Background While biologics are a significant therapeutic advance for many conditions, there is a paucity of studies that directly assess their comparative safety making choosing between them a difficult clinical decision.
Objectives To perform a network meta-analysis to determine the comparative safety of the nine currently available biologics used in rheumatoid arthritis (adalimumab, certolizumab, etanercept, golimumab, infliximab, anakinra, tocilizumab, abatacept and rituximab).
Methods We searched The Cochrane Library, MEDLINE, and EMBASE (to January 2010) for RCTs of biologics versus placebo or active controls for any conditions other than HIV/AIDs. Outcomes were withdrawals due to AEs (WtdAE), total adverse events (TAE), serious adverse events (SAE), serious infections (SInf); and specifically: tuberculosis reactivation (TB), lymphoma and congestive heart failure (CHF). For the network meta-analysis, we performed both Bayesian mixed-treatment comparison and empirical Bayes generalized linear mixed models. Results were interpreted using the Number Needed to Treat in order to Harm (NNTH).
Results We included 160 RCTs with 48,676 participants. Median duration of RCTs was 6 months. Data were limited for TB, lymphoma and CHF. Using standard dose, biologics compared to control were associated with a statistically significant higher rate of TAE (OR 1.28, 95% CI 1.09 to 1.50; NNTH =22, 95% CI 4 to 60), WtdAE (OR 1.47, 95% CI 1.20 to 1.86; NNTH =26, 95% CI 15 to 58), SAE (OR 1.37, 95% CI 1.04 to 1.82; NNTH=108 95% CI, 50 to 989) and TB reactivation (OR 4.68, 95% CI 1.18 to 18.60; NNTH =168, 95% CI 143 to 14706). The rate of SAE, lymphoma and CHF were not statistically significantly different.
Compared to control, certolizumab pegol and anakinra were associated with a statistically significantly higher risk of SInf (OR 4.75 [95%CI 1.52 to 18.65]; NNTH =12 [95%CI 4 to 79]; and OR 4.05 [1.22 to 16.84]; NNTH =14 [4 to 81], respectively). Certolizumab pegol was associated with a statistically significantly higher risk of SAE (OR 1.57 [1.06 to 2.32]; NNTH =18 [9 to 162]; infliximab was associated with a statistically significantly higher risk of TAE (OR 1.55 [1.01 to 2.35]; NNTH =13 [8 to 505]) and WtdAE (OR 2.34 [1.40 to 4.14]; NNTH =10 [5 to 30]). Indirect comparisons revealed that certolizumab pegol was associated with a statistically significantly higher odds of SInf compared to abatacept, adalimumab, etanercept, golimumab and rituximab (P<0.05); and anakinra was statistically significantly more likely than rituximab to be associated with SInf. Certolizumab pegol was associated with a statistically significant higher odds of SAE compared to adalimumab and abatacept. No statistically significant differences were noted between biologics in TAE or WtdAE in indirect comparisons.
Conclusions Overall, based upon short-term trials, biologics were associated with statistically significantly higher rates of SInf, TB reactivation, TAE and WtdAE compared to controls. Indirect comparisons between biologics suggested some differences between drugs in adverse events. With only a moderate confidence in the estimates, there is a need for a head-to-head trial to verify these differences.
Disclosure of Interest J. Singh Grant/Research support from: Savient, Takeda, Consultant for: Savient, Takeda, Ardea, Novartis, URL, G. Wells Grant/Research support from: Bristol Myers, Consultant for: Abbott, Amgen, UCB, Novartis, R. Christensen Grant/Research support from: Abbott, Astellas Pharma, Axellus, Bristol-Myers Squibb, Cambridge Nutritional Foods, Centocor, DSM Nutritional Products, Hypo-Safe, MSD, MundiPharma, NorPharma, Pharmavie, Pfizer, Roche, Sanofi-Aventis, Scandinavian Clinical Nutrition, Consultant for: Abbott, Astellas Pharma, Axellus, Bristol-Myers Squibb, Cambridge Nutritional Foods, Centocor, DSM Nutritional Products, Hypo-Safe, MSD, MundiPharma, NorPharma, Pharmavie, Pfizer, Roche, Sanofi-Aventis, Scandinavian Clinical Nutrition, E. Tanjong: None Declared, J. MacDonald: None Declared, P. Tugwell Grant/Research support from: Bristol Myers, UCB, R. Buchbinder Grant/Research support from: unrestricted educational grants from Abbott, Amgen, Roche and Wyeth, Consultant for: Abbott
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