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↗

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

Acquired anaemias and polycythaemia.

Explore the source record for details and available documents.

Humans↗

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↗

PubMed2000

Talking about treatment.

Explore the source record for details and available documents.

Antihypertensive Agents↗

PubMed2000

Reporting and dissemination of industry versus non-profit sponsored economic analyses of six novel drugs used in oncology.

PURPOSE: Our prior study found that pharmaceutical-sponsored and non-profit sponsored analyses differed in their published assessments of the economic value of six new oncology drugs. In this study, we expand on our earlier findings and evaluate the association between funding source and 1) characteristics of the published study report and 2) journal type for dissemination of the previously evaluated economic studies. METHODS: We reviewed the published cost-effectiveness literature for hematopoietic colony stimulating factors, 5-HT3 antagonist antiemetics. and taxanes. Two blinded investigators rated specific aspects of study reporting based on the US Public Health Service Panel on Cost-effectiveness in Health and Medicine criteria. Dissemination strategies were evaluated using impact factor scores from the Science Citation Index. RESULTS: The operational aspects of pharmaceutical-sponsored study reporting were better overall than those associated with non-profit sponsored studies. Specifically, pharmaceutical-sponsored studies were more likely to be reported based on data obtained from randomized clinical trials or detailed cost-models (90% vs. 70%), to include descriptions of the source of cost differences (90% vs. 79%), to state whether the study was carried out from a societal, governmental, or insurer perspective (70% vs. 42%), and to clearly indicate the time-period over which costs were evaluated (65% vs. 50%). Nonprofit sponsored studies were more likely than pharmaceutical sponsored studies to report the generalizability of the findings, including being more likely to include information about how the data could be extrapolated to other clinical settings (58% vs. 35%), to include statements on the statistical significance of the findings (38% vs. 20%), and to clearly outline the cost per unit and data sources for the cost analyses (67% vs. 45%). A similar percent of pharmaceutical and non-profit sponsored studies reported background and conclusions with about 80% providing literature comparisons of the results (about 80%) and two thirds to three fourths discussing the limitations of the finding (75% for pharmaceutical-sponsored and 67% for non-profit sponsored studies). Most studies were published in low impact factor peer-reviewed journals, and journal impact factor scores were similar between pharmaceutical and nonprofit sponsored studies. CONCLUSIONS: Upon reviewing the entire pharmacoeconomic literature for six new oncology drugs, we identified differences in study reporting, but not in types of journals where studies were published, between pharmaceutical-sponsored and non-profit sponsored studies. These results, particularly the observed differences in data generalizability, may account in part for our previous finding of lower likelihood of reporting unfavorable conclusions in pharmaceutical-sponsored studies.

Antineoplastic Agents↗

PubMed2000

Evidentiary challenges to evidence-based medicine.

The evidence-based medicine (EBM) movement has exerted a strong influence on contemporary medicine. It has been used to define the hierarchy of knowledge in clinical medicine by classifying clinical findings according to the perceived relevance and validity of the respective methodologies of studies from which evidence was collected. In the spectrum of theories of knowledge, EBM predominantly relies on findings obtained from population-derived clinical research. This reliance on knowledge obtained from population studies sharply contrasts with a physiologic model of clinical knowledge advocated by basic science researchers and many clinicians. An apparent schism between proponents of physiologic and population models in the approach to the practice of medicine has been created. This dichotomy between practising physicians and EBM physicians in the approach to clinical knowledge should not be irreconcilable. We advocate a consilient approach to the interpretation of evidence and the integration of medical knowledge. This approach relies on 'linking of facts and fact-based theory across various disciplines to create a common groundwork of explanation'.

Decision Making↗

PubMed1999

Using the Internet to calculate clinical action thresholds.

Understanding the risks and benefits of available treatments represents an essential element of clinical practice. Previous work has demonstrated that knowledge of net benefits and net risks can relate to our decisions on whether or not to administer a particular treatment or order a diagnostic test. A wider application of this model has been difficult because data on net benefits and net risks are not directly reported. We used more frequently reported data on treatment efficacy (E) and risks (Rrx) to obtain an equation for the treatment threshold probability above which treatment should be given and below which it should be withheld. The diagnostic test should only be performed if the probability of a disease is between the testing threshold and the treatment threshold. We first described a theoretical background for these calculations. We then used a JavaScript programming language to write a computer program which physicians can use to calculate these threshold probabilities effortlessly through the Internet. In most clinical situations we do not have to achieve maximum diagnostic certainty in order to act. However, we should never treat or order a diagnostic test if the risk of the treatment is greater than its efficacy. The minimally required E/R ratio of a particular treatment is equal to the reciprocal value of the mortality/morbidity of untreated disease. Similarly, the lowest number of patients needed to be treated (NNT) for therapy to be worth administering is equal to the reciprocal of the treatment risk. We show how evidence-based summary measures of therapeutic effects, such as the treatment efficacy, harms, and NNT, can successfully be integrated within a decision analytic model. This in turn will facilitate wider use of the quantitative benefit-risk analysis. Accessing the Internet for direct and immediate approach to the formulas described here should make this task even easier in everyday clinical decision making.

Adult↗

PubMed1999

The quality of medical evidence in hematology-oncology.

PURPOSE: The purpose of this study was to evaluate the quality of the medical evidence available to the clinician in the practice of hematology/oncology. METHODS: We selected 14 neoplastic hematologic disorders and identified 154 clinically important patient management decision/interventions, ranging from initial treatment decisions to those made for the treatment of recurrent or refractory disease. We also performed a search of the scientific literature for the years 1966 through 1996 to identify all randomized controlled trials in hematology/oncology. RESULTS: We identified 783 randomized controlled trials (level 1 evidence) pertaining to 37 (24%) of the decision/interventions. An additional 32 (21%) of the decision/interventions were supported by evidence from single arm prospective studies (level 2 evidence). However, only retrospective or anecdotal evidence (level 3 evidence) was available to support 55% of the identified decision/interventions. In a retrospective review of the decision/interventions made in the management of 255 consecutive patients, 78% of the initial decision/interventions in the management of newly diagnosed hematologic/oncologic disorders could have been based on level 1 evidence. However, more than half (52%) of all the decision/interventions made in the management of these 255 patients were supported only by level 2 or 3 evidence. CONCLUSIONS: We conclude that level 1 evidence to support the development of practice guidelines is available primarily for initial decision/interventions of newly diagnosed diseases. Level 1 evidence to develop guidelines for the management of relapsed or refractory malignant diseases is currently lacking.

Evidence-Based Medicine↗

PubMed1999

Acceptable regret in medical decision making.

When faced with medical decisions involving uncertain outcomes, the principles of decision theory hold that we should select the option with the highest expected utility to maximize health over time. Whether a decision proves right or wrong can be learned only in retrospect, when it may become apparent that another course of action would have been preferable. This realization may bring a sense of loss, or regret. When anticipated regret is compelling, a decision maker may choose to violate expected utility theory to avoid regret. We formulate a concept of acceptable regret in medical decision making that explicitly introduces the patient's attitude toward loss of health due to a mistaken decision into decision making. In most cases, minimizing expected regret results in the same decision as maximizing expected utility. However, when acceptable regret is taken into consideration, the threshold probability below which we can comfortably withhold treatment is a function only of the net benefit of the treatment, and the threshold probability above which we can comfortably administer the treatment depends only on the magnitude of the risks associated with the therapy. By considering acceptable regret, we develop new conceptual relations that can help decide whether treatment should be withheld or administered, especially when the diagnosis is uncertain. This may be particularly beneficial in deciding what constitutes futile medical care.

Brain Ischemia↗