Excess deaths associated with tigecycline after approval based on noninferiority trials

Abstract

Background: On the basis of noninferiority trials, tigecycline received Food and Drug Administration (FDA) approval in 2005. In 2010, the FDA warned in a safety communication that tigecycline was associated with an increased risk of death.

Methods: PubMed, EMBASE, Scopus, and ClinicalTrials.gov were searched using the terms "tigecycline" and "randomized controlled trial (RCT)" through April 2011. Excess deaths and noncure rates for both approved and nonapproved indications were examined using meta-analysis.

Results: Ten published and 3 unpublished studies met inclusion criteria (N = 7434). No significant heterogeneity was seen for mortality (I(2 )= 0%; P = .99) or noncure rates (I(2 )= 25%; P = .19). Across randomized controlled trials, tigecycline was associated with increased mortality (risk difference [RD], 0.7%; 95% confidence interval [CI], 0.1%-1.2%; P = .01) and noncure rates (RD, 2.9%; 95% CI, 0.6%-5.2%; P = .01). Effects were not isolated to type of infection or comparator antibiotic regimen, and the impact on survival remained significant when limited to trials of approved indications (I(2 )= 0%; RD, 0.6%; P = .04). A pooled analysis of the 5 trials completed by early 2005 before tigecycline was approved would have demonstrated a similar harmful effect of tigecycline on survival (I(2 )= 0%; RD, 0.7%; P = .06).

Conclusions: Pooling noninferiority studies to examine survival may help ensure the safety and efficacy of new antibiotics. The association of tigecycline with excess deaths and noncure includes indications for which it is approved and marketed. Tigecycline cannot be relied on in serious infections.

Figure 1.

Study selection.

Figure 2.

Mortality and noncure rates using RD. The size of data markers is proportional to the inverse variance of each point estimate. RR, another commonly used summary statistic, was examined to test the consistency of the above findings. Tigecycline versus comparator antibiotics was associated with a significant 30% increase in mortality rates (RR, 1.30; 95% CI, 1.02–1.65; P = .04) and a significant 12% increase in c-mITT noncure (RR, 1.12; 95% CI, 1.02–1.23; P = .02). Abbreviations: CI, confidence interval; RD, risk difference; RR, relative risk.

Figure 3.

Subgroup analysis (types of infections). The actual increase in mortality and P value by type of infection using the RD are as follows: across the 5 intra-abdominal infection studies, RD was 0.8% (P = .13); across the 3 skin and skin structure studies, RD was 0.6% (P = .14); across the 2 community-acquired pneumonia studies, RD was 0.2% (P = .86); in the 1 diabetic foot infection study, RD was 0.7% (P = .25); in the 1 hospital-acquired pneumonia study, RD was 1.9% (P = .38); and in the 1 study of MSRA and VRE infections, RD was 3.9% (P = .33). Infection-specific results for noncure are as follows: across the 5 intra-abdominal infection studies, RD was 2.7% (P = .16); across the 3 skin and skin structure studies, RD was 1.5% (P = .54); across the 2 community-acquired pneumonia studies, RD was -1.3% (P = .70); in the 1 diabetic foot infection study, RD was 9.1% (P = .01); in the 1 hospital-acquired pneumonia study, RD was 4.9% (P = .23); and in the 1 study of MRSA and VRE infections, RD was 8.3% (P = .31). For comparison, a subgroup analysis examining another summary statistic, the RR of death and noncure for each of 5 indications showed the following: for complicated skin and skin structure infections, mortality RR was 1.72 (P = .28) and noncure RR was 1.02 (P = .76); for complicated intra-abdominal infections, mortality RR was 1.48 (P = .11) and noncure RR was 1.15 (P = .07); for diabetic foot infections, mortality RR was 2.14 (P = .27) and noncure RR was 1.39 (P = .001); for community-acquired pneumonia, mortality RR was 1.08 (P = .85) and noncure RR was 0.94 (P = .67); for hospital-acquired pneumonia, mortality RR was 1.15 (P = .13) and noncure RR was 1.15 (P = .15);and for drug-resistant pathogen infections (MRSA and VRE), mortality RR was 1.85 (P = .41) and noncure RR was 1.43 (P = .34).

Figure 4.

Subgroup analysis (approved vs nonapproved indications). Abbreviations: CI, confidence interval; RD, risk difference.

Figure 5.

Cumulative mortality and cumulative noncure rate analyses for the tigecycline noninferiority trials identified in this meta-analysis from mid-2005 (the date when tigecycline received FDA approval as monotherapy for complicated intra-abdominal and skin infections) through the end of 2009 (the date by which the last study in this meta-analysis was completed).