The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol.

STUDY OBJECTIVE To compare the safety of salmeterol xinafoate or placebo added to usual asthma care. DESIGN A 28-week, randomized, double-blind, placebo-controlled, observational study. SETTING Study subjects were seen once in the study physician's office for screening and were provided all blinded study medication for the entire study period. Follow-up by telephone was scheduled every 4 weeks. PARTICIPANTS Subjects (> 12 years old) with asthma as judged by the study physician were eligible. Individuals with a history of long-acting beta2-agonist use were excluded. INTERVENTIONS Salmeterol, 42 mug bid via metered-dose inhaler (MDI), and placebo bid via MDI. MEASUREMENTS AND RESULTS Following an interim analysis in 26,355 subjects, the study was terminated due to findings in African Americans and difficulties in enrollment. The occurrence of the primary outcome, respiratory-related deaths, or life-threatening experiences was low and not significantly different for salmeterol vs placebo (50 vs 36; relative risk [RR] = 1.40; 95% confidence interval [CI], 0.91 to 2.14). There was a small, significant increase in respiratory-related deaths (24 vs 11; RR, 2.16; 95% CI, 1.06 to 4.41) and asthma-related deaths (13 vs 3; RR, 4.37; 95% CI, 1.25 to 15.34), and in combined asthma-related deaths or life-threatening experiences (37 vs 22; RR, 1.71; 95% CI, 1.01 to 2.89) in subjects receiving salmeterol vs placebo. The imbalance occurred largely in the African-American subpopulation: respiratory-related deaths or life-threatening experiences (20 vs 5; RR, 4.10; 95% CI, 1.54 to 10.90) and combined asthma-related deaths or life-threatening experiences (19 vs 4; RR, 4.92; 95% CI, 1.68 to 14.45) in subjects receiving salmeterol vs placebo. CONCLUSIONS For the primary end point in the total population, there were no significant differences between treatments. There were small, but statistically significant increases in respiratory-related and asthma-related deaths and combined asthma-related deaths or life-threatening experiences in the total population receiving salmeterol. Subgroup analyses suggest the risk may be greater in African Americans compared with Caucasian subjects. Whether this risk is due to factors including but not limited to a physiologic treatment effect, genetic factors, or patient behaviors leading to poor outcomes remains unknown.

[1]  B. Butland,et al.  Bronchodilator treatment and deaths from asthma: case-control study , 2004, BMJ : British Medical Journal.

[2]  A. Fuhlbrigge,et al.  How and by whom care is delivered influences anti-inflammatory use in asthma: Results of a national population survey. , 2003, The Journal of allergy and clinical immunology.

[3]  S. Dzik.  Early goal-directed therapy in the treatment of severe sepsis and septic shock , 2002 .

[4]  D. Mannino,et al.  Surveillance for asthma--United States, 1980-1999. , 2002, Morbidity and mortality weekly report. Surveillance summaries.

[5]  M. Kennedy,et al.  Beta-adrenergic receptor polymorphisms and drug responses in asthma. , 2002, Pharmacogenomics.

[6]  J. Ford,et al.  Reducing disparities in asthma care: priorities for research--National Heart, Lung, and Blood Institute workshop report. , 2002, The Journal of allergy and clinical immunology.

[7]  R. Pauwels,et al.  Low-dose inhaled corticosteroids and the prevention of death from asthma. , 2000, The New England journal of medicine.

[8]  Richard M. Martin,et al.  Age- and Gender-Specific Asthma Death Rates in Patients Taking Long-Acting β2-Agonists , 2001 .

[9]  R S Judson,et al.  Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[10]  S. Shrewsbury,et al.  Meta-analysis of increased dose of inhaled steroid or addition of salmeterol in symptomatic asthma (MIASMA) , 2000, BMJ : British Medical Journal.

[11]  C. Wentworth,et al.  Risk of emergency care, hospitalization, and ICU stays for acute asthma among recipients of salmeterol. , 1998, American journal of respiratory and critical care medicine.

[12]  J. Donahue,et al.  Inhaled Steroids and the Risk of Hospitalization for Asthma , 1998 .

[13]  L. Crossland,et al.  Case-control study of salmeterol and near-fatal attacks of asthma. , 1998, Thorax.

[14]  H. Jick,et al.  Drug use and pulmonary death rates in increasingly symptomatic asthma patients in the UK. , 1997, Thorax.

[15]  R. Mann,et al.  Salmeterol: a study by prescription-event monitoring in a UK cohort of 15,407 patients. , 1996, Journal of clinical epidemiology.

[16]  W. Castle,et al.  Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment. , 1993, BMJ.

[17]  J Crane,et al.  Prescribed fenoterol and death from asthma in New Zealand, 1981-7: a further case-control study. , 1991, Thorax.

[18]  N. Pearce,et al.  Case-control study of prescribed fenoterol and death from asthma in New Zealand, 1977-81. , 1990, Thorax.

[19]  N. Pearce,et al.  PRESCRIBED FENOTEROL AND DEATH FROM ASTHMA IN NEW ZEALAND, 1981-83; CASE-CONTROL STUDY , 1989, The Lancet.

[20]  Stolley Pd.  Asthma mortality. Why the United States was spared an epidemic of deaths due to asthma. , 1972 .

[21]  P. Stolley.  Asthma mortality. Why the United States was spared an epidemic of deaths due to asthma. , 1972, The American review of respiratory disease.

[22]  F. Speizer,et al.  Investigation into use of drugs preceding death from asthma. , 1968, British medical journal.