Romiplostim and eltrombopag for immune thrombocytopenia: methods for indirect comparison.

OBJECTIVES: Immune thrombocytopenia (ITP) causes increased platelet destruction and suboptimal platelet production, increasing risk of bleeding. This analysis uses a Bayesian metaregression model to indirectly compare effectiveness of the thrombopoietin mimetics romiplostim and eltrombopag for increasing platelet counts, and contrasts the results with those of non-Bayesian approaches. METHODS: Ten databases were searched during 2010. Placebo-controlled trials of 24 weeks' duration were included. An indirect comparison was undertaken using Bayesian metaregression, which includes all trials in a single model. This was compared with previous analyses in which data for each intervention were combined using simple pooling, logistic regression or meta-analysis, followed by indirect comparison of pooled values using the Bucher method. RESULTS: Two trials of romiplostim and one of eltrombopag were included. The indirect evidence suggests romiplostim significantly improves overall platelet response compared with eltrombopag. Bayesian metaregression gave an odds ratio (OR) for eltrombopag versus romiplostim of 0.11 (95 percent credible interval 0.02-0.66); p values and Bayesian posterior probabilities ranged from 0.01 to 0.05 for all analyses. There was no significant difference in durable platelet response in any of the analyses, although the direction of effect favored romiplostim (OR = 0.15; 95 percent credible interval, 0.01-1.88); p values and Bayesian posterior probabilities ranged from 0.08 to 0.40 across analyses. Results were relatively consistent between analyses. CONCLUSIONS: Bayesian metaregression generated similar results to other indirect comparison methods, and may be considered the most robust as it incorporates all data in a single model and accounts appropriately for parameter uncertainty.

Granulocyte colony-stimulating factors for febrile neutropenia prophylaxis following chemotherapy: systematic review and meta-analysis.

BACKGROUND: Febrile neutropenia (FN) occurs following myelosuppressive chemotherapy and is associated with morbidity, mortality, costs, and chemotherapy reductions and delays. Granulocyte colony-stimulating factors (G-CSFs) stimulate neutrophil production and may reduce FN incidence when given prophylactically following chemotherapy. METHODS: A systematic review and meta-analysis assessed the effectiveness of G-CSFs (pegfilgrastim, filgrastim or lenograstim) in reducing FN incidence in adults undergoing chemotherapy for solid tumours or lymphoma. G-CSFs were compared with no primary G-CSF prophylaxis and with one another. Nine databases were searched in December 2009. Meta-analysis used a random effects model due to heterogeneity. RESULTS: Twenty studies compared primary G-CSF prophylaxis with no primary G-CSF prophylaxis: five studies of pegfilgrastim; ten of filgrastim; and five of lenograstim. All three G-CSFs significantly reduced FN incidence, with relative risks of 0.30 (95% CI: 0.14 to 0.65) for pegfilgrastim, 0.57 (95% CI: 0.48 to 0.69) for filgrastim, and 0.62 (95% CI: 0.44 to 0.88) for lenograstim. Overall, the relative risk of FN for any primary G-CSF prophylaxis versus no primary G-CSF prophylaxis was 0.51 (95% CI: 0.41 to 0.62). In terms of comparisons between different G-CSFs, five studies compared pegfilgrastim with filgrastim. FN incidence was significantly lower for pegfilgrastim than filgrastim, with a relative risk of 0.66 (95% CI: 0.44 to 0.98). CONCLUSIONS: Primary prophylaxis with G-CSFs significantly reduces FN incidence in adults undergoing chemotherapy for solid tumours or lymphoma. Pegfilgrastim reduces FN incidence to a significantly greater extent than filgrastim.

Cost-effectiveness of granulocyte colony-stimulating factor prophylaxis for febrile neutropenia in breast cancer in the United Kingdom.

OBJECTIVE: We report a cost-effectiveness evaluation of granulocyte colony-stimulating factors (G-CSFs) for the prevention of febrile neutropenia (FN) after chemotherapy in the United Kingdom (UK). METHODS: A mathematical model was constructed simulating the experience of women with breast cancer undergoing chemotherapy. Three strategies were modeled: primary prophylaxis (G-CSFs administered in all cycles), secondary prophylaxis (G-CSFs administered in all cycles after an FN event), and no G-CSF prophylaxis. Three G-CSFs were considered: filgrastim, lenograstim, and pegfilgrastim. Costs were taken from UK databases and utility values from published sources. A systematic review provided data on G-CSF efficacy. Probabilistic sensitivity analyses examined the effects of uncertainty in model parameters. RESULTS: In the UK, base-case analysis with a willingness-to-pay (WTP) threshold of £20K per quality-adjusted life year gained and also using list prices, the most cost-effective strategy was primary prophylaxis with pegfilgrastim for a patient with baseline FN risk greater than 38%, secondary prophylaxis with pegfilgrastim for baseline FN risk 11% to 37%, and no G-CSFs for baseline FN risk less than 11%. Using a WTP threshold of £30K and list prices, primary prophylaxis with pegfilgrastim was cost-effective for baseline FN risks greater than 29%. In all analyses, pegfilgrastim dominated filgrastim and lenograstim. Sensitivity analyses demonstrated that higher WTP threshold, younger age, earlier stage at diagnosis, or reduced G-CSF prices result in G-CSF prophylaxis being cost-effective at lower baseline FN risk levels. CONCLUSION: Pegfilgrastim was the most cost-effective G-CSF. The most cost-effective strategy (primary or secondary prophylaxis) was dependent on the FN risk level for an individual patient, patient age and stage at diagnosis, and G-CSF price.

Consistency between direct and indirect trial evidence: is direct evidence always more reliable?

OBJECTIVES: To present a case study involving the reduction in incidence of febrile neutropenia (FN) after chemotherapy with granulocyte colony-stimulating factors (G-CSFs), illustrating difficulties that may arise when following the common preference for direct evidence over indirect evidence. METHODS: Evidence of the efficacy of treatments was identified from two previous systematic reviews. We used Bayesian evidence synthesis to estimate relative treatment effects based on direct evidence, indirect evidence, and both pooled together. We checked for inconsistency between direct and indirect evidence and explored the role of one specific trial using cross-validation. A subsequent review identified further studies not available at the time of the original analysis. We repeated the analyses on the enlarged evidence base. RESULTS: We found substantial inconsistency in the original evidence base. The median odds ratio of FN for primary pegfilgrastim versus no primary G-CSF was 0.06 (95% credible interval: 0.02-0.19) based on direct evidence, but 0.27 (95% credible interval: 0.13-0.53) based on indirect evidence (P value for consistency hypothesis 0.027). The additional trials were consistent with the earlier indirect, rather than the direct, evidence, and there was no inconsistency between direct and indirect estimates in the updated evidence. The earlier inconsistency was due to one trial comparing primary pegfilgrastim with no primary G-CSF. Predictive cross-validation showed that this study was inconsistent with the evidence as a whole and with other trials making this comparison. CONCLUSIONS: Both the Cochrane Handbook and the NICE Methods Guide express a preference for direct evidence. A more robust strategy, which is in line with the accepted principles of evidence synthesis, would be to combine all relevant and appropriate information, whether direct or indirect.

Prevalence of visits to massage therapists by the general population: a systematic review.

OBJECTIVE: To systematically review 12-month prevalence of visits to massage therapists by representative samples of the general population across countries. METHODS: Surveys reporting estimates of overall CAM use were included. Studies were identified via database searches. Study quality was assessed using a six-item tool. RESULTS: Twenty-two surveys across six countries were included. Estimates for 12-month prevalence of visits to massage therapists by adults ranged from 0.4% to 20% and the median was 5.5%. Estimates for children were 0.3%-3.8% (median 0.7%), while estimates for older adults were 1.5%-16.2% (median 5.2%). 16 surveys (73%) met at least four of six quality criteria. CONCLUSIONS: This review summarises 12-month prevalence of visits to massage therapists in six countries (USA, UK, Canada, Australia, Singapore and South Korea). A small but significant percentage of these general populations visit massage therapists each year.

A structured judgement method to enhance mortality case note review: development and evaluation.

BACKGROUND: Case note review remains a prime means of retrospectively assessing quality of care. This study examines a new implicit judgement method, combining structured reviewer comments with quality of care scores, to assess care of people who die in hospital. METHODS: Using 1566 case notes from 20 English hospitals, 40 physicians each reviewed 30-40 case notes, writing structured judgement-based comments on care provided within three phases of care, and on care overall, and scoring quality of care from 1 (unsatisfactory) to 6 (very best care). Quality of care comments on 119 people who died (7.6% of the cohort) were analysed independently by two researchers to investigate how well reviewers provided structured short judgement notes on quality of care, together with appropriate care scores. Consistency between explanatory textual data and related scores was explored, using overall care score to group cases. RESULTS: Physician reviewers made informative, clinical judgement-based comments across all phases of care and usually provided a coherent quality of care score relating to each phase. The majority of comments (83%) were explicit judgements. About a fifth of patients were considered to have received less than satisfactory care, often experiencing a series of adverse events. CONCLUSIONS: A combination of implicit judgement, explicit explanatory comment and related quality of care scores can be used effectively to review the spectrum of care provided for people who die in hospital. The method can be used to quickly evaluate deaths so that lessons can be learned about both poor and high quality care.

Prevalence of visits to five types of complementary and alternative medicine practitioners by the general population: a systematic review.

OBJECTIVE: To systematically review surveys of 12-month prevalence of visits to complementary and alternative medicine (CAM) practitioners for five therapies: acupuncture, homeopathy, osteopathy, chiropractic, and medical herbalism. METHODS: Studies were identified via database searches to 2011. Study quality was assessed using a six-item tool. RESULTS: Forty-one surveys across 12 countries were included. Twenty-five (61%) met four of six quality criteria. Prevalence of visits by adults were (median, range): acupuncturists 1.4% (0.2-7.5%, N = 27 surveys), homeopaths 1.5% (0.2-2.9%, N = 20 surveys), osteopaths 1.9% (0.2-4.4%, N = 9 surveys), chiropractors 7.5% (0.3-16.7, N = 33 surveys), medical herbalists 0.9% (0.3-4.7%, N = 14 surveys). Estimates were slightly lower for children and higher for older adults. There was little change over the past 15-20 years. CONCLUSIONS: This review summarises 12-month prevalence of visits to CAM practitioners in Europe, North America, Australia, East Asia, Saudi Arabia and Israel. A small but significant percentage of these general populations visit CAM practitioners each year.

Oseltamivir, zanamivir and amantadine in the prevention of influenza: a systematic review.

OBJECTIVE: To systematically review evidence relating to the clinical efficacy of oseltamivir, zanamivir and amantadine in the prevention of influenza. METHODS: RCTs evaluating these interventions in seasonal prophylaxis and post-exposure prophylaxis were identified using electronic bibliographic databases and handsearching of retrieved articles. RESULTS: Oseltamivir was effective in preventing symptomatic laboratory-confirmed influenza (SLCI) in seasonal prophylaxis in healthy adults and at-risk elderly subjects and in post-exposure prophylaxis within households of mixed composition. Post-exposure prophylaxis using oseltamivir for paediatric contacts was observed to prevent SLCI. Zanamivir prevented SLCI in seasonal prophylaxis in healthy adults, at-risk adults and adolescents and in post-exposure prophylaxis within mixed households, with a trend for seasonal and post-exposure preventative effects in elderly subjects. Evidence for amantadine prophylaxis across subgroups was very limited. However, amantadine prevented SLCI in seasonal prophylaxis in healthy adults and in outbreak control amongst adolescent subjects. Interventions were reported to be well tolerated by subjects, with a relatively low proportion of subjects experiencing drug-related adverse events and drug-related withdrawals. CONCLUSIONS: Evidence was identified for the efficacy of oseltamivir and zanamivir in preventing influenza in a range of population subgroups. The evidence base for amantadine was considerably more limited.

Homeopathy for insomnia: a systematic review of research evidence.

BACKGROUND: Insomnia is a common problem which impacts on quality of life. Current management includes psychological and behavioural therapies and/or pharmacological treatments. OBJECTIVE: To systematically review research evidence for effectiveness of homeopathy in the management of insomnia. METHODS: Comprehensive searches of biomedical databases (MEDLINE, EMBASE, CINAHL, Cochrane library, Science Citation Index), homeopathy-specific and complementary medicine-specific databases were conducted. RESULTS: (A) Homeopathic medicines: four randomised controlled trials (RCTs) compared homeopathic medicines to placebo. All involved small patient numbers and were of low methodological quality. None demonstrated a statistically significant difference in outcomes between groups, although two showed a trend favouring homeopathic medicines and three demonstrated significant improvements from baseline in both groups. A cohort study reported significant improvements from baseline. (B) Treatment by a homeopath: No randomised controlled trials of treatment by a homeopath were identified. One cohort study, three case series and over 2600 case studies were identified. CONCLUSIONS: The limited evidence available does not demonstrate a statistically significant effect of homeopathic medicines for insomnia treatment. Existing RCTs were of poor quality and were likely to have been underpowered. Well-conducted studies of homeopathic medicines and treatment by a homeopath are required to examine the clinical and cost effectiveness of homeopathy for insomnia.