REDUCE LEUPPI JD, ET AL. "SHORT-TERM VS CONVENTIONAL GLUCOCORTICOID

THERAPY IN ACUTE EXACERBATIONS OF CHRONIC OBSTRUCTIVE

PULMONARY DISEASE: THE REDUCE RANDOMIZED CLINICAL TRIAL".

JAMA. 2013. 309(21):2223-2231.

SALT-E: OVMC LANDMARK TRIAL SERIES

2016

ACCESS THIS ONLINE: HTTP://TINYURL.COM/SALTE6

BACKGROUND

The SCCOPE trial in 1999 proved the efficacy of systemic steroids in the treatment of acute COPD

exacerbation.

Subsequent studies suggested that IV and PO administration of steroids were equivalent and that low doses

did not result in greater treatment failures compared to high doses

Prior to REDUCE, the GOLD COPD guidelines stated:

Systemic corticosteroids in COPD exacerbations shortens recovery time, improves lung function, reduces risk of early

relapse, and shortens hospital stay (Grade A)

Prednisolone 30-40 mg daily are recommended for 10-14 days, though there is insufficient evidence regarding optimal

duration of therapy (Grade D)

A Cochrane review in 2011 suggested that there was no difference in outcomes between a longer course of steroids versus

a shorter course

CLINICAL QUESTION:

In patient with an acute COPD exacerbation, is 5 days

glucocorticoid treatment NON-INFERIOR to 14 days of

glucocorticoid treatment in preventing repeat exacerbations?

DESIGN

Multicenter, double-blind, randomized, non-inferiority controlled trial

N=314

5-day treatment (n=156)

14-day treatment (n=155)

Setting: 5 academic centers in Switzerland

Follow-up: 6 months

Analysis: Intention-to-treat

Primary outcome: Rate of COPD re-exacerbation

SUBJECTS

Inclusion Criteria:

Exacerbation of COPD, defined as two or more of:

Change in baseline dyspnea

Change in baseline cough

Change in sputum quantity or purulence

Age >40 years

≥20 pack-years smoking history

INTERVENTION

Randomized to:

5-days of glucocorticoids with 9 days of placebo

14-days of glucocorticoids

Methylprednisolone 40 mg IV on day 1, then prednisone 40 mg PO daily for the remaining days

Additional treatments provided:

7 days of antibiotics

Nebulized short-acting bronchodilator 4-6 times daily

Tiotropium and inhaled glucocorticoid/long-acting beta-agonist combination inhalers daily

OUTCOMES

Primary Outcome

Rate of re-exacerbation: Defined as an acute clinical deterioration requiring interaction with a clinician.

38.3% vs. 36.7% (HR 0.93; 90% CI 0.68-1.26; P=0.005) (non-inferiority analysis)

Secondary Outcomes

No significant differences in all-cause mortality, need for mechanical ventilation, additional glucocorticoids during follow-up,

any infection, new or worsening hyperglycemia or hypertension at discharge, other potential glucocorticoid adverse events

including GI bleeding, symptomatic GERD, symptoms of HF or ischemic heart disease, sleep disturbance, fractures, or

depression

Median hospital stay: 9 vs. 8 days (HR 1.25; 95% CI 0.99-1.59; P=0.04)

CRITICISMS

Baseline characteristics of study group skewed to severe and very severe COPD which limits generalizability to

milder disease

GOLD: Class I: 0%, Class II: 12.1%, Class III: 35.6%, Class IV: 52.3%

Not powered to detect differences in the subgroups of GOLD classes

6 month follow-up period limits data on potential adverse events in patients with multiple exacerbations

Use of adjunctive treatments including antibiotics, inhaled corticosteroids, inhaled long-acting anticholinergics,

and inhaled beta-agonists potentially limits generalizability

BOTTOM LINE

A 5-day course of glucocorticoids is non-inferior to a

14-day course for treatment of acute COPD

exacerbations in prevention of re-exacerbations

QUESTION 1:

What steroid dose and duration would you prescribe

for a patient with an acute COPD exacerbation?

QUESTION 2

Did the REDUCE trial demonstrate that a shorter

course of steroids is better than a longer course in the

treatment of acute COPD exacerbation?

QUESTION 3

What is a major limitation of the REDUCE trial?

CURRENT GOLD GUIDELINES

Treatment options:

supplemental oxygen should be titrated to improve the patient’s hypoxaemia with a target saturation of 88–92%

short-acting inhaled β2-agonists with or without short-acting anticholinergics are the preferred bronchodilators for treatment of an exacerbation

systemic corticosteroids shorten recovery time, improve lung function (FEV1) and arterial hypoxaemia (PaO2), and reduce the risks of early relapse, treatment failure, and length of hospital stay. A dose of 40 mg prednisone per day for 5 days is recommended

antibiotics should be given to patients:

with the following three cardinal symptoms—increased dyspnoea, increased sputum volume, increased sputum purulence

with increased sputum purulence and one other cardinal symptom

who require mechanical ventilation