Salmeterol and Fluticasone Propionate and survival in Chronic Pulmonary Disease Claverley et' al'

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Salmeterol and Fluticasone Propionate and
survival in Chronic Pulmonary DiseaseClaverley
et. al.

• Saed S. Nemr, MD
• Memorial Hospital of RI
• Alpert Medical School
• Brown University
• Journal Club 2007

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Background

• Long acting beta-agonists and inhaled
  corticosteroids are used to treat COPD, but their
  effect on survival is unknown.
• Anti-inflammatory drugs such as inhaled
  corticosteroids have little or no effect on the
  rate of decline of lung function but may reduce
  the frequency of exacerbations, especially when
  combined with an inhaled long acting B-agonist.
• Retrospective analysis suggest that inhaled
  corticosteroids reduce the mortality rate among
  patients with COPD.

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Previous study Inhaled corticosteroids and
mortality in COPD (D D Sin et. al.) Thorax 2005

• A pooled analysis, based on intention to treat,
  of individual patient data from seven randomized
  trials (involved 5085 patients).
• Effect of inhaled corticosteroids and placebo
  were compared over at least 12 months in patients
  with stable COPD.
• The end point was all-cause mortality.
• Conclusion Inhaled corticosteroids reduced
  all-cause mortality in COPD.

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Aims of the study

• The authors hypothesized that the combination of
  the long acting B-agonist Salmeterol and the
  inhaled corticosteroid Fluticasone would reduce
  mortality in pts. with COPD, as compared with
  usual care.

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TORCH study

• Patients
• -Current or former smokers with at least
  10-pack-year history.
• -Eligible patients were 40 to 80 years of
  age.
• -Have the diagnosis of COPD with
• Prebronchodilator FEV1 lt 60 of
  predicted.
• An increase of FEV1 after
  Albuterol of lt 10.
• FEV1/FVC lt or 0.70.

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Study design

• Double-blind study conducted at 444 centers in 42
  countries.
• Eligible patients were randomly assigned to
  treatment with a combination of Salmeterol
  (50mcg) and Fluticasone (500mcg), salmeterol
  alone, Fluticasone alone, or placebo.
• Study medications taken twice daily for 3 years.

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• Medications administered as a dry powder with the
  use of an inhaler.
• Inhalers collected every 12 wks to record the
  remaining doses in each inhaler to check
  adherence to study regimen.
• Before the run-in period, all corticosteroids and
  long acting bronchodilators were stopped.
  (time??).
• Patients were seen every 12 wks to confirm
  status, record unscheduled visits to health care
  providers, and record any adverse events.

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• Postbronchodilator Spirometry was assessed every
  24 wks .
• An independent safety and efficacy data
  monitoring committee performed safety reviews
  every 6 months.
• Two interim efficacy analyses were performed, the
  first after the first 358 deaths had occurred
• and the second after a total of 680 deaths had
• occurred.

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Outcome Measurements

• Vital status was assessed until 3 years after
  treatment had begun, regardless of whether the
  patients continued to take study medication.
• The primary end point was the time to death from
  any cause by 3 years.
• Secondary end points were the frequency of
• exacerbations, defined as a symptomatic
  deterioration
• requiring treatment with antibiotic agents,
  systemic corticosteroids, hospitalization, or a
  combination of these.

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• Secondary end points were assessed according to
  scores on the St. Georges Respiratory
  Questionnaire. 16 scores are based on a scale of
  0 to 100, with lower scores indicating better
  functioning.
• A change of 4 units is generally considered
• clinically relevant.
• For patients who withdrew from the study
  prematurely, all data on exacerbations, health
  status, and lung function available at the time
  of a patients withdrawal from the study were
  included in the analysis.

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Results

• Of 8554 patients recruited, 6184 underwent
  randomization.
• The mean age was 65 years, and the mean value of
  postbronchodilator FEV1 was 44 of the predicted
  value.
• During the year before entry into the study, more
  than half the patients had used inhaled
  corticosteroids, a long-acting beta-agonist, or
  both, and 57 of the patients had reported an
  exacerbation.

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Statistical Analysis

• The difference in times to death from any cause
  between the combination-therapy group and the
  placebo group was analyzed with the use of the
  log-rank test (with stratification according to
  smoking status) and expressed as a hazard Ratio.
  A Cox proportional-hazards model was used as a
  supportive secondary analysis.
• The frequency of exacerbations was analyzed with
  the use of a generalized linear model.
• All efficacy analyses were performed according to
  the intention-to-treat principle.

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• The proportion of patients who withdrew from the
  study was significantly higher in the placebo
  group (44) than in the three other groups, and
  the proportion was lowest in the
  combination-therapy group (34).
• The rate of adherence to treatment was similar in
  all groups ranging from 88 to 89 of the
  prescribed doses taken.

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Mortality

• Vital status was known at 3 years for 6111 of the
• 6112 patients included in the efficacy
  population.
• There were 875 deaths within 3 years after
  randomization.
• The proportions of deaths from any cause at 3
  years were 12.6 in the combination therapy
  group, 15.2 in the placebo group, 13.5 in the
  salmeterol group, and 16.0 in the fluticasone
  group.
• The absolute risk reduction for death in the
  combination-therapy group as compared with the
  placebo group was 2.6.
• Overall, 27 of the deaths were adjudicated as
  due to cardiovascular causes, 35 to pulmonary
  causes, and 21 to cancer.

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Exacerbations, Health Status, and LungFunction

• The annual rate of exacerbations was 0.85 (95
  CI, 0.80 to
• 0.90) in the combination-therapy group and 1.13
  (95 CI, 1.07 to 1.20) in the placebo group,
  resulting in a rate ratio for exacerbations of
  0.75 (95 CI, 0.69 to 0.81 Plt0.001).
• corresponds to a number needed to treat of four
  to prevent one exacerbation in 1 year.
• Annual rates of exacerbations in the salmeterol
  group and the fluticasone group were
  significantly lower than in the placebo group.
• Health status and FEV1 (see figures).

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Discussion and results

• The reduction in mortality from any cause in the
  combination-therapy group, as compared with the
  placebo group, did not meet the predetermined
  level of statistical significance.
• Treatment with the combination regimen resulted
  in significantly fewer exacerbations and improved
  health status and lung function, as compared with
  placebo.

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Thank you