AFP Journal Club

The Story Behind the Study

Fluticasone or Salmeterol Alone vs. Combination Therapy for COPD

Am Fam Physician. 2008 Mar 1;77(5):586-588.

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From left: Dr. Mark Graber, Dr. Andrea Darby-Stewart, and Dr. Robert Dachs

Purpose

Each month, three presenters will review an interesting journal article in a conversational manner. These articles will involve “hot topics” that affect family physicians or will “bust” commonly held medical myths. The presenters will give their opinions about the clinical value of the studies discussed. The opinions reflect the views of the presenters, not those of AFP or the AAFP.

This Month's Article

Calverley P, Anderson JA, Celli B, et al.; for the TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356(8):775–789.

Is fluticasone plus salmeterol better than fluticasone or salmeterol alone for treating patients with COPD?

What does this article say?

Mark: This was a randomized, double-blind trial of 6,112 patients with COPD (defined as airway disease that is less than 10 percent reversible with beta agonists). The participants were randomized to one of four groups: (1) fluticasone (Flovent); (2) salmeterol (Serevent); (3) a combination of fluticasone and salmeterol (Advair); or (4) placebo. The primary outcome was mortality, and secondary outcomes were the number of COPD exacerbations and hospitalizations. Patients were followed for up to three years.

The study authors found no difference in mortality among the groups. The overall number needed to treat (NNT) for one year to prevent one COPD exacerbation is four, and the NNT for one year to prevent one hospitalization is 33. There was a trend towards increased mortality in the fluticasone group; however, it did not reach statistical significance (Table 1).

Should we believe this study?

Mark: Sort of. Most importantly, the NNT for one year to prevent one hospitalization is 33. The balance to this, however, is the number needed to harm (NNH). How many patients are you going to harm with this medication? As it turns out, a lot. Pneumonia was found in 12.3 percent of patients in the placebo group, 18.3 percent in the fluticasone group, and 19.6 percent in the combination group over three years (Table 1). That gives you an NNH of 41 for one year in the combination group. This is almost the same number as the NNT to prevent one hospitalization.

Andrea: The authors didn't calculate the NNH in the original paper. In fact, they obfuscated this value by reporting some findings as annual rates (events per year) and others as a percentage over three years.

Bob: There are a lot of nuances to this paper. First, note that the drugs are all made by the same company (GlaxoSmithKline), which sets up the study so that no matter how the results turned out, the manufacturer could not lose. Second, be sure to look at the data in the article. It is from these data that the useful measures (NNT and NNH) can be easily calculated and identified. Third, notice that there is a 34 to 44 percent dropout rate (depending on the group). This may have influenced the outcome.

Mark: And the study authors compared the active drug with a placebo. It would have been better if they compared it with another drug that is known to be active in COPD (e.g., ipratropium [Atrovent], tiotropium [Spiriva]). Anticholinergics (not beta agonists) are the bronchodilators of choice in patients with COPD.1 Maybe there would have been no benefit at all if the control group was given an active drug.

Table 1

Results from the TORCH Study

Drug Death at three years (%) COPD exacerbation (annual rate) Pneumonia at three years (%) Withdrawal rate (%)

Fluticasone/salmeterol (Advair)

12.6

0.85*

19.6*

34.1

Fluticasone (Flovent)

16.0

0.93

18.3*

38.3

Salmeterol (Serevent)

13.5

0.97

13.3

36.9

Placebo

15.2

1.13

12.3

44.2


*—Statistically significant difference.

TORCH = Toward a Revolution in COPD Health; COPD = chronic obstructive pulmonary disease.

Table 1   Results from the TORCH Study

View Table

Table 1

Results from the TORCH Study

Drug Death at three years (%) COPD exacerbation (annual rate) Pneumonia at three years (%) Withdrawal rate (%)

Fluticasone/salmeterol (Advair)

12.6

0.85*

19.6*

34.1

Fluticasone (Flovent)

16.0

0.93

18.3*

38.3

Salmeterol (Serevent)

13.5

0.97

13.3

36.9

Placebo

15.2

1.13

12.3

44.2


*—Statistically significant difference.

TORCH = Toward a Revolution in COPD Health; COPD = chronic obstructive pulmonary disease.

Bob: Agreed. When you look over the data, bronchodilators get a thumbs up; however, one has to wonder about the role of inhaled steroids in COPD. The data remain mixed on the risk of bone demineralization and osteoporotic fractures with inhaled steroids.2 And now the suggestion that rates of pneumonia are increased in those taking inhaled steroids makes me a little more apprehensive to prescribe these agents for patients with COPD.

What should the family physician do?

Andrea: Inhaled anticholinergics should be the first-line treatment for COPD (but not in patients with asthma). I would follow the Global Initiative for Chronic Obstructive Lung Disease recommendations to use inhaled steroids only in those patients with COPD who have moderate to severe disease (FEV1 less than 50 percent predicted) or who have repeated exacerbations.3 And even in these groups, the benefit is marginal. A meta-analysis of inhaled steroids in patients with severe COPD found an NNT of 18 for one year to prevent one exacerbation.2

Bob: Don't be afraid to look at data presented in journal articles—it helps you better describe to your patients the magnitude of the benefit or harm of a drug. In this case, inhaled steroids prevent one exacerbation in every four patients treated for one year and prevent one hospitalization in every 33 patients treated for one year. The balance to this is a one-in-41 risk of developing pneumonia.

Main Points

  • Anticholinergics (e.g., ipratropium, tiotropium) are the bronchodilators of choice in patients with COPD.

  • Inhaled steroids may reduce the number of exacerbations in patients with moderate to severe COPD. Neither fluticasone nor the combination of fluticasone and salmeterol were any better than placebo at preventing mortality.

  • Inhaled steroids in patients with COPD may increase the incidence of pneumonia.

EBM Points

  • Calculate NNT and NNH. They tell you the real magnitude of benefit and harm. P-values only tell you that there is a difference between two groups; this difference can be clinically meaningless.

  • How to calculate NNT or NNH: 1/(absolute difference in treated versus untreated patients). For example, if 5 percent of treated patients have a heart attack and 10 percent of untreated patients have a heart attack, the NNT calculation is 1/(0.10 − 0.05). That equals 20.

  • Let your patients know the magnitude of benefit and risk in language that is easy for them to understand. In this case, 33 patients need to be treated for one year to prevent one hospitalization, at a risk of one in 41 patients developing pneumonia.

coming next month: Bateman BT, Schumacher HC, Boden-Albala B, et al. Factors associated with in-hospital mortality after administration of thrombolysis in acute ischemic stroke patients: an analysis of nationwide inpatient sample 1999 to 2002 [published correction appears in Stroke. 2007;282:28(2):451]. Stroke. 2006;37(2):440–446.

Address correspondence to Mark A. Graber, MD, at mark-graber@uiowa.edu. Reprints are not available from the authors.

Author disclosure: Nothing to disclose.

REFERENCES

1. Salpeter SR, Buckely NS, Salpeter EE. Meta-analysis: anticholinergics, but not beta-agonists, reduce severe exacerbations and respiratory mortality in COPD [published correction appears in J Gen Intern Med. 2006;21(10):1131]. J Gen Intern Med. 2006;21(10):1011–1019.

2. Gartlehner G, Hansen RA, Carson SS, Lohr KN. Efficacy and safety of inhaled corticosteroids in patients with COPD: a systematic review and meta-analysis of health outcomes. Ann Fam Med. 2006;4(3):253–262.

3. Rabe KF, Hurd S, Anzueto A, et al., for the Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2007;176(6):532–555.

For more information on EBM terms, see the EBM Toolkit at http://www.aafp.org/afp/ebmtoolkit.


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