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B Djulbegovic

Publications and source records attributed to B Djulbegovic.

At least 19 recordsLinked to original sources
PubMed2006

Erythropoietin or darbepoetin for patients with cancer.

BACKGROUND: Anaemia associated with cancer and cancer therapy is an important clinical factor in the treatment of malignant diseases. Therapeutic alternatives are recombinant human erythropoietin (Epo), darbepoetin (Darbepo) and red blood cell transfusions. OBJECTIVES: The aim of this systematic review was to assess the effects of Epo or Darbepo to either prevent or treat anaemia in cancer patients. SEARCH STRATEGY: We searched the Central Register of Controlled Trials, MEDLINE and EMBASE and other data bases. Searches were done for the periods 01/1985 to 12/2001 for the first review and 1/2002 to 04/2005 for the update. We also contacted experts in the field and pharmaceutical companies. SELECTION CRITERIA: Randomised controlled trials on managing anaemia in cancer patients that compared the use of Epo/Darbepo (plus transfusion if needed) with observation until red blood cell transfusion was required. DATA COLLECTION AND ANALYSIS: Several reviewers independently assessed trial quality and extracted data. MAIN RESULTS: This update of the systematic review included a total of 57 trials with 9,353 patients. Of these, 27 trials with 3,287 adults were also included in the first Cochrane Review. Thirty trials with 6,066 patients were added during the update process. Use of Epo/Darbepo significantly reduced the relative risk of red blood cell transfusions (RR 0.64; 95% CI 0.60 to 0.68, 42 trials, n = 6,510). On average participants in the Epo/Darbepo group received one unit of blood less than the control group (WMD -1.05; 95% CI -1.32 to -0.78, 14 trials, n = 2,353). For participants with baseline haemoglobin below 12 g/dL haematological response was observed more often in participants receiving Epo/Darbepo (RR 3.43; 95% CI 3.07 to 3.84, 22 trials, n = 4,307). There was suggestive evidence that Epo/Darbepo may improve Quality of Life (QoL). The relative risk for thrombo embolic complications was increased in patients receiving Epo/Darbepo compared to controls (RR 1.67, 95% CI 1.35 to 2.06; 35 trials, n = 6,769). Uncertainties remain whether and how Epo/Darbepo effects tumour response (fixed effect RR 1.12; 95% CI 1.01 to 1.23, 13 trials, n = 2,833; random effects: RR 1.09; 95% CI 0.94 to 1.26) or overall survival (unadjusted and adjusted data: HR 1.08; 95% CI 0.99 to 1.18; 42 trials, n = 8,167). AUTHORS' CONCLUSIONS: There is consistent evidence that administration of Epo/Darbepo reduces the relative risk for blood transfusions and the number of units transfused in cancer patients. For patients with baseline haemoglobin below 12 g/dL (mild anaemia) there is strong evidence that Epo/Darbepo improves haematological response. There is suggestive evidence that Epo/Darbepo may improve QoL. However, there is strong evidence that Epo/Darbepo increases the relative risk for thrombo embolic complications. Whether and how Epo/Darbepo effects tumour response and overall survival remains uncertain.

Anemia↗
PubMed2003

Colony stimulating factors for chemotherapy induced febrile neutropenia.

BACKGROUND: Febrile neutropenia is a frequent event for cancer patients undergoing chemotherapy and it is potentially a life threatening situation. The current treatment is supportive care plus antibiotics. Colony stimulating factors (CSF) are cytokines that stimulate and accelerate the production of one or more cellular lines in bone marrow. Some clinical trials addressed the question of whether the addition of CSF to antibiotics (ATB) could improve the outcomes of patients with febrile neutropenia. The results of these trials are conflicting and no definitive conclusion could be reached. OBJECTIVES: To evaluate the safety and effectiveness of adding colony stimulating factors to ATB when treating febrile neutropenia caused by cancer chemotherapy. SEARCH STRATEGY: The search covered the major electronic databases: CANCERLIT, EMBASE, LILACS, MEDLINE, SCI and The Cochrane Controlled Trials Register. Experts were consulted and references from the relevant articles scanned. SELECTION CRITERIA: We looked for all randomized controlled trials (RCTs) that compare CSF plus antibiotics versus antibiotics alone for the treatment of established febrile neutropenia in adults and children. DATA COLLECTION AND ANALYSIS: Two of the reviewers independently selected, critically appraised and extracted data from the studies. A meta-analysis of the select studies was performed, using Review Manager. MAIN RESULTS: More than 8000 references were screened. Thirteen studies were included. The overall mortality was not influenced by the use of CSF [Odds Ratio (OR) = 0.68; 95% Confidence Interval (CI) = 0.43 to 1.08; p=0.1]. A marginally significant result was obtained for the use of CSF in reducing infection related mortality [OR= 0.51; 95% CI = 0.26 to 1.00; p=0.05], but this result was highly influenced by one study. When this study is excluded from our analysis, this possible benefit disappears [OR= 0.85; 95% CI = 0.33 to 2.20; p= 0.7]. The group of patients treated with CSF had a shorter length of hospitalization [Hazard Ratio (HR) = 0.63; 95% CI = 0.49 to 0.82; p=0.0006] and a shorter time to neutrophil recovery [HR= 0.32; 95% CI = 0.23 to 0.46; p < 0.00001]. REVIEWER'S CONCLUSIONS: The use of CSF in patients with febrile neutropenia due to cancer chemotherapy does not affect overall mortality, but reduces the amount of time spent in hospital and the neutrophil recovery period. It was not clear whether CSF has an effect on infection-related mortality.

Adult↗
PubMed2003

Early versus deferred treatment for early stage multiple myeloma.

BACKGROUND: Early stage multiple myeloma (MM) represents about 20% of MM. Most of the patients are asymptomatic. Thus, it is far less dramatic than advanced disease and may require different treatment strategies. For these patients, it is not clear whether it is better to start chemotherapy right after the diagnosis or to delay the treatment until symptoms become obvious as the disease progresses. OBJECTIVES: To identify and synthesize all available research evidence on whether early treatment intervention results in improved clinical outcomes when compared with observation alone. The main outcomes of interest that were examined included mortality, disease progression, response rate, and toxicity of early treatment. SEARCH STRATEGY: Searches of the following electronic databases were undertaken: MEDLINE, EMBASE, CANCERLIT, LILLIACS and Cochrane Database of RCTs. We have recently compiled a comprehensive database of RCTs in myeloma. This search was updated and supplemented by hand-search of abstracts from main society meetings such as the ASH (American Society of Hematology), ASCO (American Society of Clinical Oncology), and EHA (European Haematology Association). In addition, we compared our list with a list of RCTs maintained by the Oxford Clinical Trial Service Unit. SELECTION CRITERIA: Randomized controlled trials (RCT) with a parallel design that compared early versus deferred treatment of patients with early stage multiple myeloma based on Durie-Salmon (D-S) staging system. We also considered those trials that did not define early stage myeloma according to D-S staging system, but enrolled patients according to clinical uncertainty about the benefits of immediate intervention. DATA COLLECTION AND ANALYSIS: Data synthesis was performed for all studies and according to the defined quality criteria. The first reviewer and the contact reviewer of this proposal independently extracted data. Disagreement was resolved by consensus. Revman software (ver 4.1) was used to combine results from all studies and expressed as an overall odds ratio or Peto's Odds Ratio, with 95% confidence interval. MAIN RESULTS: Three trials were included with a total of 131 patients in each of the early treatment and deferred treatment groups. Early MM is asymptomatic stage I in these trials. All trials used standard Melphalan treatment but not stem cell transplantation. No statistically significant heterogeneity among the studies was detected. Beneficial effects of early treatment were seen in delay of myeloma progression (Peto's OR = 0.16, 95% CI: 0.09-0.29), and reduced vertebral compression (OR = 0.18, 95%CI: 0.02-1.59, NNT = 23, 95% CI: an NNT of 11, via infinity, to an NNH of 50). No significant effects on mortality and response rate were seen (Peto's OR = 1.11, 95% CI: 0.67-1.84, and OR = 0.63, 95% CI: 0.33-1.23, respectively). Early treatment may increase the risk of acute leukemia (Peto's OR = 3.20, 95% CI: 0.55-18.73, NNH = 44, 95% CI: an NNT of 63, via infinity, to an NNH of 15). REVIEWER'S CONCLUSIONS: Early treatment of early stage multiple myeloma inhibits disease progression, and may reduce vertebral compression. However, early treatment may increase the risk of acute leukemia. However, the data on vertebral compression and leukaemic transformation may not be interpretable due to very small numbers. Based on the current evidence, mortality and response rate are not significantly affected by introducing early treatment in the progression of myeloma. However, it is quite possible that the lack of beneficial effects of early intervention in myeloma is a false negative result due to the paucity of the existing evidence. In addition, data on quality of life and toxicity were sparsely reported adding to additional difficulties about management decisions in early stage myeloma.

Disease Progression↗
PubMed2001

Bisphosphonates in multiple myeloma.

BACKGROUND: Multiple myeloma is a disease characterized by the neoplastic proliferation of a clone of plasma cells that can lead to bone destruction. Bisphosphonates are specific inhibitors of osteoclastic activity. Therefore, there is a pharmacological basis for their use in multiple myeloma. However, the exact clinical role of bisphosphonates in multiple myeloma remains unclear. OBJECTIVES: Primary: to determine whether adding bisphosphonates to standard therapy in multiple myeloma decreases skeletal-related morbidity (pathological fractures), skeletal-related mortality and overall mortality. Secondary: to determine the effects of bisphosphonates on pain, quality of life and incidence of hypercalcemia. SEARCH STRATEGY: We searched MEDLINE (1966 - June 2001), LILACS (1982 - June 2001), EMBASE (1974 - December 2000) and the Cochrane Controlled Trials Register (all years, latest Issue 03/2001) to identify all randomized trials in multiple myeloma. All of these references were accessed in order to identify trials related to the use of bisphosphonates in myeloma. All relevant references in each article were also scanned. We also performed a handsearch of relevant meeting proceedings from 1993 to 2000. Additionally, manufacturers of bisphosphonates and researchers in the field were contacted. SELECTION CRITERIA: Randomised trials with a parallel design on the use of bisphosphonate in myeloma compared with placebo or no treatment as a control group. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial eligibility, methodological quality and abstracted data. A third reviewer checked all data after the extraction was completed. Statistical heterogeneity was tested using random and fixed effect models. All pooled data are reported using Peto odds ratios and, when appropriate, as absolute risk reduction and the number needed to treat to prevent or to cause a pathological event. MAIN RESULTS: Eleven trials were included with 1113 patients analysed in bisphosphonates groups, and 1070 analysed in control groups. There was no significant statistical heterogeneity among trials for the endpoints selected for comparison in this review. The pooled analysis of the published evidence demonstrated the beneficial effect of bisphosphonates on prevention of pathological vertebral fractures [OR=0.59 (95% confidence interval (CI) 0.45-0.78); P=0.0001] and on amelioration of pain [OR = 0.59 (95%CI 0.46-0.76); P=0.00005]. However, the analysis of the effect of bisphosphonates on pain was based on clinically heterogeneous data and must be interpreted with caution. Although there was no statistical heterogeneity between groups, the benefit was most apparent with clodronate and pamidronate. In absolute terms, the result may be interpreted to mean that 10 (95%CI 7-20) patients with multiple myeloma should be treated to prevent one vertebral fracture, and 11 (95%CI 7-28) to prevent one patient experiencing pain. We found no significant effect of bisphosphonates on mortality, on the reduction of non-vertebral fractures or on the incidence of hypercalcemia. There were no significant adverse effects associated with the administration of bisphosphonates. Our results are based on the extraction of published data, which were sometimes poorly reported, and thus the results should be understood as the best possible summation of available evidence. REVIEWER'S CONCLUSIONS: Adding bisphosphonates to the treatment of myeloma reduces pathological vertebral fractures and pain but - from the published evidence - not mortality. On current evidence, clodronate or pamidronate may be the preferred agents.

Bone Diseases↗
PubMed2001

Acknowledgment of uncertainty: a fundamental means to ensure scientific and ethical validity in clinical research.

Recognition of the importance of uncertainty in the design of randomized, controlled trials (RCT) has reached the status of a principle. The "uncertainty principle," or less ambiguously, equipoise, holds that a patient should be enrolled in an RCT only if there is substantial uncertainty about which of the trial treatments would benefit the patient most. In fact, the "uncertainty principle" addresses the most important issue of a clinical trial--the choice of an adequate comparative control. Studies in which intervention and control group are believed to be non-equivalent violate the uncertainty principle. Therefore, one would expect that both editors and authors would be particularly careful to include a statement concerning prior beliefs of the investigator(s) about the uncertainty of the treatments that are reported. However, we found no evidence of such a policy in the randomized, controlled trials we examined. We also show that there is a predictable relationship between the uncertainty principle, that is, the moral principle upon which trials are based, and the ultimate outcomes of clinical trials. We postulate that about 50% of innovations are successful, leading to the conclusion that preserving the ethics of clinical research may be the best investment strategy available.

Ethics, Professional↗
PubMed2001

Evaluation and appraisal of randomized controlled trials in myeloma.

PURPOSE: To critically appraise therapeutic innovations tested in randomized controlled trials (RCTs) in multiple myeloma from 1966-1998. DESIGN: We performed a comprehensive search to identify published RCTs in multiple myeloma. Quality dimensions of the design, conduct, analysis and reporting of each trial were assessed. RESULTS: We identified 136 RCTs reported in 114 papers. Overall, therapeutic efforts in multiple myeloma resulted in a 5% absolute gain in five-year survival at a cost of a 0.35% increase in treatment related deaths. Hence on average a patient enrolled in a RCT in myeloma is 14 (5/35) times more likely to be helped than harmed. However, when the RCTs were critically appraised for key quality dimensions of trials' conduct, we found that only 7%) of the trials (10 of 136) were analyzed according to intention-to-treat (ITT), 9% (12 of 136) reported a power analysis (beta error), 32% (35 of 111) adequately concealed treatment allocation, 78% (106 of 136) provided a detailed description of patient withdrawals, and 83%) (19 of 22) of the double blind RCTs had appropriately described methodology. CONCLUSIONS: Therapeutic innovations tested through RCTs have improved the outcomes of patients with multiple myeloma. However, the quality of RCT reporting and methodology in multiple myeloma could be substantially improved. Most therapeutic strategies in multiple myeloma are based on modest quality, low power evidence. Despite these shortcomings our findings suggest patients may often clinically benefit from enrollment in clinical trials when available. Patients on average received modest benefit from innovative therapies tested in RCTs at little additional risk of side effects.

Humans↗
PubMed2000

The uncertainty principle and industry-sponsored research.

BACKGROUND: Reporting of pharmaceutical-industry-sponsored randomised clinical trials often result in biased findings, either due to selective reporting of studies with non-equivalent arms or publication of low-quality papers, wherein unfavourable results are incompletely described. A randomised trial should be conducted only if there is substantial uncertainty about the relative value of one treatment versus another. Studies in which intervention and control are thought to be non-equivalent violates the uncertainty principle. METHODS: We examined the quality of 136 published randomised trials that focused on one disease category (multiple myeloma) and adherence to the uncertainty principle. To evaluate whether the uncertainty principle was upheld, we compared the number of studies favouring experimental treatments over standard ones. We analysed data according to the source of funding. FINDINGS: Trials funded solely or in part by 35 profit-making organisations had a trend toward higher quality scores (mean 2.94 [SD 1.3]; median 3) than randomised trials supported by 95 governmental or other non-profit organisations (2.4 [0.8]; 2; p=0.06). Overall, the uncertainty principle was upheld, with 44% of randomised trials favouring standard treatments and 56% innovative treatments (p=0.17); mean and median preference evaluation scores were 3.7 (1.0) and 4. However, when the analysis was done according to the source of funding, studies funded by non-profit organisations maintained equipoise favouring new therapies over standard ones (47% vs 53%; p=0.608) to a greater extent than randomised trials supported solely or in part by profit-making organisations (74% vs 26%; p=0.004). INTERPRETATION: The reported bias in research sponsored by the pharmaceutical industry may be a consequence of violations of the uncertainty principle. Sponsors of clinical trials should be encouraged to report all results and to choose appropriate comparative controls.

Bias↗
PubMed2000

The bleeding risk and natural history of idiopathic thrombocytopenic purpura in patients with persistent low platelet counts.

BACKGROUND: No firm data are available on the natural history of idiopathic thrombocytopenic purpura (ITP) or on mortality rates or frequency of major bleeding episodes associated with this condition. The disease is thought to have a relatively benign course, despite the frequent occurrence of very low platelet counts. This prevailing conception often guides therapeutic decisions. OBJECTIVE: To estimate the bleeding risk of ITP involving persistent low platelet counts (<30 x 10(9)/L) and its impact on prognosis. DESIGN: Age-adjusted bleeding risk was derived from a pooled analysis of ITP clinical series based on a systematic literature search. The risk estimate was incorporated into a Markov model to determine its impact on prognosis. RESULTS: Seventeen case series complied with inclusion criteria, including 1,817 patients with ITP. There were 49 cases of fatal hemorrhage over an estimated 1,258 to 3,023 patient-years at risk. The rate of fatal hemorrhage before age adjustment was estimated at between 0.0162 and 0.0389 cases per patient-year. Age-adjusted rates were 0.004, 0.012, and 0.130 cases per patient-year for age groups younger than 40, 40 to 60, and older than 60 years, respectively. Predicted 5-year mortality rates ranged from 2.2% for patients younger than 40 years to 47.8% for those older than 60 years. A 30-year-old woman remaining thrombocytopenic due to ITP was predicted to lose 20.4 years (14.9 quality-adjusted life years) of her potential life expectancy. At age 70, predicted loss was 9.4 years (5.0 quality-adjusted life years). CONCLUSIONS: Idiopathic thrombocytopenic purpura with persistent low platelet counts carries a grave prognosis. Therefore, an active therapeutic approach in the clinical management of affected patients should be considered. In view of the significant potential implications of the model results, we call for initiating a well-designed prospective inception cohort study of patients with ITP.

Adult↗
PubMed2000

Linking evidence-based medicine therapeutic summary measures to clinical decision analysis.

OBJECTIVE: Evidence-based medicine (EBM) seeks to improve clinical practice by evaluating the quality of clinical evidence and ensuring that only the "best" evidence from clinical research is used in the management of individual patients. EBM has contributed to our understanding of the meaning of the benefit and harm of treatment as reported in the literature, and it is often promoted as an aid to clinical decision making. However, EBM therapeutic summary measures reflect only a single dimension of clinical decision making. The purpose of this work is to show how EBM therapeutic summary measures can be effectively incorporated into medical decision making. DESIGN: The effective application of the therapeutic summary measures advocated by EBM requires their integration into the framework of clinical decision analysis. Clinical decision analysis involves not only the identification and specification of the probabilities of clinical events but also the assessment of their relative values or utilities. We present here several analytic models for the integration of EBM therapeutic summary measures within the framework of clinical decision analysis. MAIN RESULTS: As expected, our analysis demonstrated that treatment should never be administered if its harm is greater than its efficacy, which is generally expressed as relative risk reduction. Likewise, a diagnostic test should never be ordered if the therapeutic harm is greater than the therapeutic efficacy. Intervention is always favored if the number needed to treat to avoid one adverse outcome (NNT) is smaller than the number needed to treat to harm one individual (NNH). When faced with a choice between two therapeutic options, the action threshold above which an intervention is favored can be expressed in terms of the harm inflicted (H) as H x NNT or NNT/NNH. If a patient's preferences are taken into account as relative value judgments (RV) of adverse events relative to that of therapeutic events, the action threshold is defined as NNT x (RV/NNH). CONCLUSIONS: In the setting of clinical decision making, EBM summary measures derived from population studies can be effectively used to define diagnostic and therapeutic action thresholds that may help in the management of individual patients.

Aged↗