TORCH

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Calverley PM, et al. "Salmeterol and Fluticasone Propionate and Survival in Chronic Obstructive Pulmonary Disease". The New England Journal of Medicine. 2007. 356(8):775-789.
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Clinical Question

In patients with COPD, what are the effects of combination therapy with salmeterol and fluticasone propionate on mortality?

Bottom Line

Among patients with COPD, combination salmeterol/fluticasone therapy was associated with a reduction in the rate of COPD exacerbation and hospitalizations, but there was only a trend towards improved survival at 3 years (P=0.052).

Major Points

Published in 2007, the Towards a Revolution in COPD Health (TORCH) trial studied 6,112 patients with COPD randomized to salmeterol/fluticasone, salmeterol, fluticasone, or placebo. At 3 years of follow-up, all active treatments slowed lung function decline and improved health-related quality of life compared to placebo. Combination salmeterol/fluticasone was associated with a 25% reduction in exacerbations, corresponding to a NNT of 4 to prevent one exacerbation in 1 year, and a 17% reduction in COPD-related hospitalizations, corresponding to a NNT of 32 to prevent one hospitalization in 1 year. Of note, this is counter-balanced by a 49% increased risk of pneumonia associated with inhaled steroid therapy, corresponding to a NNH of 17.

The TORCH and UPLIFT trials are among the largest COPD trials ever undertaken. In TORCH, there was a trend toward a decrease in mortality, although this reduction did not meet the predetermined level of statistical significance. However, the survival benefit of therapy may actually be larger than reported, as 44% of patients in the placebo group left the study to receive treatment compared to 36% of patients in the active treatment groups.[1]

Whether inhaled corticosteroids such as fluticasone need to be continued in patients with COPD, or whether they can be safely weaned off was addressed in the WISDOM trial (2014).

Guidelines

GOLD COPD (2015, adapted)[2]

  • Regular use of ICS improves symptoms, lung function, QOL, and reduces exacerbations in those with COPD and FEV1 <60% of predicted (evidence A)
  • Withdrawal of ICS may cause exacerbations in some patients, though gradual withdrawal over three months doesn't increase risk of exacerbations in the medium term
    • This withdrawal is associated with significant deterioration of lung function
  • Regular use of ICS doesn't alter FEV1 decline or mortality (evidence A)
  • Definitions of severity of airflow limitation, post-bronchodilation:
    • GOLD 1 (mild): FEV1 ≥80% of predicted
    • GOLD 2 (moderate): FEV1 50-80% of predicted
    • GOLD 3 (severe): FEV1 30-50% of predicted
    • GOLD 4 (very severe): FEV1 ≤30% of predicted

Design

  • Multicenter, double-blinded, parallel-group, randomized, placebo-controlled trial
  • N=6,112 patients with COPD
    • Salmeterol/fluticasone (n=1,533)
    • Salmeterol (n=1,521)
    • Fluticasone (n=1,534)
    • Placebo (n=1,524)
  • Setting: 444 centers in 42 countries
  • Mean follow-up: 3 years
  • Analysis: Intention-to-treat

Population

Inclusion Criteria

  • Age 40-80 years
  • Diagnosis of COPD:
    • Prebronchodilator FEV1 <60% predicted,
    • Poor reversibility of airflow obstruction, define as <10% predicted increase in FEV1 after inhalation of 400 μg of albuterol <10% predicted, and
    • Prebronchodilator FEV1/FVC ≤0.70
  • Current or former smokers with a ≥10 pack-year history

Exclusion Criteria

  • Asthma
  • Non-COPD pulmonary condition (e.g., lung cancer, sarcoidosis, tuberculosis, lung fibrosis)
  • CXR indicating diagnosis other than COPD that might interfere with study
  • Prior lung-volume reduction surgery and/or lung transplant
  • Long-term supplemental oxygen ≥12h/day
  • >6 weeks of oral corticosteroids
  • Serious, uncontrolled disease (including serious psychological disorders) likely to interfere with study and/or likely to cause death within 3-year study duration
  • Received any other investigational drugs in last 4 weeks prior to entry
  • Evidence of alcohol, drug, or solvent abuse
  • Known or suspected hypersensitivity to inhaled corticosteroids, bronchodilators, or lactose
  • Known deficiency of α1-antitrypsin

Baseline Characteristics

  • Age: 65 years
  • Male: 76%
  • BMI: 25.4 kg/m²
  • Geographic region: US (23%), Asia-Pacific (12%), Eastern Europe (19%), Western Europe (31%)
  • Current smoker: 43%, 49 pack-years
  • Previous treatment: >50%
    • Inhaled corticosteroid: 20%
    • LABA: 9%
    • Inhaled corticosteroid plus LABA : 28%
  • Lung function:
    • Prebronchodilator FEV1: 1.12 L
    • Postbronchodilator FEV1: 1.22 L
    • FEV1: 44% predicted
    • Reversibility: 3.7% predicted FEV1
    • Prebronchodilator FEV1/FVC: 48.7%
  • Total score at baseline on SGRQ: 49.5

Interventions

  • 2-week run-in period in which all inhaled corticosteroids and inhaled long-acting bronchodilators discontinued
  • 156-week (3 year) randomisation period. Eligible patients randomized, in permuted blocks with stratification according to country and smoking status, to one of following:
    • Combination salmeterol 50μg/fluticasone 500μg strength inhaler
    • Salmeterol 50μg strength inhaler
    • Fluticasone 500μg strength inhaler
    • Placebo inhaler
  • Clinic visits occurred 12-weekly (0, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, and 156 weeks)
    • Inhalers collected every 12 weeks, and number of doses remaining in each inhaler was recorded to check adherence
  • Posbronchodilator spirometry and health status assessed every 24 weeks
  • 2-week follow-up

Outcomes

Primary Outcomes

All-cause mortality at 3 years
Combination vs. placebo: 12.6% vs. 15.2% (HR 0.825, 95% CI 0.68-1.00, P=0.052)
Combination vs. salmeterol: 12.6% vs. 13.5% (HR 0.932, 95% CI 0.765-1.134, P=0.48)
Combination vs. fluticasone: 12.6% vs. 16.0% (HR 0.774, 95% CI 0.641-0.934, P=0.007)
Salmeterol vs. placebo: 13.5% vs. 15.2% (HR 0.879, 95% CI 0.729-1.061, P=0.18)
Fluticasone vs. placebo: 16.0% vs. 15.2% (HR 1.060, 95% CI 0.886-1.268, P=0.53)
COPD-related mortality at 3 years
Combination vs. placebo: 4.7% vs. 6.0% (HR 0.78, 95% CI 0.57-1.06, P=0.011)
Combination vs. salmeterol: 4.7% vs. 6.1% (HR 0.77, 95% CI 0.56-1.04, P=0.09)
Combination vs. fluticasone: 4.7% vs. 6.9% (HR 0.67, 95% CI 0.50-0.90, P=0.008)
Salmeterol vs. placebo: 6.1% vs. 6.0% (HR 1.01, 95% CI 0.76-1.35, P=0.93)
Fluticasone vs. placebo: 6.9% vs. 6.0% (HR 1.16, 95% CI 0.88-1.53, P=0.30)

Secondary Outcomes

Annual rate of moderate or severe exacerbations
Combination vs. placebo: 0.85 vs. 1.13 (RR 0.75, 95% CI 0.69-0.81, P<0.001)
Combination vs. salmeterol: 0.85 vs. 0.97 (RR 0.88, 95% CI 0.81-0.95, P=0.002)
Combination vs. fluticasone: 0.85 vs. 0.93 (RR 0.91, 95% CI 0.84-0.99, P=0.02)
Salmeterol vs. placebo: 0.87 vs. 1.13 (RR 0.85, 95% CI 0.78-0.93, P<0.001)
Fluticasone vs. placebo: 0.93 vs. 1.13 (RR 0.82, 95% CI 0.76-0.89, P<0.001)
Annual rate of moderate exacerbations (defined as requiring systemic corticosteroids)
Combination vs. placebo: 0.46 vs. 0.80 (RR 0.57, 95% CI 0.51-0.64, P<0.001)
Combination vs. salmeterol: 0.46 vs. 0.64 (RR 0.71, 95% CI 0.63-0.79, P<0.001)
Combination vs. fluticasone: 0.46 vs. 0.52 (RR 0.87, 95% CI 0.78-0.98, P=0.02)
Salmeterol vs. placebo: 0.64 vs. 0.80 (RR 0.80, 95% CI 0.72-0.90, P<0.001)
Fluticasone vs. placebo: 0.52 vs. 0.80 (RR 0.65, 95% CI 0.58-0.73, P<0.001)
Annual rate of severe exacerbations (defined as requiring hospitalization)
Combination vs. placebo: 0.16 vs. 0.19 (RR 0.83, 95% CI 0.71-0.98, P=0.03)
Combination vs. salmeterol: 0.16 vs. 0.16 (RR 1.02, 95% CI 0.87-1.20, P=0.79)
Combination vs. fluticasone: 0.16 vs. 0.17 (RR 0.95, 95% CI 0.82-1.12, P=0.56)
Salmeterol vs. placebo: 0.16 vs. 0.19 (RR 0.82, 95% CI 0.69-0.96, P=0.02)
Fluticasone vs. placebo: 0.17 vs. 0.19 (RR 0.88, 95% CI 0.74-1.03, P=0.10)
Health status, as measured by adjusted mean change in SGRQ score averaged over 3 years (units)
Higher indicated worse overall health function.[3]
Combination vs. placebo: -3.0 vs. +0.2 (δ-3.1, 95% CI -4.1 to -2.1, P<0.001)
Combination vs. salmeterol: -3.0 vs. -0.8 (δ-2.2, 95% CI -3.1 to -1.2, P<0.001)
Combination vs. fluticasone: -3.0 vs. -1.8 (δ-1.2, 95% CI -2.1 to -0.2, P=0.02)
Salmeterol vs. placebo: -0.8 vs. +0.2 (δ-1.0, 95% CI -2.0 to 0, P=0.06)
Fluticasone vs. placebo: -1.8 vs. +0.2 (δ-2.0, 95% CI -2.9 to -1.0, P<0.001)
Adjusted mean change in FEV1 averaged over 3 years (mL)
Combination vs. placebo: +29 vs. -62 (δ92, 95% CI 75-108, P<0.001)
Combination vs. salmeterol: +29 vs. -21 (δ50, 95% CI 34-67, P<0.001)
Combination vs. fluticasone: +29 vs. -15 (δ44, 95% CI 28-61, P<0.001)
Salmeterol vs. placebo: -21 vs. -62 (δ42, 95% CI 25-58, P<0.001)
Fluticasone vs. placebo: -15 vs. -62 (δ47, 95% CI 31-64, P<0.001)
Cumulative incidence of discontinuation
Combination vs. placebo: 33.7% vs. 43.5% (HR 0.69, 95% CI 0.62-0.78, P<0.001)
Combination vs. salmeterol: 33.7% vs. 36.4% (HR 0.89, 95% CI 0.79-0.999, P<0.05)
Combination vs. fluticasone: 33.7% vs. 38.1% (HR 0.86, 95% CI 0.76-0.96, P=0.010)
Salmeterol vs. placebo: 38.1% vs. 43.5% (HR 0.78, 95% CI 0.70-0.86, P<0.001)
Fluticasone vs. placebo: 38.1% vs. 43.5% (HR 0.81, 95% CI 0.72-0.90, P<0.001)

Subgroup Analysis

No interaction between treatment and age, sex, region of country, baseline FEV1 categorized by disease stage according to GOLD, BMI, or smoking status.

Adverse Events

  • Any: 90%
  • Serious: 42%
  • Most commonly reported event during treatment was COPD exacerbation.
  • Pneumonia
    • Combination vs. placebo: 19.6% vs. 12.3% (P<0.001)
    • Fluticasone vs. placebo: 18.3% vs. 12.3% (P<0.001)
  • No significant difference in probability of fractures, bone mineral density or in the number of cataracts

Criticisms

  • Lower-than-expected mortality meant that enrollment needed to be increased[1]
  • Differential drop-out rate likely skewed results[1]
  • Setting mortality as the primary outcome may have been too ambitious[1]
  • Treatment with fluticasone alone may have increased mortality[4]
  • Randomizing symptomatic patients to placebo may have been unethical[4]

Funding

Sponsored by GlaxoSmithKline; authors with multiple disclosures.

Further Reading