RESUMO
BACKGROUND: The safe and appropriate use of long-acting beta-agonists (LABAs) for the treatment of asthma has been widely debated. In two large clinical trials, investigators found a potential risk of serious asthma-related events associated with LABAs. This study was designed to evaluate the risk of administering the LABA salmeterol in combination with an inhaled glucocorticoid, fluticasone propionate. METHODS: In this multicenter, randomized, double-blind trial, adolescent and adult patients (age, ≥12 years) with persistent asthma were assigned to receive either fluticasone with salmeterol or fluticasone alone for 26 weeks. All the patients had a history of a severe asthma exacerbation in the year before randomization but not during the previous month. Patients were excluded from the trial if they had a history of life-threatening or unstable asthma. The primary safety end point was the first serious asthma-related event (death, endotracheal intubation, or hospitalization). Noninferiority of fluticasone-salmeterol to fluticasone alone was defined as an upper boundary of the 95% confidence interval for the risk of the primary safety end point of less than 2.0. The efficacy end point was the first severe asthma exacerbation. RESULTS: Of 11,679 patients who were enrolled, 67 had 74 serious asthma-related events, with 36 events in 34 patients in the fluticasone-salmeterol group and 38 events in 33 patients in the fluticasone-only group. The hazard ratio for a serious asthma-related event in the fluticasone-salmeterol group was 1.03 (95% confidence interval [CI], 0.64 to 1.66), and noninferiority was achieved (P=0.003). There were no asthma-related deaths; 2 patients in the fluticasone-only group underwent asthma-related intubation. The risk of a severe asthma exacerbation was 21% lower in the fluticasone-salmeterol group than in the fluticasone-only group (hazard ratio, 0.79; 95% CI, 0.70 to 0.89), with at least one severe asthma exacerbation occurring in 480 of 5834 patients (8%) in the fluticasone-salmeterol group, as compared with 597 of 5845 patients (10%) in the fluticasone-only group (P<0.001). CONCLUSIONS: Patients who received salmeterol in a fixed-dose combination with fluticasone did not have a significantly higher risk of serious asthma-related events than did those who received fluticasone alone. Patients receiving fluticasone-salmeterol had fewer severe asthma exacerbations than did those in the fluticasone-only group. (AUSTRI ClinicalTrials.gov number, NCT01475721.).
Assuntos
Asma/tratamento farmacológico , Broncodilatadores/uso terapêutico , Combinação Fluticasona-Salmeterol/uso terapêutico , Fluticasona/uso terapêutico , Administração por Inalação , Adolescente , Adulto , Idoso , Asma/complicações , Asma/mortalidade , Criança , Método Duplo-Cego , Feminino , Humanos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Índice de Gravidade de DoençaRESUMO
RATIONALE: Retrospective pharmacogenetic studies have questioned whether patients with asthma who are arginine homozygous at the beta(2-)adrenergic receptor (position 16) should use long-acting beta-agonists. OBJECTIVES: To examine whether the response to salmeterol alone or in combination with an inhaled corticosteroid is influenced by beta- receptor polymorphisms. METHODS: Subjects using only as-needed albuterol were screened and completed two sequential open-label run-in periods (8 wk on as-needed albuterol; 8 wk on as-needed ipratropium). Five hundred forty-four subjects were randomized by Arg16Gly genotype to salmeterol alone or with fluticasone propionate for 16 weeks. Change from baseline in morning peak expiratory flow was the primary endpoint. MEASUREMENTS AND MAIN RESULTS: Lung function responses were sustained over treatment and no statistically significant changes from baseline between genotypes within treatments were observed. Overall mean changes in morning peak flow for salmeterol with fluticasone propionate were 32.6 L/min (Arg/Arg vs. Gly/Gly, 95% confidence interval [CI], -6.3, 22.1), 25.9 L/min (Arg/Arg vs. Arg/Gly, 95% CI, -7.1, 21.3), and 24.9 L/min (Arg/Gly vs. Gly/Gly, 95% CI, -13.0, 14.6), and for salmeterol alone were 19.4 L/min (Arg/Arg vs. Gly/Gly, 95% CI, -1.7, 21.4), 24.6 L/min (Arg/Arg vs. Arg/Gly, 95% CI, -13.0, 10.6), and 12.4 L/min (Arg/Gly vs. Gly/Gly, 95% CI, -0.2, 22.3) for Arg/Arg, Arg/Gly, and Gly/Gly genotypes, respectively. Other measures of asthma control showed similar responses. CONCLUSIONS: The results showed no evidence of a pharmacogenetic effect of beta-receptor variation on salmeterol response. Clinical trial registered with www.clinicaltrials.gov (NCT 00102882).
Assuntos
Agonistas Adrenérgicos beta/administração & dosagem , Albuterol/análogos & derivados , Androstadienos/administração & dosagem , Asma/tratamento farmacológico , Asma/genética , Receptores Adrenérgicos beta 2/genética , Adolescente , Corticosteroides/administração & dosagem , Corticosteroides/uso terapêutico , Agonistas Adrenérgicos beta/efeitos adversos , Adulto , Idoso , Albuterol/administração & dosagem , Arginina/genética , Asma/fisiopatologia , Broncodilatadores/administração & dosagem , Broncodilatadores/efeitos adversos , Criança , Feminino , Fluticasona , Glicina/genética , Humanos , Masculino , Pessoa de Meia-Idade , Farmacogenética , Polimorfismo Genético , Estudos Prospectivos , Xinafoato de Salmeterol , Adulto JovemRESUMO
We studied the relationship between body mass index (BMI) on responses to asthma therapy using a retrospective analysis of four previously reported clinical trials. Fluticasone propionate (FP)/salmeterol via Diskus 100/50 microg twice daily and montelukast (MON) 10 mg daily were compared. BMI was classified as underweight (less than 20 kg/m(2)), normal (20-24.9 kg/m(2)), overweight (25-29.9 kg/m(2)), obese-1 (30-34.9 kg/m(2)), obese-2 (35-39.9 kg/m(2)), or obese-3 (at least 40 kg/m(2)). Outcomes assessed included forced expiratory volume in one second (FEV(1)), asthma symptom score, and albuterol use. FP/salmeterol produced greater improvements compared to MON in each of the asthma outcomes studied over the entire BMI range at the week-12 endpoint, with statistically significant differences noted among normal, overweight, obese-1, and obese-3 subjects. The within-treatment responses to FP/salmeterol across BMI ranges at the week-12 endpoint was statistically significantly greater in normal compared to obese-3 for FEV(1) and albuterol use, and in overweight compared to the obese-3 for each outcome studied. The within-treatment comparisons of MON across BMI ranges were significant for albuterol use in normal and underweight compared to obese-3 at the week-12 endpoint. Compared to subjects with normal BMI, the onset to peak FEV(1) may require longer treatment exposure in the very obese. Treatment responses to FP/salmeterol were consistently greater compared to MON and persisted at higher BMI.
Assuntos
Acetatos/uso terapêutico , Albuterol/análogos & derivados , Androstadienos/uso terapêutico , Asma/complicações , Asma/tratamento farmacológico , Índice de Massa Corporal , Quinolinas/uso terapêutico , Acetatos/farmacologia , Adulto , Albuterol/farmacologia , Albuterol/uso terapêutico , Androstadienos/farmacologia , Antiasmáticos/farmacologia , Antiasmáticos/uso terapêutico , Asma/diagnóstico , Asma/fisiopatologia , Ciclopropanos , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Combinação Fluticasona-Salmeterol , Volume Expiratório Forçado/efeitos dos fármacos , Volume Expiratório Forçado/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Obesidade/complicações , Obesidade/patologia , Sobrepeso/complicações , Sobrepeso/patologia , Quinolinas/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Sulfetos , Fatores de Tempo , Resultado do TratamentoRESUMO
Increases in body mass index (BMI) are reported to influence asthma severity and response to treatment. This analysis was designed to explore whether increasing BMI altered the comparative response to treatment with either fluticasone propionate (FP) or montelukast. Two double-blind, randomized, parallel-group trials of 12-weeks duration comparing FP, 88 micrograms, twice daily or montelukast, 10 mg, daily were evaluated. Subjects with mild-moderate persistent asthma were retrospectively stratified by BMI of <20 kg/m(2) (underweight), 20-24.9 kg/m(2) (normal weight), 25-29.9 kg/m(2) (overweight), and > or =30 kg/m(2) (obese). Outcomes included mean changes in forced expiratory volume in 1 second (FEV(1)) and morning peak flow, daily albuterol use, and daily symptom scores. There were 1052 subjects evenly distributed between FP and montelukast by baseline parameters, including BMI. FP was statistically superior to montelukast for all BMI categories of normal, overweight, and obese subjects for FEV(1) (p < 0.008), morning peak flow (p < 0.002), albuterol use (p < 0.02), and symptom scores (p < 0.05). FP produced a significantly greater clinical response for normal, overweight, and obese subjects compared with montelukast. Irrespective of BMI, FP appears to be the more effective asthma controller therapy.
Assuntos
Acetatos , Androstadienos , Antiasmáticos , Asma/complicações , Asma/tratamento farmacológico , Índice de Massa Corporal , Quinolinas , Acetatos/administração & dosagem , Acetatos/uso terapêutico , Administração por Inalação , Adolescente , Adulto , Androstadienos/administração & dosagem , Androstadienos/uso terapêutico , Antiasmáticos/administração & dosagem , Antiasmáticos/uso terapêutico , Asma/fisiopatologia , Asma/prevenção & controle , Ciclopropanos , Método Duplo-Cego , Esquema de Medicação , Feminino , Fluticasona , Volume Expiratório Forçado , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/tratamento farmacológico , Sobrepeso/complicações , Sobrepeso/tratamento farmacológico , Quinolinas/administração & dosagem , Quinolinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Sulfetos , Resultado do Tratamento , Adulto JovemAssuntos
Albuterol/análogos & derivados , Androstadienos/administração & dosagem , Tolerância ao Exercício , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Derivados da Escopolamina/administração & dosagem , Idoso , Albuterol/administração & dosagem , Broncodilatadores/administração & dosagem , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Combinação Fluticasona-Salmeterol , Volume Expiratório Forçado , Humanos , Masculino , Pessoa de Meia-Idade , Resistência Física , Simpatomiméticos/administração & dosagem , Brometo de Tiotrópio , Resultado do Tratamento , CaminhadaAssuntos
Asma/tratamento farmacológico , Temas Bioéticos , Ensaios Clínicos como Assunto/ética , Corticosteroides/uso terapêutico , Agonistas Adrenérgicos beta/efeitos adversos , Agonistas Adrenérgicos beta/uso terapêutico , Albuterol/análogos & derivados , Albuterol/uso terapêutico , Asma/genética , Broncodilatadores/efeitos adversos , Broncodilatadores/uso terapêutico , Ensaios Clínicos como Assunto/métodos , Humanos , Farmacogenética , Xinafoato de SalmeterolRESUMO
BACKGROUND: Combining maintenance medications with different mechanisms of action may improve outcomes in COPD. In this study we evaluated the efficacy and safety of fluticasone/salmeterol (FSC) (250/50 mcg twice daily) when added to tiotropium (18 mcg once daily) (TIO) in subjects with symptomatic moderate to severe COPD. METHODS: This was a 24-week, randomized, double-blind, parallel group, multi-center study. Subjects 40 years or older with cigarette smoking history ≥10 pack-years and with the diagnosis of COPD and post-bronchodilator FEV(1) ≥40 to ≤ 80% of predicted normal and FEV(1)/FVC of ≤0.70 were enrolled. Following a 4-week treatment with open-label TIO 18 mcg once daily, subjects were randomized in a double-blind fashion to either the addition of FSC 250/50 DISKUS twice daily or matching placebo. The primary efficacy endpoint was AM pre-dose FEV(1) and secondary endpoints included other measures of lung function, rescue albuterol use, health status and exacerbations. RESULTS: The addition of FSC to TIO significantly improved lung function indices including AM pre-dose FEV(1), 2 h post-dose FEV(1), AM pre-dose FVC, 2 h post-dose FVC and AM pre-dose IC compared with TIO alone. Furthermore, this combination was superior to TIO alone in reducing rescue albuterol use. However, there were no significant differences between the treatment groups in health status or COPD exacerbations. The incidence of adverse events was similar in both groups. CONCLUSIONS: The addition of FSC to subjects with COPD treated with TIO significantly improves lung function without increasing the risk of adverse events. NCT00784550.
Assuntos
Albuterol/análogos & derivados , Albuterol/uso terapêutico , Androstadienos/uso terapêutico , Broncodilatadores/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Derivados da Escopolamina/uso terapêutico , Método Duplo-Cego , Combinação de Medicamentos , Quimioterapia Combinada , Feminino , Combinação Fluticasona-Salmeterol , Volume Expiratório Forçado/efeitos dos fármacos , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Testes de Função Respiratória , Brometo de Tiotrópio , Resultado do Tratamento , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: COPD is associated with increased arterial stiffness which may in part explain the cardiovascular morbidity observed in the disease. A causal relationship between arterial stiffness and cardiovascular events has not been established, though their strong association raises the possibility that therapies that reduce arterial stiffness may improve cardiovascular outcomes. Prior studies suggest that fluticasone propionate/salmeterol (FSC) may improve cardiovascular outcomes in COPD and we hypothesized that FSC would reduce arterial stiffness in these patients. METHODS: This multicenter, randomized, double-blind, placebo-controlled study compared the effects of FSC 250/50 µg twice-daily and placebo on aortic pulse wave velocity (aPWV) as determined by ECG-gated carotid and femoral artery waveforms. The primary endpoint was aPWV change from baseline at 12-weeks (last measure for each patient). RESULTS: 249 patients were randomized; the mean FEV(1) in each group was similar (55% predicted) and 60% of patients reported a cardiovascular disorder. At 12-weeks, aPWV between FSC and placebo was -0.42 m/s (95%CI -0.88, 0.03; p = 0.065). A statistically significant reduction in aPWV between FSC and placebo was observed in those who remained on study drug throughout the treatment period [-0.49 m/s (95%CI -0.98, -0.01; p = 0.045)]. A post hoc analysis suggested the effect of FSC was greater in patients with higher baseline aPWV. CONCLUSION: FSC does not reduce aPWV in all patients with moderate to severe COPD, but may have effects in those with elevated arterial stiffness. Additional studies are required to determine if aPWV could serve as a surrogate for cardiovascular events in COPD.
Assuntos
Albuterol/análogos & derivados , Androstadienos/efeitos adversos , Artérias/fisiopatologia , Doenças Cardiovasculares/fisiopatologia , Volume Expiratório Forçado/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Simpatomiméticos/efeitos adversos , Resistência Vascular/efeitos dos fármacos , Albuterol/efeitos adversos , Albuterol/farmacologia , Androstadienos/farmacologia , Artérias/efeitos dos fármacos , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Doenças Cardiovasculares/induzido quimicamente , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Combinação Fluticasona-Salmeterol , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Simpatomiméticos/farmacologia , Resultado do TratamentoRESUMO
OBJECTIVE: To explore whether obesity alters the risk, impairment and response to treatment in African Americans with asthma. METHODS: The data used for this secondary analysis are from a 1-year study in African American subjects comparing fluticasone propionate/salmeterol 100/50 microg combination (FSC) and fluticasone propionate 100 microg (FP). Subjects were retrospectively stratified by body mass index (BMI) <20 [underweight], 20-24.9 [normal weight], 25-29.9 [overweight], 30-34.9 [obese I], 35-39.9 [obese II], and >or=40 [obese III] kg/m(2). Outcomes studied included impairment domains: FEV(1), morning and evening peak expiratory flow (AM and PM PEF), daily albuterol use, daily symptom scores and future risk domain: exacerbations. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov; NCT00102765. RESULTS: There were 475 subjects evenly distributed between FSC and FP by baseline parameters. There were 207 subjects with a BMI >or=30, including 70 subjects with a BMI >or=40. Baseline BMI >or=40 was associated with numerically lower baseline AM and PM PEF. There was an attenuation of response to both treatments for only PM PEF (p < 0.05). By contrast, subjects with lower degrees of obesity or overweight did not differ from those with normal weight. The total population exacerbation rate was 2-fold greater in obese III subjects (39%) compared with subjects in other BMI categories (16-21%) (p < 0.05). A potential study limitation is the retrospective analysis of existing data. DISCUSSION: Response to treatment was attenuated for PM PEF for subjects with BMI >or=40 and was also associated with an increased rate of asthma exacerbations.
Assuntos
Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Asma/etiologia , Negro ou Afro-Americano , Índice de Massa Corporal , Adolescente , Adulto , Negro ou Afro-Americano/estatística & dados numéricos , Idoso , Asma/diagnóstico , Asma/etnologia , Criança , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: An analysis of 5 double-blinded, randomized, 12-week asthma trials was undertaken to evaluate pediatric subjects (4 to 11 years; n=276) who were previously receiving short-acting beta2-agonists alone and subsequently received treatment with placebo. At baseline, all subjects met National Asthma Education and Prevention Program criteria for moderate/severe asthma. STUDY DESIGN: Asthma severity was categorized individually for symptoms, albuterol use, and morning peak expiratory flow and then overall taking into account all three parameters. RESULTS: Subjects spent the majority of weeks (55%) in the moderate/severe category. Subjects spent approximately 48%, 31%, and 22% of weeks in intermittent, mild, and moderate/severe categories and 57%, 27%, and 15% of weeks, respectively, based on asthma symptoms and albuterol use. Subjects spent approximately 62%, 31%, and 8% of weeks in intermittent/mild, moderate, and severe categories, based on peak expiratory flow; however, >35% of subjects exhibited >or=15 changes in asthma severity classification, based on peak expiratory flow. CONCLUSIONS: Asthma is a disease with varying symptomatology, and pediatric subjects frequently move between severity categories, especially in children with inadequate asthma control. These data also emphasize that asthma severity cannot be determined in many pediatric subjects by discrete, point-in-time assessments of lung function, albuterol use, or asthma symptoms. Failure to recognize this problem may contribute to underestimation of disease severity in pediatric subjects.