodilator therapies in COPD: a network meta-analysis.

BACKGROUND: Several new fixed-dose combination bronchodilators have been recently launched, and assessing their efficacy relative to each other, and with open dual combinations is desirable. This network meta-analysis (NMA) assessed the efficacy of umeclidinium and vilanterol (UMEC/VI) with that of available dual bronchodilators in single/separate inhalers. METHODS: A systematic literature review identified randomized controlled trials of ≥10 weeks among chronic obstructive pulmonary disease patients (≥40 years), assessing the efficacy of combination bronchodilators in single or separate inhalers. Comparative assessment was conducted on change from baseline in trough forced expiratory volume in 1 second (FEV1), St George's Respiratory Questionnaire (SGRQ) total scores, transitional dyspnea index (TDI) focal scores, and rescue medication use at 12 weeks and 24 weeks using an NMA within a Bayesian framework. RESULTS: A systematic literature review identified 77 articles of 26 trials comparing UMEC/VI, indacaterol/glycopyrronium (QVA149), formoterol plus tiotropium (TIO) 18 µg, salmeterol plus TIO, or indacaterol plus TIO, with TIO and placebo as common comparators at 12 weeks and approximately 24 weeks. The NMA showed that at 24 weeks, efficacy of UMEC/VI was not significantly different compared with QVA149 on trough FEV1 (14.1 mL [95% credible interval: -14.2, 42.3]), SGRQ total score (0.18 [-1.28, 1.63]), TDI focal score (-0.30 [-0.73, 0.13]), and rescue medication use (0.02 [-0.27, 0.32]); compared with salmeterol plus TIO on trough FEV1 (67.4 mL [-25.3, 159.4]), SGRQ total score (-0.11 [-1.84, 1.61]), and TDI focal score (0.58 [-0.33, 1.50]); and compared with formoterol plus TIO 18 µg on SGRQ total score (-0.68 [-1.77, 0.39]). Results at week 12 were consistent with week 24 outcomes. Due to lack of availability of evidence, no comparison was made with formoterol plus TIO on FEV1 or TDI at 24 weeks. CONCLUSION: UMEC/VI has comparable efficacy to other dual-bronchodilator combinations on available efficacy endpoints.

Systematic Review of the Association Between Laboratory- and Field-Based Exercise Tests and Lung Function in Patients with Chronic Obstructive Pulmonary Disease.

Introduction: Typical symptoms of chronic obstructive pulmonary disease (COPD) include breathlessness and reduced exercise capacity. Several laboratory- and field-based exercise tests are used to assess the exercise capacity of patients with COPD. It is unclear whether these exercise tests reflect the spirometric measures recommended for diagnosis of COPD. We therefore aimed to systematically assess the correlation between these exercise tests and common measures of lung function. Methods: A search of Embase™, MEDLINE® and The Cochrane Library identified primary publications in English that reported data on the correlations (Pearson's r or Spearman's rho) between the outcomes of exercise tests and the physiological measures of interest: forced expiratory volume in 1 second (FEV1), forced vital capacity, inspiratory capacity and arterial oxygen saturation. We included studies reporting on the following exercise tests: 6- and 12-minute walk tests (6MWT and 12 MWT), incremental and endurance shuttle walk tests, incremental and endurance cycle ergometer tests, and treadmill tests. Results: Of 1781 articles screened, 45 were ultimately deemed eligible for inclusion in this review. The most commonly reported lung function variable was FEV1 (reported by 39 studies); the most commonly reported exercise test was the 6-minute walk test (reported by 24 studies). FEV1 appears to correlate moderately-to-strongly with 6MWT and 12MWT; and moderately-to-very strongly with incremental cycle ergometer tests (ICET); evidence for other exercise tests was limited. Conclusion: There is evidence that 6MWT, 12MWT and ICET correlate with FEV1 to some degree; - evidence for associations of other exercise tests with measures of lung function in patients with COPD is limited. Clinicians must consider this when deciding to use these tests. Further comparisons of these tests must be made in order to assess which physiological and hemodynamic characteristics they reflect in patients with COPD.

Comparison of laboratory- and field-based exercise tests for COPD: a systematic review.

Exercise tests are often used to evaluate the functional status of patients with COPD. However, to the best of our knowledge, a comprehensive systematic comparison of these tests has not been performed. We systematically reviewed studies reporting the repeatability and/or reproducibility of these tests, and studies comparing their sensitivity to therapeutic intervention. A systematic review identified primary manuscripts in English reporting relevant data on the following exercise tests: 6-minute walk test (6MWT) and 12-minute walk test, incremental and endurance shuttle walk tests (ISWT and ESWT, respectively), incremental and endurance cycle ergometer tests, and incremental and endurance treadmill tests. We identified 71 relevant studies. Good repeatability (for the 6MWT and ESWT) and reproducibility (for the 6MWT, 12-minute walk test, ISWT, ESWT, and incremental cycle ergometer test) were reported by most studies assessing these tests, providing patients were familiarized with them beforehand. The 6MWT, ISWT, and particularly the ESWT were reported to be sensitive to therapeutic intervention. Protocol variations (eg, track layout or supplemental oxygen use) affected performance significantly in several studies. This review shows that while the validity of several tests has been established, for others further study is required. Future work will assess the link between these tests, physiological mechanisms, and patient-reported measures.