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Long-Term Evaluation of the Effects of Aclidinium Bromide on Major Adverse Cardiovascular Events and COPD Exacerbations in Patients with Moderate to Very Severe COPD: Rationale and Design of the ASCENT COPD Study.

ABSTRACT: Introduction: Chronic obstructive pulmonary disease (COPD) is a heterogeneous illness characterized by persistent airflow obstruction and exacerbations. Patients typically experience a decline in lung function, increasingly impaired health-related quality of life, and high mortality. Poor lung function and exacerbations are associated with an increased risk of cardiovascular (CV) and cerebrovascular events, and approximately 30% of patients with COPD die from CV?related disease. Treatment with inhaled long-acting bronchodilators, such as long-acting muscarinic antagonists (LAMAs), is recommended; however, some studies have suggested that LAMAs may increase the risk of CV events. As patients with CV and cerebrovascular conditions are often excluded from clinical trials, an evaluation of the safety of COPD treatments in an at-risk population is vital. Aclidinium bromide is a LAMA approved for the long-term maintenance treatment of COPD. Methods and Objectives: The Phase 4, multicenter, double-blind, randomized, placebo-controlled, parallel-group Aclidinium Bromide on Long-Term Cardiovascular Safety and COPD Exacerbations in PatieNTs with Moderate to Very Severe COPD (ASCENT COPD) study (NCT01966107) is being conducted at 500 sites in the United States and Canada. The primary objectives are to evaluate the long-term effects of twice-daily aclidinium bromide 400 µg on CV safety and exacerbations in patients with moderate to very severe COPD with a history of cerebrovascular, coronary, or peripheral artery disease, or the presence of ?2 atherothrombotic risk factors. The primary safety and efficacy variables are time to first major adverse CV event (MACE) (on-study analysis) and rate of moderate to severe COPD exacerbations during the first year of treatment (on-treatment analysis), respectively. The study will be terminated after approximately 122 MACE have occurred.

SUBMITTER: Wise RA

PROVIDER: S-EPMC5870740 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Long-Term Evaluation of the Effects of Aclidinium Bromide on Major Adverse Cardiovascular Events and COPD Exacerbations in Patients with Moderate to Very Severe COPD: Rationale and Design of the ASCENT COPD Study.

Wise Robert A RA Chapman Kenneth R KR Scirica Benjamin M BM Schoenfeld David A DA Bhatt Deepak L DL Daoud Sami Z SZ Seoane Beatriz B Reisner Colin C Garcia Gil Esther E

Chronic obstructive pulmonary diseases (Miami, Fla.) 20180124 1

<b>Introduction:</b> Chronic obstructive pulmonary disease (COPD) is a heterogeneous illness characterized by persistent airflow obstruction and exacerbations. Patients typically experience a decline in lung function, increasingly impaired health-related quality of life, and high mortality. Poor lung function and exacerbations are associated with an increased risk of cardiovascular (CV) and cerebrovascular events, and approximately 30% of patients with COPD die from CV‑related disease. Treatment ...[more]

PMID: 29629400

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Project description:ImportanceThere is concern that long-acting muscarinic antagonists increase cardiovascular morbidity or mortality in patients with chronic obstructive pulmonary disease (COPD).ObjectiveTo determine the cardiovascular safety (noninferiority) and efficacy (superiority) of aclidinium bromide, 400 μg twice daily, in patients with COPD and cardiovascular disease or risk factors.Design, setting, and participantsMulticenter, randomized, placebo-controlled, double-blind, parallel-design study conducted at 522 sites in North America. A total of 3630 patients with moderate to very severe COPD and either a history of cardiovascular disease or at least 2 atherothrombotic risk factors were randomized; follow-up occurred for up to 3 years until at least 122 major adverse cardiovascular events (MACE) occurred. The first patient was enrolled on October 16, 2013 and the last on August 22, 2016. The final patient completed follow-up on September 21, 2017.InterventionsPatients were randomized to receive aclidinium (n = 1812) or placebo (n = 1818) by dry-powder inhaler, twice daily for up to 3 years.Main outcomes and measuresThe primary safety end point was time to first MACE over up to 3 years (hazard ratio [HR] 1-sided 97.5% CI noninferiority margin = 1.8). The primary efficacy end point was the annual COPD exacerbation rate during the first year of treatment. Secondary outcomes included an expanded MACE definition (time to first MACE or serious cardiovascular event of interest) and annual rate of exacerbations requiring hospitalization.ResultsAmong 3589 patients analyzed (mean age, 67.2 years; 58.7% male), 2537 (70.7%) completed the study. Of these, 69 (3.9%) aclidinium and 76 (4.2%) placebo patients had a MACE (HR, 0.89; 1-sided 97.5% CI, 0-1.23); the expanded MACE definition included 168 (9.4%) aclidinium vs 160 (8.9%) placebo patients with events (HR, 1.03; 1-sided 97.5% CI, 0-1.28). Annual moderate to severe exacerbation rates (aclidinium, 0.44; placebo, 0.57; rate ratio, 0.78; 2-sided 95% CI, 0.68-0.89; P < .001) and rate of exacerbations requiring hospitalization (aclidinium, 0.07; placebo, 0.10; rate ratio, 0.65; 2-sided 95% CI, 0.48-0.89; P = .006) decreased significantly with aclidinium vs placebo. The most common adverse events were pneumonia (aclidinium, 109 events [6.1%]; placebo, 105 events [5.8%]), urinary tract infection (aclidinium, 93 events [5.2%]; placebo, 89 events [5.0%]), and upper respiratory tract infection (aclidinium, 86 events [4.8%]; placebo, 101 events [5.6%]).Conclusions and relevanceAmong patients with COPD and increased cardiovascular risk, aclidinium was noninferior to placebo for risk of MACE over 3 years. The rate of moderate to severe COPD exacerbations was reduced over the first year.Trial registrationClinicalTrials.gov Identifier: NCT01966107.

Project description:IntroductionLong-acting muscarinic antagonists (LAMAs), long-acting β2-agonists (LABAs), inhaled corticosteroids (ICS), and their combinations, are recommended for the treatment of chronic obstructive pulmonary disease (COPD). This study aimed to determine whether the safety and efficacy of aclidinium bromide differs by baseline maintenance LABA and ICS therapies.MethodsASCENT-COPD was a phase 4, multicenter, double-blind, randomized, placebo-controlled, parallel-group study of patients with moderate-to-very severe COPD and increased cardiovascular risk. Patients were randomized 1:1 to receive aclidinium 400 μg or placebo twice daily, via a multidose dry-powder inhaler for up to 3 years. Outcomes included time to first major adverse cardiovascular events (MACE), all-cause mortality, change from baseline in trough forced expiratory volume in 1 s (FEV1), and COPD assessment test (CAT) total score over 3 years, and annual moderate-to-severe COPD exacerbation rate in patients receiving aclidinium or placebo with maintenance LABA monotherapy, ICS monotherapy, LABA + ICS (fixed/free), or no maintenance therapy (neither LABA nor ICS) at baseline.ResultsA total of 3589 patients were included (LABA, n = 227; ICS, n = 290; LABA + ICS, n = 2058; no maintenance, n = 1130). Aclidinium did not increase the risk of MACE or all-cause mortality versus placebo, regardless of baseline maintenance treatment. Reductions in moderate-to-severe exacerbation rates were observed with aclidinium versus placebo in all subgroups [LABA 43% (P = 0.046); ICS 25% (P = 0.202); LABA + ICS 22% (P = 0.003); no maintenance 18% (P = 0.130)]. Aclidinium improved morning trough FEV1 irrespective of baseline therapy and CAT total scores, except for LABA and ICS subgroups, versus placebo at several time points.ConclusionIn patients with moderate-to-severe COPD and CV risk factors, the addition of aclidinium to maintenance therapy with LABA or LABA + ICS provided further benefit.Trial registrationClinicalTrials.gov identifier NCT01966107.

Project description:Aclidinium-formoterol 400/12 µg is a long-acting muscarinic antagonist (LAMA) and a long-acting ?2-agonist in a fixed-dose combination used in the management of patients with COPD. This study aimed to assess the cost-effectiveness of aclidinium-formoterol 400/12 µg against the long-acting muscarinic antagonist aclidinium bromide 400 µg.A five-health-state Markov transition model with monthly cycles was developed using MS Excel to simulate patients with moderate-to-severe COPD and their initial lung-function improvement following treatment with aclidinium-formoterol 400/12 µg or aclidinium 400 µg. Health states were based on severity levels defined by Global Initiative for Chronic Obstructive Lung Disease 2010 criteria. The analysis was a head-to-head comparison without step-up therapy, from the NHS Scotland perspective, over a 5-year time horizon. Clinical data on initial lung-function improvement were provided by a pooled analysis of the ACLIFORM and AUGMENT trials. Management, event costs, and utilities were health state-specific. Costs and effects were discounted at an annual rate of 3.5%. The outcome of the analysis was expressed as cost (UK£) per quality-adjusted life-year (QALY) gained. The analysis included one way and probabilistic sensitivity analyses to investigate the impact of parameter uncertainty on model outputs.Aclidinium-formoterol 400/12 µg provided marginally higher costs (£41) and more QALYs (0.014), resulting in an incremental cost-effectiveness ratio of £2,976/QALY. Sensitivity analyses indicated that results were robust to key parameter variations, and the main drivers were: mean baseline forced expiratory volume in 1 second (FEV1), risk of exacerbation, FEV1 improvement from aclidinium-formoterol 400/12 µg, and lung-function decline. The probability of aclidinium-formoterol 400/12 µg being cost-effective (using a willingness-to-pay threshold of £20,000/QALY) versus aclidinium 400 µg was 79%.In Scotland, aclidinium-formoterol 400/12 µg can be considered a cost-effective treatment option compared to aclidinium 400 µg alone in patients with moderate-to-severe COPD.

Project description:BACKGROUND:The combination of aclidinium bromide, a long-acting anticholinergic, and formoterol fumarate, a long-acting beta2-agonist (400/12 ?g twice daily) achieves improvements in lung function greater than either monotherapy in patients with chronic obstructive pulmonary disease (COPD), and is approved in the European Union as a maintenance treatment. The effect of this combination on symptoms of COPD and exacerbations is less well established. We examined these outcomes in a pre-specified analysis of pooled data from two 24-week, double-blind, parallel-group, active- and placebo-controlled, multicentre, randomised Phase III studies (ACLIFORM and AUGMENT). METHODS:Patients ?40 years with moderate to severe COPD (post-bronchodilator forced expiratory volume in 1 s [FEV1]/forced vital capacity <70 % and FEV1??30 % but <80 % predicted normal) were randomised (ACLIFORM: 2:2:2:2:1; AUGMENT: 1:1:1:1:1) to twice-daily aclidinium/formoterol 400/12 ?g or 400/6 ?g, aclidinium 400 ?g, formoterol 12 ?g or placebo via Genuair™/Pressair®. Dyspnoea (Transition Dyspnoea Index; TDI), daily symptoms (EXAcerbations of Chronic pulmonary disease Tool [EXACT]-Respiratory Symptoms [E-RS] questionnaire), night-time and early-morning symptoms, exacerbations (Healthcare Resource Utilisation [HCRU] and EXACT definitions) and relief-medication use were assessed. RESULTS:The pooled intent-to-treat population included 3394 patients. Aclidinium/formoterol 400/12 ?g significantly improved TDI focal score versus placebo and both monotherapies at Week 24 (all p?<?0.05). Over 24 weeks, significant improvements in E-RS total score, overall night-time and early-morning symptom severity and limitation of early-morning activities were observed with aclidinium/formoterol 400/12 ?g versus placebo and both monotherapies (all p?<?0.05). The rate of moderate or severe HCRU exacerbations was significantly reduced with aclidinium/formoterol 400/12 ?g compared with placebo (p?<?0.05) but not monotherapies; the rate of EXACT-defined exacerbations was significantly reduced with aclidinium/formoterol 400/12 ?g versus placebo (p?<?0.01) and aclidinium (p?<?0.05). Time to first HCRU or EXACT exacerbation was longer with aclidinium/formoterol 400/12 ?g compared with placebo (all p?<?0.05) but not the monotherapies. Relief-medication use was reduced with aclidinium/formoterol 400/12 ?g versus placebo and aclidinium (p?<?0.01). CONCLUSIONS:Aclidinium/formoterol 400/12 ?g significantly improves 24-hour symptom control compared with placebo, aclidinium and formoterol in patients with moderate to severe COPD. Furthermore, aclidinium/formoterol 400/12 ?g reduces the frequency of exacerbations compared with placebo. TRIAL REGISTRATION:NCT01462942 and NCT01437397 (ClinicalTrials.gov).

Project description:Retrospective studies have shown that statins decrease the rate and severity of exacerbations, the rate of hospitalization, and mortality in chronic obstructive pulmonary disease (COPD). We prospectively studied the efficacy of simvastatin in preventing exacerbations in a large, multicenter, randomized trial.We designed the Prospective Randomized Placebo-Controlled Trial of Simvastatin in the Prevention of COPD Exacerbations (STATCOPE) as a randomized, controlled trial of simvastatin (at a daily dose of 40 mg) versus placebo, with annual exacerbation rates as the primary outcome. Patients were eligible if they were 40 to 80 years of age, had COPD (defined by a forced expiratory volume in 1 second [FEV1] of less than 80% and a ratio of FEV1 to forced vital capacity of less than 70%), and had a smoking history of 10 or more pack-years, were receiving supplemental oxygen or treatment with glucocorticoids or antibiotic agents, or had had an emergency department visit or hospitalization for COPD within the past year. Patients with diabetes or cardiovascular disease and those who were taking statins or who required statins on the basis of Adult Treatment Panel III criteria were excluded. Participants were treated from 12 to 36 months at 45 centers.A total of 885 participants with COPD were enrolled for approximately 641 days; 44% of the patients were women. The patients had a mean (±SD) age of 62.2±8.4 years, an FEV1 that was 41.6±17.7% of the predicted value, and a smoking history of 50.6±27.4 pack-years. At the time of study closeout, the low-density lipoprotein cholesterol levels were lower in the simvastatin-treated patients than in those who received placebo. The mean number of exacerbations per person-year was similar in the simvastatin and placebo groups: 1.36±1.61 exacerbations and 1.39±1.73 exacerbations, respectively (P=0.54). The median number of days to the first exacerbation was also similar: 223 days (95% confidence interval [CI], 195 to 275) and 231 days (95% CI, 193 to 303), respectively (P=0.34). The number of nonfatal serious adverse events per person-year was similar, as well: 0.63 events with simvastatin and 0.62 events with placebo. There were 30 deaths in the placebo group and 28 in the simvastatin group (P=0.89).Simvastatin at a daily dose of 40 mg did not affect exacerbation rates or the time to a first exacerbation in patients with COPD who were at high risk for exacerbations. (Funded by the National Heart, Lung, and Blood Institute and the Canadian Institutes of Health Research; STATCOPE ClinicalTrials.gov number, NCT01061671.).

Dataset Information

Long-Term Evaluation of the Effects of Aclidinium Bromide on Major Adverse Cardiovascular Events and COPD Exacerbations in Patients with Moderate to Very Severe COPD: Rationale and Design of the ASCENT COPD Study.

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Long-Term Evaluation of the Effects of Aclidinium Bromide on Major Adverse Cardiovascular Events and COPD Exacerbations in Patients with Moderate to Very Severe COPD: Rationale and Design of the ASCENT COPD Study.

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