A systematic review of the effectiveness of adalimumab

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70 TABLE 17 Effectiveness Summary of the results of primary analyses for key outcomes included in this review TNF inhibitor ACR20 ACR70 HAQ change Modified Sharp score Withdrawal for SAEs Serious infections and population RR a : (95% CI) RRa : (95% CI) Mean differenceb Mean differenceb any reasons RRc (95% CI) RRc (95% CI) (and NNT) (and NNT) (95% CI) (95% CI) RRc (95% CI) (and NNH) Anti-TNF vs MTX Adalimuma 0.88 (0.75 to 1.03) 0.99 (0.75 to 1.30) 0.00 (–0.13 to 0.13) –2.70 (–4.74 to –0.66)/ 1.14 (0.91 to 1.43) [Commercial-in- [Commercial-in- (early RA) b 1 year, –4.90 confidence confidence ([Commercial-in- information information removed] confidence information removed] removed])/2 years Etanercept 1.22 (1.06 to 1.40) 1.23 (0.89 to 1.70) –0.10 (–0.23 to 0.03) –0.97 (–1.65 to –0.29)/ 0.63 (0.48 to 0.84) NR 0.82 (0.31 to 2.15) (early RA) NNT 7.7 1 year (4.5 to 25.0) Etanercept 1.28 (1.06 to 1.54) 1.46 (1.00 to 2.14) –0.10 (–0.23 to 0.03) –2.28 (–4.11 to –0.45)/ 0.81 (0.65 to 1.00) 1.10 (0.75 to 1.61) 0.95 (0.85 to 1.06) (established RA) NNT 8.3 1 year (4.8 to 33.3) Anti-TNF versus placebo Adalimumab 2.11 (1.84 to 2.42) 5.22 (3.45 to 7.89) –0.31 (–0.36 to –0.26) –2.20 (–3.33 to –1.07)/ 0.62 (0.53 to 0.73) 1.05 (0.78 to 1.41) 2.35 (1.00 to 5.53) (established RA) NNT 3.6 (3.1 to 4.2) NNT 7.7 (5.9, 11.1) 1 year Etanercept 3.59 (2.89 to 4.46) 9.44 (3.98 to 22.38) –0.50 (–0.59 to –0.42) No data available 0.37 (0.29 to 0.46) 1.25 (0.75 to 2.08) 0.78 (0.37 to 1.62) (established RA) NNT 2.1 (1.9 to 2.4) NNT 7.7 (6.3 to 10.0) Infliximab 2.30 (1.90 to 2.78) 3.16 (1.89 to 5.27) –0.27 (–0.35 to –0.19) –5.70 (–8.58 to –2.82)/ 0.76 (0.36 to 1.60) 0.84 (0.56 to 1.26) 0.61 (0.26 to 1.46) (established RA) NNT 3.2 (2.7 to 4.0) NNT 11.1 (7.7 to 20.0) 1 year Anti-TNF + MTX vs MTX Adalimumab + MTX 1.24 (1.08 to 1.42) 1.64 (1.30 to 2.07) –0.10 (–0.23 to 0.03) –4.40 (–6.14 to –2.66)/ 0.71 (0.54 to 0.93) [Commercial-in- [Commercial-in- (early RA) NNT 7.7 (4.5 to 20.0) NNT 5.6 (3.8 to 10.0) 1 year [Commercial-in- confidence confidence confidence information information information removed] removed] removed] Etanercept + MTX 1.49 (1.25 to 1.77) 2.53 (1.82 to 3.54) –0.40 (–0.52 to –0.28) –3.34 (–5.12 to –1.56]/ 0.61 (0.48 to 0.77) 1.25 (0.87 to 1.81) 0.86 (0.42 to 1.76) (established RA) NNT 4.5 (3.3 to 7.7) NNT 4.0 (3.0 to 5.9) 1 year Infliximab + MTX 1.17 (1.02 to 1.34) 1.57 (1.20 to 2.05) –0.17 (–0.29 to –0.06) –3.28 (–4.55 to –2.01]/ 0.87 (0.64 to 1.19) 1.27 (0.84 to 1.92) 2.74 (1.12 to 6.70) (early RA) NNT 11.1 (5.9 to 100) NNT 8.3 (5.3 to 20.0) 1 year NNH 25 (16.7 to 100) Bold type indicates statistically significant results p < 0.05 a b c RR>1 favours anti-TNFs. Negative value favours anti-TNFs. RR
combination, which was associated with nearly a three-fold increase in withdrawal owing to adverse events (RR 2.99, 95% CI 1.49 to 6.03) and serious infections (RR 2.74, 95% CI 1.12 to 6.70). Adalimumab combined with methotrexate was associated with a slight, but significant increase in [Commercial-in-confidence information removed]. Risks of serious infection (RR [Commercial-in-confidence information removed]) and withdrawal owing to adverse events (RR = 1.62, 95% CI 0.94 to 2.77) were also increased, compared with methotrexate alone, but these did not reach statistical significance. No significant differences in safety outcomes were found between etanercept combined with methotrexate and methotrexate alone. More malignancy occurred in the combination group but this did not reach statistical significance. All three TNF inhibitors, when combined with methotrexate, showed a trend towards increased SAEs, but again this was not statistically significant. Additional information on effectiveness and safety This section summarises additional evidence that is not included in the meta-analyses. Information cited in this section is collated from FDA reports, published reviews and observational studies, summaries of product characteristics, and submissions from the BSR and manufacturers of TNF inhibitor to NICE. Lack of appropriate, unbiased comparison groups is a major problem for the validity of comparative results from non-RCTs. This should be borne in mind when interpreting observational data. Issues related to tuberculosis and blood monitoring were discussed in the section ‘Special precautions for use of TNF inhibitors’ (p. 9) and are not described here. Mortality Mortality data from long-term follow-up programmes for patients treated with adalimumab and etanercept were reviewed by the FDA in 2003. 146 The observed death rates in the follow-up programmes, adjusted for age and gender, were lower than would be expected among US general populations and do not indicate a higher death rate with TNF inhibitor treatments. Malignancies including lymphomas A significant increase in the incidence of lymphoma compared with the general population was noted for all three TNF inhibitors in the 2003 FDA review. 146 Controversy remains with regard to whether the observed higher incidences indicate © Queen’s Printer and Controller of HMSO 2006. All rights reserved. Health Technology Assessment 2006; Vol. 10: No. 42 additional risk due to TNF treatment, or whether they are in line with the increased risk of lymphoma observed in RA patients with high inflammatory activity. 147–151 In general, the incidence of other types of malignancies in TNF inhibitor-treated patients was found to be similar to, or lower than that observed in the general population 146,152,153 and other RA populations. 85,151 Congestive heart failure Adalimumab and infliximab are contraindicated in moderate to severe heart failure (New York Heart Association class III or IV). Two RCTs (not included in this systematic review) that evaluated the use of etanercept in the treatment of congestive failure were terminated early owing to lack of efficacy, and data from one of these trials suggested a possible tendency towards worsening of congestive heart failure and increased all-cause mortality in patients treated with etanercept. 154,155 In another trial that evaluated the use of infliximab in congestive heart failure, no clinical benefit was observed and high-dose infliximab (10 mg kg –1 at 0, 2 and 6 weeks) was associated with an increased risk for a composite outcome that included death from any cause and hospitalisation for heart failure (hazard ratio 2.84, 95% CI 1.01 to 7.97). 156 Pulmonary fibrosis In an investigation of pulmonary fibrosis and associated death, BSRBR found that there was a two- to three-fold increase in mortality for patients with pulmonary fibrosis at baseline compared with those without it among all patients (including TNF-treated and control group) with 6 months’ follow-up data. 85 As the vast majority of the patients with pulmonary fibrosis at baseline were in the TNF-treated groups and only one death associated with pulmonary fibrosis occurred in the control group, it was not possible to conclude whether there is a potential association between TNF treatment and death associated with pulmonary fibrosis. Combination of TNF inhibitors with anakinra Results from an RCT (not included in this systematic review, see Appendix 3) by Genovese and colleagues 157 suggest that combination therapy with etanercept plus anakinra provided no treatment benefit over etanercept alone, and was associated with an increased risk of serious infections (0% for etanercept alone and 3.7–7.4% for combination therapy). The combination of TNF inhibitors and anakinra is therefore not recommended. 71
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A systematic review of the effectiv
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A systematic review of the effectiv
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Objectives: This report reviews the
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Glossary and list of abbreviations
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viii Glossary and list of abbreviat
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Background Rheumatoid arthritis (RA
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increased risk of serious infection
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Summary RA is a common, chronic, in
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(IL-2) and interleukin-6 (IL-6), pr
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Assessment of response to DMARDs Re
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combination with methotrexate or al
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disease between clinic appointments
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14 Effectiveness in juvenile arthri
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16 Effectiveness adalimumab plus me
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18 Effectiveness Monoclonal Antibod
Page 36 and 37: 20 TABLE 1 Description of included
Page 38 and 39: 22 TABLE 2 Quality of included RCTs
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Page 42 and 43: 26 Effectiveness TABLE 4 Meta-analy
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Page 46 and 47: 30 Effectiveness Review: Adalimumab
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Page 52 and 53: 36 TABLE 7 Effectiveness Quality of
Page 54 and 55: 38 Effectiveness etanercept trials.
Page 56 and 57: 40 Effectiveness TABLE 9 Summary of
Page 58 and 59: 42 Effectiveness Review: Etanercept
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Page 74 and 75: 58 TABLE 13 Quality of included RCT
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Page 82 and 83: 66 Effectiveness Review: Infliximab
Page 84 and 85: 68 Effectiveness FIGURE 44 Malignan
Page 89 and 90: Summary of review of existing econo
Page 91 and 92: TABLE 20 Summary of published ICERs
Page 93 and 94: TABLE 21 Published etanercept econo
Page 95 and 96: TABLE 23 Published economic analyse
Page 97 and 98: TABLE 25 Treatment sequences: adali
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Page 103 and 104: TABLE 32 TNF inhibitors as last act
Page 105 and 106: TABLE 34 Basic structure of the mod
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Page 109 and 110: TABLE 39 Strategy set: adalimumab a
Page 111 and 112: TABLE 43 Beta distributions for HAQ
Page 113 and 114: TABLE 44 Early cessation of DMARDs:
Page 115 and 116: TABLE 46 Unit costs for tests and v
Page 117 and 118: following properties, according to
Page 119 and 120: TABLE 52 Base case: TNF inhibitors
Page 121 and 122: TABLE 54 Base case: TNF inhibitors
Page 123 and 124: TABLE 59 Third TNF inhibitor follow
Page 125 and 126: TABLE 65 Sensitivity analyses: TNF
Page 127 and 128: TABLE 67 Sensitivity analyses: TNF
Page 129: The substantial economic impact of
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introduce bias which generally exag
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Adalimumab, etanercept and inflixim
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1. Jobanputra P, Barton P, Bryan S,
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46. Young A, Dixey J, Cox N, Davies
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tumor necrosis factor therapy in th
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arthritis: a 12-week, double-blind,
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171. Geborek P, Crnkic M, Petersson
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216. Schotte H, Willeke P, Mickholz
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The Health Assessment Questionnaire
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Cochrane Library (CENTRAL) 2005 Iss
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Appendix 3 © Queen’s Printer and
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TABLE 69 Studies excluded from clin
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148 Appendix 4 TABLE 71 Meta-analys
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150 Appendix 4 TABLE 73 Meta-analys
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152 Appendix 4 Infliximab versus pl
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154 Appendix 4 Infliximab plus MTX
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Ovid MEDLINE(R) 1966 to February we
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Appendix 8 © Queen’s Printer and
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TABLE 79 Wong et al., 2002 161 © Q
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TABLE 80 Kobelt et al., 2003 162 (c
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TABLE 82 Brennan et al., 2004 160
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TABLE 85 Bansback et al., 2005 166
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176 Appendix 9 TABLE 89 Strategy se
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Extensive sensitivity analysis was
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TABLE 96 Variation 1: TNF inhibitor
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TABLE 99 Variation 2: TNF inhibitor
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TABLE 102 Variation 3: TNF inhibito
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TABLE 132 Variation 10: TNF inhibit
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A systematic review of the effectiveness of adalimumab

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