A systematic review and economic model of the clinical effectiveness and cost-effectiveness of interventions for preventing relapse in people with bipolar disorder.

OBJECTIVES: To determine the clinical effectiveness and cost-effectiveness of pharmacological and/or psychosocial interventions for the prevention of relapse in people with bipolar disorder. DATA SOURCES: Major electronic databases were searched up to September 2005. REVIEW METHODS: Systematic reviews were undertaken on the clinical and economic effectiveness of treatments. An analysis was performed using the methods of mixed treatment comparison (MTC) to enable indirect comparisons to be made between the treatments. An economic model of treatments for the prevention of relapse in bipolar disorder was developed. RESULTS: Forty-five trials were included in the clinical effectiveness review; all but one studied adults. This review found that for the prevention of all relapses, lithium, valproate, lamotrigine and olanzapine performed better than placebo, with lithium and lamotrigine having the strongest evidence. For depressive relapse prevention, valproate, lamotrigine and imipramine performed better than placebo, with evidence strongest for lamotrigine and weakest for imipramine. For manic relapses, lithium and olanzapine performed significantly better than placebo. The MTC found that the best treatment for bipolar I patients with mainly depressive symptoms was valproate, followed by lithium plus imipramine. For bipolar I patients with mainly manic symptoms, olanzapine was the best treatment. From the studies investigating psychosocial interventions, there were few data for each comparison and outcome. The evidence suggests that cognitive behaviour therapy (CBT), in combination with usual treatment, is effective for the prevention of relapse. Group psychoeducation and possibly family therapy may also have roles as adjunctive therapy for preventing relapse. The results from the decision analytic model developed on the cost-effectiveness of long-term maintenance treatments of bipolar I patients suggest that the choice of treatment is dependent upon a number of factors: the previous episode history of a patient and the mortality benefit assumed for lithium strategies. The results from the base-case analysis for patients with a recent history of depression suggest that valproate, lithium and the combination of lithium and imipramine are potentially cost-effective depending upon the amount that a decision-maker is willing to pay for additional health gain. Using conventional amounts that the NHS is prepared to pay for health gain, then the lithium-based strategies appear to be potentially cost-effective for this group. For patients with a recent history of mania, the choice of pharmacological intervention appears to be between olanzapine and lithium monotherapy. Again using conventional threshold as a reference point, the results suggest that lithium is the most cost-effective therapy. Excluding the additional mortality benefit associated with lithium-based strategies resulted in all treatments for patients with a recent history of a depressive episode being dominated by valproate and, in the case of patients with a recent history of a manic episode, by olanzapine. CONCLUSIONS: Lithium, valproate, lamotrigine and olanzapine are effective as maintenance therapy for the prevention of relapse in bipolar disorder. Olanzapine and lithium are efficacious for the prevention of manic relapses and valproate, lamotrigine and imipramine for the prevention of depressive relapse. There is some evidence that CBT, group psychoeducation and family therapy might be beneficial as adjuncts to pharmacological maintenance treatments. Insufficient information is available regarding the relative tolerability of the treatments or their relative effects on suicide rate and mortality. For patients with a recent depressive episode, valproate, lithium monotherapy and the combination of lithium and imipramine are potentially cost-effective. For patients with a recent manic episode, olanzapine and lithium monotherapy are potentially cost-effective. The cost-effectiveness estimates in both groups of patients were shown to be sensitive to the assumption of a reduced suicidal risk associated with lithium-based strategies. Further research is needed into the adverse effects of all treatments and the differential effects of agents. Good-quality trials of valproate, of combination therapy, e.g. lithium plus a selective serotonin reuptake inhibitor antidepressant, of psychosocial interventions and of the disorder in children are also required.

Etanercept and infliximab for the treatment of psoriatic arthritis: a systematic review and economic evaluation.

OBJECTIVES: To evaluate the clinical effectiveness, safety, tolerability and cost-effectiveness of etanercept and infliximab for the treatment of active and progressive psoriatic arthritis (PsA) in patients who have inadequate response to standard treatment, including disease-modifying antirheumatic drug (DMARD) therapy. DATA SOURCES: Electronic databases were searched up to July 2004. REVIEW METHODS: A systematic review evaluated the clinical efficacy and adverse effects of etanercept and infliximab. The efficacy of DMARDs in the treatment of PsA was also reviewed and treatments were compared using Bayesian evidence synthesis methods. Following evaluation of existing economic evaluations of etanercept and infliximab in PsA, a new economic model was developed (the York Model). This utilised the results from the evidence synthesis and data from a range of other sources. RESULTS: Across the two trials, at 12 weeks, around 65% of patients treated with etanercept achieved an American College of Rheumatology (ACR) 20 {pooled relative risk (RR) 4.19 [95% confidence interval (CI) 2.74 to 6.42]}, demonstrating a basic degree of efficacy in terms of arthritis-related symptoms. In addition, around 45% of patients treated with etanercept achieved an ACR 50 [pooled RR 10.84 (95% CI 4.47 to 26.28)] and around 12% achieved an ACR 70 [pooled RR 16.28 (95% CI 2.20 to 120.54)], demonstrating a good level of efficacy. The subgroup analyses conducted in one trial revealed that the effect of etanercept was not dependent upon patients' concomitant use of methotrexate. In addition, almost 85% of patients treated with etanercept achieved a Psoriatic Arthritis Response Criteria (PsARC) [pooled RR 2.60 (95% CI 1.96 to 3.45). The Psoriatic Area and Severity Index (PASI) results indicate some beneficial effect on psoriasis at 12 weeks; however, the data are sparse. The statistically significant reduction (improvement) in Health Assessment Questionnaire (HAQ) score with etanercept compared with placebo indicates a beneficial effect of etanercept on function. Similar results were seen at 24 weeks, except that the results for PASI 75 and PASI 50 now achieved statistical significance and data for Total Sharp Score annualised rate of progression were available; this was statistically significantly lower in etanercept-treated patients than in placebo-treated patients. Uncontrolled follow-up of patients indicates that treatment benefit may be maintained for at least 50 weeks. At 16 weeks, 65% of patients treated with infliximab achieved an ACR 20 [RR 6.80 (95% CI 2.89 to 16.01)], demonstrating a basic degree of efficacy in terms of arthritis-related symptoms. This level of efficacy was not dependent upon patients' concomitant use of methotrexate. Almost half the patients treated with infliximab achieved an ACR 50 [RR 49.00 (95% CI 3.06 to 785.06)] and over one-quarter achieved an ACR 70 [RR 31.00 (95% CI 1.90 to 504.86)] compared with none of the placebo group, demonstrating a good level of efficacy. In addition, 75% of patients treated with infliximab achieved a PsARC [RR 3.55 (95% CI 2.05 to 6.13)]. The beneficial treatment effect on psoriasis was also statistically significant with a mean difference in percentage change from baseline in PASI of -5 (95% CI -6.8 to -3.3), as was the percentage improvement from baseline in HAQ score with infliximab compared with placebo [mean difference 51.4 (95% CI 48.08 to 54.72)], indicating a beneficial effect of infliximab on functional status. Uncontrolled data from all measures of joint disease, psoriasis and HAQ collected up to 50 weeks of follow-up reflect those at 16 weeks. There were no radiographic assessments, so nothing can be determined about the potential or otherwise of infliximab to delay the progression of joint disease. Using the York cost-effectiveness model, infliximab was consistently dominated by etanercept because of its higher acquisition and administration costs without superior effectiveness. The incremental cost per quality-adjusted life-year (QALY) gained of etanercept compared with palliative care ranged from 14,818 pounds (females, 40-year time horizon) to 49,374 pounds (males, 1-year time horizon) if it is assumed that, when patients eventually fail on biological therapy, their disability (in terms of HAQ score) deteriorates by the same amount as it improved when they initially respond to treatment (rebound equal to gain). Results for etanercept ranged from 25,443 pounds (females, 40-year time horizon) to 49,441 pounds (males, 1-year time horizon) per QALY gained under the assumption that, when patients fail on therapy, their disability level returns to what it would have been had they never responded (rebound equal to natural history). CONCLUSIONS: The limited data available indicated that etanercept and infliximab are efficacious in the treatment of PsA with beneficial effects on both joint and psoriasis symptoms and on functional status. Short-term data indicated that etanercept can delay joint disease progression, but long-term data are needed. There are no controlled data as yet to indicate that infliximab can delay joint disease progression. Treatment with both etanercept and infliximab for 12 weeks demonstrated a significant degree of efficacy, with no statistically significant difference between them. For both drugs, adverse events were common with mild injection/infusion reactions being the main treatment-related effect. The York model indicated that etanercept is more cost-effective than infliximab as it has a lower cost with little difference in outcomes. The cost-effectiveness of etanercept is also sensitive to assumptions made about the extent of disease progression when patients are responding to therapy. The number of years for which a patient can be safely on biologicals is uncertain so these results should be considered with caution. Further research should include long-term controlled trials to confirm benefits, review adverse events and to explore further the implications of biologic therapy.

The cost-effectiveness of etanercept and infliximab for the treatment of patients with psoriatic arthritis.

OBJECTIVE: Tumour necrosis factor (TNF) antagonists have been shown to improve the outcomes in patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA). We assess the cost-effectiveness of two TNF antagonists and so-called 'palliative care' for the treatment of active PsA from the perspective of the UK National Health Service (NHS). METHODS: Bayesian statistical methods were used to synthesize evidence from three Phase III trials, identified through a systematic review, and estimate the relative efficacy of etanercept, infliximab and palliative care. A probabilistic decision analytic model was then used to compare these treatments after the failure of at least two conventional disease-modifying anti-rheumatic drugs (DMARDs), following the British Society for Rheumatology (BSR) guidelines for use. The primary outcome measure, quality-adjusted life years (QALYs), was derived from utility values estimated as a function of disability measured by the Health Assessment Questionnaire (HAQ). The deterioration experienced in HAQ at treatment withdrawal (rebound) was incorporated using alternative scenarios to represent best- and worst-case assumptions. The model was extended beyond the trial duration to a 10-yr and lifetime horizon, using available evidence and expert opinion-based assumptions on disease progression. Resource utilization was based on literature, national databases and expert opinion. Prices were obtained from routine NHS sources and published literature. RESULTS: At a 10-yr time horizon, the incremental cost-effectiveness ratio (ICER) for etanercept compared with palliative care was pound sterling26 361 per QALY gained for the best-case rebound scenario, which increased to pound sterling30 628 for the worst-case. The ICERs for infliximab compared with etanercept were pound sterling165 363 and pound sterling205 345 per QALY, respectively. These findings are mainly explained by the fact that infliximab has higher acquisition and administration costs without substantially superior effectiveness compared with etanercept. Results were sensitive to estimates of rebound assumptions at withdrawal and the time horizon. CONCLUSIONS: Only results for etanercept remained within the range of cost-effectiveness estimates considered to represent value for money in the NHS by the National Institute for Health and Clinical Excellence. Further research appears most valuable in relation to the short-term effectiveness, utility parameters and assumptions regarding the effect of rebound.