NIEWOEHNER 1999: Systemic Steroids for COPD Exacerbations (1999)

“In patients hospitalized for an exacerbation of COPD, treatment with systemic corticosteroids improves clinical outcomes and shortens the hospital stay.”

— The Niewoehner et al. Study Group

1. Publication Details

  • Trial Title: Effect of Systemic Glucocorticoids on Exacerbations of Chronic Obstructive Pulmonary Disease.
  • Citation: Niewoehner DE, Erbland ML, Deupree RH, et al. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. N Engl J Med. 1999;340(25):1941-1947. doi:10.1056/NEJM199906243402502.
  • Published: June 24, 1999, in The New England Journal of Medicine.
  • Author: Dennis E. Niewoehner, M.D.
  • Funding: U.S. Department of Veterans Affairs.

2. Keywords

Chronic Obstructive Pulmonary Disease (COPD), COPD Exacerbation, Corticosteroids, Methylprednisolone, Prednisone, Lung Function.

3. The Clinical Question

In patients hospitalized for an acute exacerbation of COPD (Population), does treatment with systemic corticosteroids (Intervention) compared to placebo (Comparison) reduce the rate of treatment failure (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Acute exacerbations of chronic obstructive pulmonary disease (COPD) are a major cause of hospitalization and morbidity. Systemic corticosteroids were widely used to treat these exacerbations based on their potent anti-inflammatory effects.
  • Knowledge Gap: Despite widespread use, the evidence supporting the benefit of corticosteroids was based on small, often conflicting trials. A large, definitive, multicenter randomized trial was needed to establish their efficacy and safety.
  • Proposed Hypothesis: The authors hypothesized that systemic glucocorticoids would reduce the rate of treatment failure in patients hospitalized for an exacerbation of COPD.

5. Study Design and Methods

  • Design: A prospective, multicenter, randomized, double-blind, placebo-controlled trial.
  • Setting: Veterans Affairs medical centers across the United States.
  • Trial Period: Enrollment from October 1996 to February 1998.
  • Population:
    • Inclusion Criteria: Patients (predominantly male veterans) hospitalized for an acute exacerbation of COPD, defined by increased dyspnea, sputum production, and sputum purulence.
    • Exclusion Criteria: Patients requiring immediate mechanical ventilation, or those with pneumonia, asthma, or other clear causes for their respiratory distress.
  • Intervention: Systemic corticosteroids, administered either as intravenous methylprednisolone for 3 days followed by oral prednisone, or oral prednisone alone, in a tapering course over either 2 or 8 weeks.
  • Control: Matching placebo administered in the same manner.
  • Management Common to Both Groups: All patients received standard therapy, which included inhaled bronchodilators, oxygen, and a standardized course of antibiotics.
  • Power and Sample Size: The trial was powered to detect a 15% absolute reduction in the treatment failure rate, requiring 260 patients.
  • Outcomes:
    • Primary Outcome: Treatment failure, defined as a composite of death from any cause, need for intubation and mechanical ventilation, or intensification of drug therapy.
    • Secondary Outcomes: Included length of hospital stay, lung function (FEV1), and rates of hyperglycemia.

6. Key Results

  • Enrollment and Baseline: 271 patients were randomized (133 to corticosteroids, 138 to placebo). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: The rate of treatment failure was significantly lower in the corticosteroid group than in the placebo group (23% vs 33%; P=0.04). This benefit was apparent by day 3.
  • Secondary Outcomes: The corticosteroid group had a significantly shorter median hospital stay (8.5 days vs 9.5 days). Patients receiving steroids also had a more rapid improvement in their FEV1.
  • Adverse Events: Hyperglycemia was significantly more common in the corticosteroid group (92% vs 78% had at least one reading >200 mg/dL).

7. Medical Statistics

  • Analysis Principle: An intention-to-treat analysis was performed.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The proportion of patients with treatment failure was compared between the two groups.
  • Key Statistic(s) Reported: Treatment failure rate: 23% (corticosteroids) vs 33% (placebo); P=0.04.
  • Interpretation of Key Statistic(s):
    • Relative Risk (RR):
      • Formula: Conceptually, RR = (Risk in Intervention Group) / (Risk in Control Group).
      • Calculation: RR = 23.3% / 33.3% = 0.70.
      • Clinical Meaning: An RR of 0.70 means there was a 30% lower relative risk of treatment failure in the corticosteroid group compared to the placebo group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The calculated 95% CI for the RR is approximately 0.50 to 0.98.
      • Clinical Meaning: Since the 95% CI does not cross the line of no effect (1.0), the result is statistically significant.
    • P-value:
      • Calculation: The reported p-value was 0.04.
      • Clinical Meaning: The p-value of 0.04 is less than the conventional threshold of 0.05, indicating that the observed difference is unlikely to be due to chance.
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group).
      • Calculation: ARR = 33.3% – 23.3% = 10.0%.
      • Clinical Meaning: For every 100 patients with a COPD exacerbation treated with systemic steroids, 10 were prevented from experiencing treatment failure.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR.
      • Calculation: NNT = 1 / 0.10 = 10.
      • Clinical Meaning: Approximately 10 patients hospitalized for a COPD exacerbation need to be treated with systemic corticosteroids to prevent one additional treatment failure.
  • Subgroup Analyses: The benefit of corticosteroids was consistent regardless of whether they were given for 2 weeks or 8 weeks.

8. Strengths of the Study

  • Study Design and Conduct: This was a methodologically rigorous, multicenter, randomized, double-blind, placebo-controlled trial.
  • Generalizability: The pragmatic inclusion of patients from multiple VA hospitals increases the real-world applicability of the findings.
  • Patient-Centered Outcomes: The primary outcome was a composite of clinically important events, including the need for mechanical ventilation.

9. Limitations and Weaknesses

  • Internal Validity (Bias): No major limitations to internal validity.
  • External Validity (Generalizability): The study population consisted almost entirely of male veterans, which may limit generalizability to women.
  • Other: The trial did not find a difference between a 2-week and an 8-week course of steroids, suggesting shorter courses are sufficient, but it was not specifically designed to test duration.

10. Conclusion of the Authors

“Treatment with systemic glucocorticoids for exacerbations of COPD reduces the rate of treatment failure, improves lung function, and shortens the hospital stay. The optimal dose and duration of therapy remain to be determined.”

11. To Summarize

  • Impact on Current Practice: This was a landmark, practice-changing trial. It provided the first definitive, high-quality evidence that systemic corticosteroids are a cornerstone of therapy for hospitalized patients with acute exacerbations of COPD. It established a new standard of care and remains a foundational paper in respiratory medicine.
  • Specific Recommendations:
    • Patient Selection: For adult patients hospitalized with an acute exacerbation of COPD.
    • Actionable Intervention: Administer a short course of systemic corticosteroids (e.g., prednisone 40 mg daily for 5 days, as later established by the REDUCE trial).
    • Expected Benefit: A significant reduction in treatment failure (NNT ~10) and a shorter hospital stay.
  • What This Trial Does NOT Mean: This trial does not mean that long-term steroid therapy is beneficial for stable COPD. It applies only to acute exacerbations.
  • Implementation Caveats: Patients treated with corticosteroids require monitoring for side effects, particularly hyperglycemia.

12. Context and Related Studies

  • Building on Previous Evidence: This trial was designed to provide a definitive answer to a question that had been addressed by many smaller, inconclusive studies.
  • Influence on Subsequent Research: This trial cemented the role of steroids in COPD exacerbations. Subsequent research, most notably the REDUCE trial (2013), has focused on optimizing the duration of therapy, demonstrating that a short 5-day course is as effective as a longer 14-day course.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: What is the optimal dose of corticosteroids? Are there specific phenotypes of COPD exacerbation that respond differently to steroids?
  • Future Directions: Research is focused on identifying biomarkers (like blood eosinophils) to personalize steroid therapy and on developing non-steroidal anti-inflammatory treatments to reduce side effects.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The question was of fundamental importance, testing a common but unproven therapy for a major cause of hospitalization.
  • Methods: The study’s design (multicenter, randomized, double-blind, placebo-controlled) was of the highest quality.
  • Results: The trial had a clear and statistically significant positive result for its primary, patient-centered outcome, as well as for important secondary outcomes like length of stay. The NNT of 10 represents a highly effective intervention.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. The results are highly applicable and have definitively established systemic corticosteroids as a standard of care for hospitalized patients with COPD exacerbations.

16. Disclaimer and Contact

This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.

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