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PubMed1996

G-CSF for the prophylaxis of neutropenic fever in patients with small cell lung cancer receiving myelosuppressive antineoplastic chemotherapy: meta-analysis and pharmacoeconomic evaluation.

Standard meta-analytical and pharmacoeconomic techniques were used to study the clinical effectiveness and the cost-effectiveness ratio of the prophylactic (or pre-emptive) administration of G-CSF to patients with small cell lung cancer treated with conventional myelosuppressive cytotoxic chemotherapy. In the first part of our study, we conducted a meta-analysis of the randomized clinical trials evaluating G-CSF for this clinical indication. Three trials were identified by our literature search and were included in the meta-analysis (overall number of patients = 606). The end-points for evaluating G-CSF included mortality from infection and the cumulative incidence of neutropenic fever over six cycles of chemotherapy. The results of our meta-analysis demonstrate that prophylactic G-CSF did not affect mortality but significantly reduced the incidence of neutropenic fever from 68.3% to 38.7% (pooled odds ratio = 0.29, 95% CI: 0.21-0.40; P < 0.001). In the second part of our study, we carried out a pharmacoeconomic analysis to estimate the cost-effectiveness ratio of pre-emptive G-CSF (i.e. the 'average' cost associated with the prevention of an episode of neutropenic fever). This cost-effectiveness ratio was US$ 14,372 using the Italian price of the drug converted into dollars, or US$ 41 088 using the US price. Finally, we estimated the revenue-neutral price of G-CSF based on American data of the cost-of-illness. The price ranged from US$ 395 to US$ 569 per cycle, a figure higher than the value (US$ 150) previously reported in the literature.

Antineoplastic Agents↗

PubMed2000

Meta-analysis: methods, strengths, and weaknesses.

Meta-analysis is a systematic, quantitative approach to the combination of data from several clinical trials that address the same question. This analytic approach can help resolve questions that remain unclear from the results of individual trials. Meta-analysis is of particular interest in oncology because of the small differences in efficacy between therapeutic alternatives. The large number of patients included in meta-analyses permit small to moderate benefits of a treatment to be reliably detected and larger treatment benefits to be quantified more accurately. Despite these apparent benefits, the use of meta-analysis has met with a great deal of resistance and has generated much controversy in clinical journals. After a brief description of the basic methods of conducting meta-analyses, this article will explore both their advantages and disadvantages.

Bias↗

PubMed2000

Adverse events and treatment discontinuations in clinical trials of fluoxetine in major depressive disorder: an updated meta-analysis.

BACKGROUND: A 1993 meta-analysis of US Investigational New Drug clinical trials of fluoxetine reinforced this agent's more favorable adverse-event profile compared with tricyclic antidepressants (TCAs). OBJECTIVES: The present meta-analysis sought to provide a reanalysis of updated adverse-event and discontinuation data for fluoxetine 20 to 80 mg/d compared with TCAs and placebo in the treatment of major depressive disorder (MDD) in adults. A subanalysis to assess the safety profile of the most commonly used effective dose of fluoxetine in MDD (20 mg) was also conducted. METHODS: Data were obtained from 25 double-blind clinical trials involving 4016 patients with MDD randomized to treatment with fluoxetine 20 to 80 mg/d, TCAs, or placebo. The subanalysis included data from 6 trials involving 1258 patients treated with fixed 20-mg doses of fluoxetine or placebo. Spontaneously reported treatment-emergent adverse events, reasons for discontinuation, and events leading to discontinuation were compared between groups. RESULTS: The age of the 4016 randomized patients ranged from 12 to 90 years, with a mean age of 46 years. Most patients were white (92%), and 62% were female. The age of the 1258 patients in the 20-mg fixed-dose population ranged from 18 to 90 years, with a mean age of 54 years; as in the total population, most of these patients were white (92%), and 57% were female. The adverse-event profiles of fluoxetine and TCAs in these trials were consistent with the typical profiles of selective serotonin reuptake inhibitors and TCAs. At a dose of 20 mg/d, fluoxetine-treated patients had a discontinuation rate due to adverse events that was not statistically significantly different from that in placebo recipients. Discontinuation rates due to lack of efficacy were not significantly different between fluoxetine and TCAs. However, significantly more TCA-treated patients discontinued therapy because of adverse events and significantly fewer completed treatment compared with fluoxetine-treated patients (both, P < 0.001). The most common events (> or = 2%) leading to discontinuation were asthenia, dizziness, insomnia, nausea, nervousness, somnolence, and tremor in fluoxetine-treated patients and abnormal vision, agitation, constipation, dizziness, dry mouth, headache, nausea, nervousness, rash, somnolence, sweating, and tremor in TCA-treated patients. CONCLUSIONS: Data from this large series of clinical trials confirm that fluoxetine is well tolerated in the acute treatment of MDD in adults, especially at a dosage of 20 mg/d, and is better tolerated than the recommended doses of TCAs.

Adolescent↗

PubMed2001

Discontinuation of Pneumocystis carinii prophylaxis in patients infected with human immunodeficiency virus: a meta-analysis and decision analysis.

We performed a meta-analysis and a decision analysis on the discontinuation of prophylaxis for Pneumocystis carinii pneumonia (PCP) in patients infected with human immunodeficiency virus who had adequate immune recovery while receiving highly active antiretroviral therapy. In the meta-analysis (14 studies with 3584 subjects who had discontinued prophylaxis), 8 cases of PCP occurred during 3449 person-years (0.23 cases per 100 person-years [95% confidence interval, 0.10-0.46]). In the decision analysis, mortality and time spent alive without immunodeficiency in the modeled discontinuation strategy were similar to those in the continuation strategy. For patients who received primary prophylaxis, the discontinuation strategy led to slightly fewer episodes of PCP and fewer toxicity-related prophylaxis withdrawals (e.g., 8.6 vs. 34.5 cases per 100 patients during a 10-year period). Patients on the discontinuation strategy were more likely to be receiving trimethoprim-sulfamethoxazole when they became immunodeficient. Comparative results were similar for patients with prior PCP. Discontinuation of PCP prophylaxis in patients with adequate immune recovery is a useful strategy that should be widely considered.

AIDS-Related Opportunistic Infections↗

PubMed1994

Use of immune globulin to prevent symptomatic cytomegalovirus disease in transplant recipients--a meta-analysis.

The objective of this meta-analysis was to review the evidence for the use of immune globulin in the prevention of symptomatic cytomegalovirus (CMV) disease in transplant recipients. A computerized search of Medline from 1980 to October 1991 was conducted using the textword "cytomegalo:" and the subheading "prevention and control" for studies in all languages. Reference lists, a manual search of relevant literature and communication with internationally recognized experts were used to locate additional studies. Of the studies identified, 18 met the inclusion criteria (population: transplant recipients; intervention: immune globulin; outcome: symptomatic cytomegalovirus disease; study design: randomized controlled trial). The meta-analysis of the 18 studies showed a reduction in the incidence of symptomatic CMV disease in the group receiving immune globulin as compared to the untreated group. The common odds ratio was 0.58 (95% C.I. 0.42 to 0.77). Analyses of combining trials by subgroups of polyvalent immune globulin, hyperimmune globulin, bone marrow recipients and solid organ recipients resulted in common odds ratios comparable to the overall common odds ratio. Common odds ratios for the trials reporting cytomegalovirus interstitial pneumonia, cytomegalovirus death, overall death and graft loss ranged from 0.47 to 0.69. Common odds ratios for the effect of immune globulin prophylaxis analyzed by pre-transplant patient/donor cytomegalovirus antibody status ranged from 0.32 to 0.50. In conclusion, the use of immune globulin as passive immunization for the prevention of symptomatic cytomegalovirus disease in the transplant population is supported by this meta-analysis. The response is similar in both bone marrow and solid organ transplant recipients.(ABSTRACT TRUNCATED AT 250 WORDS)

Cytomegalovirus Infections↗

PubMed1989

Meta-analysis: whither narrative review?

Meta-analysis refers to methodologies that are used to integrate related empirical research to arrive at conclusions not possible by reviewing individual studies, or to improve generalizations of individual studies. It is distinguished from the traditional narrative review in that statistical methodologies are applied to derive more objective conclusions than those that typify narrative reviews. Meta-analysis has been slow to appear in the literature of clinical medicine, however, particularly when viewed in the context of the exponential expansion of literature and the availability of computer technology to facilitate its conduct.

Clinical Medicine↗

PubMed1995

The effects of endurance training on functional capacity in the elderly: a meta-analysis.

In this investigation, meta-analysis was used to delineate exercise induced changes in the VO2max of older individuals and test a null hypothesis of no significant training effects. Parameters included in the analysis were age of the subjects, length of the training regimen, frequency and duration of exercise bouts, pretraining VO2max, posttraining VO2max, and the difference between pretraining and posttraining VO2max (delta VO2max). Effect size for training-induced improvements in VO2max was calculated, corrected for bias, weighted, and analyzed according to contemporary meta-analysis procedures. The mean effect size was found to be 0.65 standard deviation units, representing an improvement in oxygen consumption of 22.8%. The mean effect size was also significantly different from 0 (P < 0.0001), and the null hypothesis was rejected. Stepwise regression analysis indicated that length of training, pretraining VO2max, and duration of training bouts accounted for 59% of the total variation in delta VO2max. In addition, age was found to be inversely correlated with pretraining VO2max (r = -0.56, P = 0.002), and delta VO2max (r = -0.56, P = 0.003). It was concluded that endurance training significantly increases functional capacity in the elderly, and that the increase is related to subject age, duration of exercise bouts, length of the training regimen, and pretraining VO2max.

Aged↗

PubMed1995

Guidelines for application of meta-analysis in environmental epidemiology. ISLI Risk Science Institute.

The use of meta-analysis in environmental epidemiology can enhance the value of epidemiologic data in debates about environmental health risks. Meta-analysis may be particularly useful to formally examine sources of heterogeneity, to clarify the relationship between environmental exposures and health effects, and to generate information beyond that provided by individual studies or a narrative review. However, meta-analysis may not be useful when the relationship between exposure and disease is obvious, when there are only a few studies of the key health outcomes, or when there is substantial confounding or other biases which cannot be adjusted for in the analysis. Recent increases in the use of meta-analysis in environmental epidemiology have highlighted the need for guidelines for the application of the technique. Guidelines, in the form of desirable and undesirable attributes, are presented in this paper for various components of a meta-analysis including study identification and selection; data extraction and analysis; and interpretation, presentation, and communication of results. Also discussed are the appropriateness of the use of meta-analysis in environmental health studies and when meta-analysis should or should not be used.

Environmental Exposure↗

PubMed2001

Risk of pancreatic cancer in workers exposed to chlorinated hydrocarbon solvents and related compounds: a meta-analysis.

This is a meta-analysis of occupational exposures to chlorinated hydrocarbon (CHC) solvents and pancreatic cancer, based primarily on studies that addressed exposure directly (agent studies) and secondarily on studies that reported data without verification of individual CHC exposures (job title studies), all of which were listed in databases for the period January 1969 to May 1998. Standardized extraction of data and double-checking of consistency of data extraction by five extractors were done. Simple random models estimated meta-relative risks. Suggestive weak excesses were found for trichloroethylene (meta-relative risk (MRR) = 1.24, 95% confidence interval (CI): 0.79, 1.97), polychlorinated biphenyls (MRR = 1.37, 95% CI: 0.56, 3.31), methylene chloride (MRR = 1.42, 95% CI: 0.80, 2.53), and vinyl chloride (MRR = 1.17, 95% CI: 0.71, 1.91) but not for carbon tetrachloride. One study addressed tetrachloroethylene (MRR = 3.08, 95% CI: 0.63, 8.99); another investigated chlorohydrin production (MRR = 4.92, 95% CI: 1.58, 11.4). Exposure-response meta-analyses for trichloroethylene and methylene chloride failed to reveal trends. Job title studies on metal degreasing and dry cleaning revealed significant MRRs (2.0 and 1.4, respectively). Publication bias was unlikely. Confounding may have remained insufficiently controlled. Unless the results are seriously biased by exposure or endpoint misclassification or by confounding, strong causal associations between CHC compounds and pancreatic cancer can be judged unlikely. Interactions between environmental and occupational agents, lifestyle factors, and genetic susceptibility remain a possibility, but the data for this meta-analysis did not address interactions.

Canada↗

PubMed1992

[Ginkgo biloba extract in peripheral arterial diseases. Meta-analysis of controlled clinical studies].

In the first part the statistical methods of meta-analysis are discussed. Meta-analysis is considered as a statistical tool for quantitatively summarizing the results of clinical trials with comparable aims (treatments) and designs. Meta-analysis can be based on the significance probabilities or effect values. The last procedure is preferable as it gives an estimate (and confidence interval) for the global effect of the treatment of interest, if homogeneity of the effects between the trials can be assumed. Such a homogeneity can be often achieved by a suitable standardization of the effect variables within the trials. In the second part the methods of meta-analysis are applied to controlled clinical trials with Ginkgo biloba extract EGb 761 in patients with peripheral arterial disease. Included were 5 placebo-controlled clinical trials with similar design and inclusion criteria. In all studies treatment effect was quantified by the increase of walking distance (measured in standardized treadmill exercise). The effect value of EGb 761 treatment was expressed by the standardized mean difference in walking distance increase between EGb 761 and placebo, standardized by the standard deviation. It could be shown that this effect value is homogeneous in all trials. The global effect size was estimated as 0.75. This means that the mean increase in walking distance achieved by EGb 761 is 0.75 times of the standard deviation higher than that achieved by placebo. This value is highly significant different from zero. So the meta-analysis revealed a highly significant therapeutic effect of EGb 761 for the treatment of peripheral arterial disease.

Arteries↗

PubMed1998

Neonatal outcome and mode of delivery after epidural analgesia for labour with ropivacaine and bupivacaine: a prospective meta-analysis.

In this prospective meta-analysis, we have evaluated the effect of epidural analgesia with ropivacaine for pain in labour on neonatal outcome and mode of delivery compared with bupivacaine. In six randomized, double-blind studies, 403 labouring women, primigravidae and multiparae, received epidural analgesia with ropivacaine or bupivacaine 2.5 mg ml-1. The drugs were administered as intermittent boluses in four studies and by continuous infusion in two. Apgar scores, neurological and adaptive capacity scores (NACS), degree of motor block and mode of delivery were recorded. The studies were designed prospectively to fit meta-analysis of the pooled results. Results showed similar pain relief and consumption of the two drugs. In the vaginally delivered neonates, NACS scores were approximately equal for both groups at 2 h, but at 24 h there were fewer infants with NACS less than 35 in the ropivacaine compared with the bupivacaine group (2.8% vs 7.6%; P < 0.05). Spontaneous vaginal deliveries occurred more frequently overall with ropivacaine than with bupivacaine (58% vs 49%; P < 0.05) and instrumental deliveries (forceps and vacuum extraction) less frequently (27% vs 40%; P < 0.01), while the frequency of Caesarean section was similar between groups. The intensity of motor block was lower with ropivacaine. There were no significant differences in adverse events.

Adolescent↗

PubMed2002

Meta-analysis: the glass eye of evidence-based practice?

Meta-analysis was developed as a technique for combining the results of many different quantitative studies: it is often used to produce quantitative estimates of causal relations and/or association between variables. Meta-analysis is sometimes regarded as a central component of evidence-based practice. We draw attention to an incompatibility in the epistemology and methods of reasoning in quantitative meta-analysis and the epistemology and reasoning implicit in expert practice. We argue that this may be because the common perception of meta-analysis appeals to truth as correspondence; we suggest that rejecting the naive realism that underpins truth as correspondence allows meta-analysis to be understood in terms of truth as coherence. We can then develop an account of meta-analysis that does not depend upon reduction to a mathematical procedure but is an attempt to maximise coherence in beliefs about what works that is consistent with clinical reasoning in expert practice.

Decision Making↗

PubMed2003

Bulky DNA adducts and risk of cancer: a meta-analysis.

We present a meta-analysis to test the hypothesis that the presence of a high level of bulky DNA adducts in tissues is associated with an increased risk of cancer in humans. Seven articles were selected that matched the selection criteria, for a total of 691 cancer patients and 632 control subjects. In five studies the cases had lung cancer, in one oral cancer, and in one bladder cancer. Six studies measured adducts in WBCs and one in normal lung tissue around tumor tissue. Six were case-control investigations, and one was a case-control study on lung cancer nested within a cohort. Current smokers showed a statistically significant difference between cases and controls, with cases having 83% higher levels of adducts than controls (95% confidence interval, 0.44-1.22). Results were negative or contradictory in ex-smokers and nonsmokers. This observation was confirmed by sensitivity analyses. Publication bias does not seem to be a problem. Despite some methodological limitations, our meta-analysis shows that current smokers with high levels of adducts have an increased risk of lung and bladder cancers. This conclusion also suggests that similar (aromatic) compounds may be involved in the etiology of both types of cancer.

Biomarkers, Tumor↗

PubMed2004

Microvessel density as a prognostic factor in women with breast cancer: a systematic review of the literature and meta-analysis.

We performed a meta-analysis of all 87 published studies linking intratumoral microvessel density (MVD), reflecting angiogenesis, to relapse-free survival (RFS) and overall survival (OS). With median MVD as cutoff, MVD impact was measured by risk ratio (RR) between the two survival distributions. Seventeen studies did not mention survival data or fit inclusion criteria. Twenty-two were multiple publications of the same series, leaving 43 independent studies (8936 patients). MVD was assessed by immunohistochemistry, using antibodies against factor VIII (27 studies; n = 5262), CD31 (10 studies; n = 2296), or CD34 (8 studies; n = 1726). MVD might be a better prognostic factor when assessed by CD31 or CD34 versus factor VIII (P = 0.11). For RFS, statistical calculations were performed in 25 studies (6501 patients). High MVD significantly predicted poor survival [RR = 1.54 for RFS and OS with the same 95% confidence interval (CI), 1.29-1.84]. Twenty-two studies analyzed separately lymph node-negative patients (n = 3580), for whom predictors of poor survival are requested. This latter meta-analysis included 15 studies for RFS (2727 patients) and 11 for OS (1926 patients). High MVD significantly predicted poor survival [RR = 1.99 for RFS (95% CI, 1.33-2.98) and RR = 1.54 for OS (95% CI, 1.01-2.33)]. Between-study variations could result from patient selection criteria, techniques to stain and count microvessels, and cutoff selection. MVD was a significant although weak prognostic factor in women with breast cancer. Standardization of MVD assessment is needed.

ADP-ribosyl Cyclase↗

PubMed1995

Qualitative assessment of studies included in a meta-analysis: DES and the risk of pregnancy loss.

Meta-analysis, the qualitative and quantitative integration of available research information, is increasingly used in clinical research. This report examines the qualitative elements of meta-analysis through critical review of two published examples that assessed the effect of diethylstilboestrol (DES) on miscarriage and neonatal mortality, respectively. Our subjective review showed the internal validity of three of five trials aggregated in the former meta-analysis to be severely compromised. The remaining two trials (data from which were aggregated in the latter meta-analysis), while internally valid, studied different clinical populations. Therefore, pooling of their results may have been clinically inappropriate. In conclusion, meta-analysis involves substantial elements of subjective judgment. Qualitative assessment of studies is of pivotal importance, because the validity of any summary estimate of effect hinges on both the methodologic quality and the combinability of the aggregated studies.

Abortion, Spontaneous↗

PubMed1997

The design and analysis of paired cluster randomized trials: an application of meta-analysis techniques.

The statistical issues in clinical trials where clusters, communities or groups rather than individuals are randomized are often not fully appreciated. In this paper we discuss the design and analysis of trials in which pairs of clusters are randomized in the context of one recent trial, the British Family Heart Study. Both sample size calculations and the analysis strategy need to take account of the between-cluster component of variance. The analysis can be considered as a random effects meta-analysis across cluster pairs, and can usefully be presented as such. Techniques developed in the context of meta-analysis can then be used in the analysis, for example using a profile likelihood method to derive a confidence interval for the overall treatment effect which takes into account the variability in the estimate of the between-cluster variance. The methods presented here are contrasted with previously published methods for cluster randomized trials.

Adult↗

PubMed1997

Strengths and limitations of meta-analysis: larger studies may be more reliable.

Meta-analysis of randomized controlled trials combines information from independent studies that address a similar question to provide more reliable estimates of treatment effects. At the present time, the methodology and usefulness of meta-analysis is under scrutiny. In the first part of this paper, we summarize the limitations of meta-analysis and make suggestions for improvements. In the second part, we illustrate strengths and limitations using examples of meta-analyses and subsequent large trials that address the same question. We develop the hypothesis that the size of the meta-analysis may be a useful measure of reliability. Small meta-analyses (i.e., those with less than 200 outcome events) may only be useful for summarizing the available information and generating hypotheses for future research. The results of small meta-analyses should be regarded with caution, even if the p value shows extreme statistical significance. Larger meta-analyses (i.e., those with several hundred events) are likely to be more reliable and may be clinically useful. Well-conducted meta-analyses of large trials using individual patient data may provide the best estimates of treatment effects in the cohort overall and in clinically important subgroups.

Bias↗

PubMed1997

Systematic reviews of medical evidence: the use of meta-analysis in obstetrics and gynecology.

OBJECTIVE: To review the technique of meta-analysis and its uses and limitations in obstetrics and gynecology. DATA SOURCES: We reviewed four major journals in obstetrics and gynecology (American Journal of Obstetrics and Gynecology, Fertility and Sterility, Journal of Reproductive Medicine, and Obstetrics & Gynecology). METHODS OF STUDY SELECTION: Journals were reviewed to determine frequency of meta-analysis as a method of systematic review in obstetrics and gynecology. We also summarized objectives and scientific guidelines for performing a meta-analysis. TABULATION, INTEGRATION, AND RESULTS: Meta-analysis is used with increased frequency in obstetrics and gynecology as a way of systematically reviewing medical evidence. This technique is an attempt to improve on traditional methods of narrative review by an expert and as a framework for evidence-based medicine and developing practice guidelines. By combining data from replicate studies, a meta-analysis can increase statistical power, more precisely estimate the typical effect size of treatment or risk factor, and attempt to resolve controversies in the medical literature. Meta-analysis is a retrospective look at data already collected and is therefore subject to the biases of all retrospective studies. CONCLUSIONS: The technique of meta-analysis requires all the scientific rigor of a randomized clinical trial with careful attention to study design, including a formal protocol for literature search strategies, quality assessment of candidate studies, specific inclusion and exclusion criteria, issues of sampling and publication bias, statistical tests of homogeneity, and sensitivity analysis.

Evidence-Based Medicine↗