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Systematic Review and Meta-analysis of Rare Harmful Effects in Randomized Controlled Trials

Tim Bongartz, MD; Alex J. Sutton, PhD; Michael J. Sweeting, MSc; Iain Buchan, MD, MFPH; Eric L. Matteson, MD, MPH; Victor Montori, MD, MSc

JAMA. 2006;295:2275-2285.

Context  Tumor necrosis factor (TNF) plays an important role in host defense and tumor growth control. Therefore, anti-TNF antibody therapies may increase the risk of serious infections and malignancies.

Objective  To assess the extent to which anti-TNF antibody therapies may increase the risk of serious infections and malignancies in patients with rheumatoid arthritis by performing a meta-analysis to derive estimates of sparse harmful events occurring in randomized trials of anti-TNF therapy.

Data Sources  A systematic literature search of EMBASE, MEDLINE, Cochrane Library, and electronic abstract databases of the annual scientific meetings of both the European League Against Rheumatism and the American College of Rheumatology was conducted through December 2005. This search was complemented with interviews of the manufacturers of the 2 licensed anti-TNF antibodies.

Study Selection  We included randomized, placebo-controlled trials of the 2 licensed anti-TNF antibodies (infliximab and adalimumab) used for 12 weeks or more in patients with rheumatoid arthritis. Nine trials met our inclusion criteria, including 3493 patients who received anti-TNF antibody treatment and 1512 patients who received placebo.

Data Extraction  Data on study characteristics to assess study quality and intention-to-treat data for serious infections and malignancies were abstracted. Published information from the trials was supplemented by direct contact between principal investigators and industry sponsors.

Data Synthesis  We calculated a pooled odds ratio (Mantel-Haenszel methods with a continuity correction designed for sparse data) for malignancies and serious infections (infection that requires antimicrobial therapy and/or hospitalization) in anti-TNF–treated patients vs placebo patients. We estimated effects for high and low doses separately. The pooled odds ratio for malignancy was 3.3 (95% confidence interval [CI], 1.2-9.1) and for serious infection was 2.0 (95% CI, 1.3-3.1). Malignancies were significantly more common in patients treated with higher doses compared with patients who received lower doses of anti-TNF antibodies. For patients treated with anti-TNF antibodies in the included trials, the number needed to harm was 154 (95% CI, 91-500) for 1 additional malignancy within a treatment period of 6 to 12 months. For serious infections, the number needed to harm was 59 (95% CI, 39-125) within a treatment period of 3 to 12 months.

Conclusions  There is evidence of an increased risk of serious infections and a dose-dependent increased risk of malignancies in patients with rheumatoid arthritis treated with anti-TNF antibody therapy. The formal meta-analysis with pooled sparse adverse events data from randomized controlled trials serves as a tool to assess harmful drug effects.

Author Affiliations: Division of Rheumatology and Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minn (Drs Bongartz and Matteson); Department of Health Sciences, University of Leicester, Leicester, England (Dr Sutton); MRC Biostatistics Unit, Institute of Public Health, Cambridge, England (Mr Sweeting); Northwest Institute for Bio-Health Informatics, University of Manchester, Manchester, England (Dr Buchan); Knowledge and Encounter Research Unit and Department of Medicine, Mayo Clinic College of Medicine, Rochester, Minn (Dr Montori).

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