Maria A. Lopez-Olivo

A network meta-analysis of randomized controlled trials of biologics for rheumatoid arthritis: a Cochrane overview

Background: We sought to compare the benefits and safety of 6 biologics (abatacept, adalimumab, anakinra, etanercept, infliximab and rituximab) in patients with rheumatoid arthritis. Methods: In this network meta-analysis, we included all completed and updated Cochrane reviews on biologics for rheumatoid arthritis. We included data from all placebo-controlled trials that used standard dosing regimens. The major outcomes were benefit (defined as a 50% improvement in patient- and physician-reported criteria of the American College of Rheumatology [ACR50]) and safety (determined by the number of withdrawals related to adverse events). We used mixed-effects logistic regression to carry out an indirect comparison of the treatment effects between biologics. Results: Compared with placebo, biologics were associated with a clinically important higher ACR50 rate (odds ratio [OR] 3.35, 95% confidence interval [CI] 2.62–4.29) and a number needed to treat for benefit of 4 (95% CI 4–6). However, biologics were associated with more withdrawals related to adverse events (OR 1.39, 95% CI 1.13–1.71), with a number needed to treat for harm of 52 (95% CI 29–152). Anakinra was less effective than all of the other biologics, although this difference was statistically significant only for the comparison with adalimumab (OR 0.45, 95% CI 0.21–0.99) and etanercept (OR 0.34, 95% CI 0.14–0.81). Adalimumab, anakinra and infliximab were more likely than etanercept to lead to withdrawals related to adverse events (adalimumab OR 1.89, 95% CI 1.18–3.04; anakinra OR 2.05, 95% CI 1.27–3.29; and infliximab OR 2.70, 95% CI 1.43–5.26). Interpretation: Given the limitations of indirect comparisons, anakinra was less effective than adalimumab and etanercept, and etanercept was safer than adalimumab, anakinra and infliximab. This summary of the evidence will help physicians and patients to make evidence-based choices about biologics for the treatment of rheumatoid arthritis.

Tocilizumab for rheumatoid arthritis: A cochrane systematic review

Objective. To compare the benefit and safety of tocilizumab to placebo in patients with rheumatoid arthritis (RA). Methods. We searched multiple databases for published randomized or controlled clinical trials comparing benefit and safety of tocilizumab to placebo, disease-modifying antirheumatic drugs (DMARD), or other biologics. For dichotomous outcomes, we calculated the relative risk, and for continuous outcomes, the mean difference. Results. Eight randomized controlled trials were included in this systematic review, with 3334 participants, 2233 treated with tocilizumab and 1101 controls. The US and Canadian approved dose of tocilizumab, 8 mg/kg every 4 weeks, was given to 1561 participants. In patients taking concomitant methotrexate, compared to placebo, patients treated with approved dose of tocilizumab were substantially and statistically significantly more likely than placebo to achieve the American College of Rheumatology 50 (absolute percentage, 38.8% vs 9.6%, respectively; RR 3.2, 95% CI 2.7, 3.7); Disease Activity Score remission (30.5% vs 2.7%; RR 8.7, 95% CI 6.3, 11.8); and a clinically meaningful decrease in Health Assessment Questionnaire (HAQ)/Modified HAQ scores (60.5% vs 34%; RR 1.8, 95% CI 1.6, 1.9). There were no substantive statistically significant differences in serious adverse effects (0.8% vs 0.7%; RR 1.2, 95% CI 0.8, 1.6) or withdrawals due to adverse events (4.9% vs 3.7%; RR 1.4, 95% CI 0.9, 2.1); however, tocilizumab-treated patients were significantly more likely to have any adverse event (74% vs 65%; RR 1.05, 95% CI 1.03, 1.07); elevation in the ratio of low-density lipoprotein to high-density lipoprotein cholesterol (HDL; 20% vs 12%; RR 1.7, 95% CI 1.2, 2.2); and increase in the ratio of total to HDL cholesterol (12% vs 7%; RR 1.7, 95% CI 1.2, 2.6); and they were less likely to withdraw from treatment for any reason (8.1% vs 14.9%; RR 0.6, 95% CI 0.5, 0.8). Conclusion. At the approved dose of 8 mg/kg every 4 weeks, tocilizumab in combination with methotrexate/DMARD is beneficial in decreasing RA disease activity and improving function. Tocilizumab treatment was associated with a significant increase in cholesterol levels and occurrence of any adverse event, but not serious adverse events. Larger safety studies are needed to address these safety concerns.

Denosumab in patients with cancer and skeletal metastases: A systematic review and meta-analysis

BACKGROUND We conducted a systematic review of the literature to determine the efficacy and safety of denosumab in reducing skeletal-related events (SRE) in patients with bone metastases. METHODS A literature search using MEDLINE, EMBASE, Web of Science and The Cochrane Collaboration Library identified relevant controlled clinical trials up-to-March 14, 2012. Two independent reviewers assessed studies for inclusion, according to predetermined criteria, and extracted relevant data. The primary outcomes of interest were SRE, time to first on-study SRE, and overall survival. Secondary outcomes included pain, quality of life, bone turnover markers (BTM), and adverse events. RESULTS Six controlled trials including 6142 patients were analyzed. Compared to zoledronic acid, denosumab had lower incidence of SRE with a risk ratio (RR) of 0.84 (95% confidence intervals (CI) 0.80-0.88), delayed the onset of first on-study SRE (RR 0.83; 95% CI 0.75-0.90) and time to worsening of pain (RR 0.84; 95% CI 0.77-0.91). No difference was observed in overall survival with pooled hazard ratio of 0.98 (95% CI 0.90-1.0). For total adverse events, denosumab was similar to zoledronic acid (RR 0.97; 95% CI 0.89-1.0). No significant differences were observed in the frequency of osteonecrosis of the jaw (RR 1.4; 95% CI 0.92-2.1). Patients on denosumab had a greater risk of developing hypocalcemia (RR 1.9; 95% CI 1.6-2.3). CONCLUSIONS Denosumab was more effective than zoledronic acid in reducing the incidence of SRE, and delayed the time to SRE. No differences were found between denosumab and zoledronic acid in reducing overall mortality, or in the frequency of overall adverse events.

A systematic review of the effect of TNF-α antagonists on lipid profiles in patients with rheumatoid arthritis

Atherosclerosis plays a key role in cardiovascular disease in patients with rheumatoid arthritis (RA). Although therapy with TNF-α antagonists has resulted in dramatic improvement in the prognosis of RA, its effects on circulatory lipids are unclear. We conducted a systematic review of the literature to summarize the available evidence on lipid profile modification in patients with RA treated with TNF-α antagonists, with extensive searches in PubMed, the Cochrane Collaboration database (Central), and SCOPUS. Twenty-four observational studies met the inclusion criteria; 12 included only patients with RA treated with infliximab and three, patients with RA treated with adalimumab. The other nine included a mix of patients with various rheumatic diseases, or receiving one of several TNF-α antagonists. Eleven studies found a statistically significant increase in total cholesterol (TC) and high-density lipoprotein (HDL); six of 20 found significant increases in triglycerides (TG). Four of 13 studies found a statistical increase in low-density lipoprotein. No major changes were observed for ApoB/ApoA1 ratios. A small trend to increased TC was observed in patients receiving TNF-α antagonists, mostly due to an increase in HDL. There was a small trend to increased TG, and no changes in ApoB/ApoA1 ratio. The clinical impact of these findings is unclear, and further studies are needed to clarify the role of these lipid changes on cardiovascular morbidity in RA.

Quality appraisal of clinical practice guidelines and consensus statements on the use of biologic agents in rheumatoid arthritis: A systematic review

OBJECTIVE To evaluate the quality of clinical practice guidelines (CPGs) and consensus statements (CS) for the treatment of rheumatoid arthritis with tumor necrosis factor alpha (TNFalpha) antagonists. METHODS We searched for CPGs and CS on the use of infliximab, etanercept, and/or adalimumab for the treatment of rheumatoid arthritis, published through October 10, 2006. Sources included electronic databases (Medline, EMBase, BIOSIS, etc.), guideline registries, and pertinent Web sites. Review of 4,915 citations revealed 16 CPGs and 20 CS. Two independent reviewers evaluated development methods of selected studies using the 23-item Appraisal of Guidelines for Research and Evaluation (AGREE) instrument and compared recommendations between guidelines. RESULTS Of the 16 guidelines, only 5 (31%) were based on a systematic review of relevant research evidence. Only 4 (25%) of the guidelines fulfilled > or = 60% of the AGREE criteria. AGREE scores were lower for guidelines from rheumatology societies than government agencies when reporting scope and purposes (P = 0.03), stakeholder involvement (P = 0.03), and clarity and presentation (P = 0.01). Guidelines scored higher than CS in most domains. Overall, guideline recommendations were consistent with respect to the use of biologic agents after failure of disease-modifying antirheumatic drugs, but differed or did not provide specific guidance on tests for screening. CONCLUSION Guidelines for introducing TNFalpha antagonists in rheumatoid arthritis often fail to meet expected methodologic criteria and therefore vary significantly in quality and with respect to some recommendations for patient assessment and management.

Rasburicase in Tumor Lysis Syndrome of the Adult: A Systematic Review and Meta-analysis

BACKGROUND The use of rasburicase has been evaluated extensively in children, but not in adults. We review the current literature to evaluate its effect on adults. STUDY DESIGN Systematic review and meta-analysis. SETTING & POPULATION Adults receiving rasburicase for tumor lysis syndrome (TLS). SELECTION CRITERIA FOR STUDIES Electronic databases, regulatory documents, and websites were searched up to August 7, 2012. Reference lists of published articles were examined for additional relevant references. Any controlled trial or observational studies (controlled before and after) were included. Studies considering children only or mixing data for children and adults were excluded. INTERVENTION Rasburicase for TLS. OUTCOMES The primary outcome was TLS development. Secondary outcomes included percentage of patients improving, total adverse events, acute kidney failure, deaths, and serum uric acid and creatinine levels. RESULTS 21 studies (24 publications) reported data for 1,261 adult patients, 768 receiving rasburicase for either the treatment or prophylaxis of TLS; these comprised 4 controlled trials and 17 observational studies. No statistically significant differences in clinical TLS development were observed in the controlled trials between the rasburicase and control groups. For the observational studies, 7.4% of patients developed clinical TLS after rasburicase (95% CI, 1.7%-16.7%), 93.4% of patients achieved normalized serum uric acid levels after rasburicase treatment (95% CI, 91.7%-94.6%), 4.4% developed acute kidney injury (95% CI, 3.0%-6.0%), and 2.6% died (95% CI, 0.95%-5.0%). The mean reduction in serum uric acid levels ranged from 5.3-12.8 mg/dL, and for serum creatinine levels, from 0.10-2.1 mg/dL. LIMITATIONS Controlled trials differed in outcomes reported; meta-analysis was not performed. CONCLUSIONS Rasburicase is effective in reducing serum uric acid levels in adults with TLS but at a significant cost, and evidence currently is lacking in adults to report whether rasburicase use improves clinical outcomes compared with other alternatives. Until new evidence is available, use of rasburicase may be limited to adult patients with a high risk of TLS.

Cost-Effectiveness of Total Knee Replacement: A Prospective Cohort Study

Total knee replacement (TKR) rates have significantly increased in the past decade. While the procedure itself might be costly, the cost‐effectiveness and potential offset costs from patient and societal benefits have not been clearly established. The objective of this study was to perform an economic evaluation of TKR in patients with knee osteoarthritis (OA).

Direct-Acting Antiviral Agents for Patients With Hepatitis C Virus Genotype 1 Infection Are Cost-Saving

Background & Aims Direct‐acting antivirals (DAAs) are effective in treatment of hepatitis C virus (HCV) genotype 1 infection, but their cost and value have been debated. We performed a systematic review of published cost‐effectiveness analyses of DAAs, synthesized their results with updated drug prices, and calculated the maximum price at which DAA therapy for HCV genotype 1 infection is cost‐effective (increased quality‐adjusted life‐years [QALYs] and increased cost that the society is willing to pay) and cost‐saving (increased QALYs and decreased costs). Methods We conducted a systematic review of the PubMed, Medline, EMBASE, Cochrane library, EconLit, Database of Abstracts of Reviews of Effects, National Health Service Economic Evaluation Database, Health Technology Assessment, and Tufts University databases for cost‐effectiveness analyses published from 2011 through 2015. Our analysis included cost effectiveness of DAAs versus previous standard‐of‐care regimens (peginterferon and ribavirin, boceprevir and telaprevir), or no treatment, performed for patients with HCV genotype 1 infection. We excluded studies that were not written in English or those that did not report QALYs. Reported incremental cost‐effectiveness ratios (ICERs) and treatment costs for each comparison were extracted; the threshold price was estimated for each analysis in which regimens were found to be cost‐effective (ICER ≤

How low should we go: A systematic review and meta-analysis of the impact of restrictive red blood cell transfusion strategies in oncology

100,000/QALY) or cost‐saving (ICER <

Cervical Spine Radiographs in Patients With Rheumatoid Arthritis Undergoing Anesthesia

0), those that decreased costs and increased QALYs. Results We identified 24 cost‐effectiveness studies that reported 170 ICERs for combinations of 11 drugs, from 11 countries. Of those, 81 ICERs were determined for first‐generation DAAs (boceprevir and telaprevir) and 89 ICERs were determined for second‐generation DAAs (drugs approved after the first‐generation DAAs) as a primary intervention. The median threshold prices at which first‐generation and second‐generation DAAs became cost‐effective were estimated as