Issues that may determine the outcome of antipsychotic trials: industry sponsorship and extrapyramidal side effect. Impact of a drug bulletin on the knowledge, perception of drug utility, and prescribing behavior of physicians. Association of funding and conclusions in randomized drug trials: a reflection of treatment effect or adverse events? The framing effect of relative and absolute risk. Framing of outcome and probability of recurrence: breast cancer patients' choice of adjuvant chemotherapy (ACT) in hypothetical patient scenarios. The evaluation of analgesic effects in cancer patients as exemplified by a double-blind, crossover study of immediate-release versus controlled-release morphine. Comparison of two methods of presenting risk information to patients about the side effects of medicines. The effect of dexamethasone on side effects after coronary revascularization procedures.
This study presents a meta-analysis of the influence of several potentially biasing factors (eg industry support, extrapyramidal side effects) on efficacy of studies comparing second-generation antipsychotic (SGA) with first-generation antipsychotic (FGA) medications. We used the dataset from our previously published meta-analysis of 124 randomized controlled trials (RCTs) comparing SGAs with FGAs, to evaluate whether certain possible biases could influence the actual outcome on the total score of the Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS), and Clinical Global Impressions (CGI) scores. Industry sponsorship was determined by contact with authors or publication statement. We calculated whether (1) industry sponsorship, (2) study quality, (3) extrapyramidal symptoms (EPS) properties, or (4) prophylactic antiparkinsonian medications influenced SGA vs FGA efficacy for each drug and averaged overall by two Hedges and Olkin-based meta-analyses. The analysis found that none of the factors was significantly associated with a particular outcome. While industry-sponsored articles may conclude their medication to be more favorable than that of a competitor in an RCT, we found that the observed efficacy was not influenced by sponsorship. Many attribute the finding that SGAs appears to be more efficacious than FGAs to be a result of EPS-decreasing efficacy (or its measurement). We were unable to confirm that the drug's EPS properties or antiparkinsonian management altered actual efficacy. The impact of a drug bulletin was tested in a randomized controlled trial that included 186 family physicians. The length of the trial was six months. It was hypothesized that printed information, such as in drug bulletins, influences physician prescribing behavior by changing their knowledge of drug efficacy and adverse effects and their perceptions of drug utility. Therefore, the impact of a drug bulletin was evaluated on these domains of influence. Interview data were used to assess changes in knowledge, perceived drug utility, and stated prescribing. Health insurance funds' records were used to collect actual prescribing data. Information in the bulletin on the treatment of renal colic changed physicians' knowledge as well as perceived utility of drugs used for renal colic (p less than 0.05). Significant changes in stated prescribing were also found. On the other hand, advice in the same bulletin on the treatment of the irritable bowel syndrome (IBS) had no impact at all. It did not even improve the knowledge of the physicians about the drugs used for IBS. Apparently, the message about the treatment of IBS failed to gain the attention of the physicians. It is suggested that some messages are sufficiently transmitted through written information, and others that are seen as less relevant or too difficult to implement need more intensive strategies. Previous studies indicate that industry-sponsored trials tend to draw proindustry conclusions.
                To explore whether the association between funding and conclusions in randomized drug trials reflects treatment effects or adverse events.
                Observational study of 370 randomized drug trials included in meta-analyses from Cochrane reviews selected from the Cochrane Library, May 2001. From a random sample of 167 Cochrane reviews, 25 contained eligible meta-analyses (assessed a binary outcome; pooled at least 5 full-paper trials of which at least 1 reported adequate and 1 reported inadequate allocation concealment). The primary binary outcome from each meta-analysis was considered the primary outcome for all trials included in each meta-analysis. The association between funding and conclusions was analyzed by logistic regression with adjustment for treatment effect, adverse events, and additional confounding factors (methodological quality, control intervention, sample size, publication year, and place of publication).
                Conclusions in trials, classified into whether the experimental drug was recommended as the treatment of choice or not.
                The experimental drug was recommended as treatment of choice in 16% of trials funded by nonprofit organizations, 30% of trials not reporting funding, 35% of trials funded by both nonprofit and for-profit organizations, and 51% of trials funded by for-profit organizations (P<.001; chi2 test). Logistic regression analyses indicated that funding, treatment effect, and double blinding were the only significant predictors of conclusions. Adjusted analyses showed that trials funded by for-profit organizations were significantly more likely to recommend the experimental drug as treatment of choice (odds ratio, 5.3; 95% confidence interval, 2.0-14.4) compared with trials funded by nonprofit organizations. This association did not appear to reflect treatment effect or adverse events.
                Conclusions in trials funded by for-profit organizations may be more positive due to biased interpretation of trial results. Readers should carefully evaluate whether conclusions in randomized trials are supported by data. To test whether a patient's perception of benefit is influenced by whether the benefit is presented in relative or absolute terms.
                Questionnaire-based study.
                A general medicine outpatient clinic at a rural tertiary care center associated with a medical school.
                470 of 511 consecutive patients who agreed to answer a questionnaire while waiting for their clinic visit. Mean age was 49.1 years, 62.1% were female, and 51.9% had at least one year of education beyond high school.
                Patient response to the choice of two equally efficacious medications for the management of a hypothetical serious disease. The benefit of one medication was stated in relative terms, the other in absolute terms. Patients could choose either medication alone, indicate indifference to the choice of medication, or choose not to answer.
                56.8% of the patients chose the medication whose benefit was in relative terms. 14.7% chose the medication whose benefit was in absolute terms. Only 15.5% were indifferent to the choice of medication. The patients preferred the medication whose benefit was in relative terms across a wide range of ages and educational levels. Further questioning suggested that the patients thought benefit was greater when expressed in relative terms because they ignored the underlying risk of disease and assumed it was one.
                The "framing" of benefit (or risk) in relative versus absolute terms may have a major influence on patient preference. To examine the effects of framing of outcome and probabilities of cancer occurrence on the treatment preference which breast cancer patients indicate for hypothetical patient scenarios.
                A modified version of the Decision Board Instrument (Levine et al. 1992) was administered to 35 breast cancer patients with past ACT experience. Patients expressed their choice regarding ACT for six scenarios which were characterized by either negative or positive framing of outcome and by one of the three levels of probability of recurrence (high, medium, low).
                The framing had no influence on ACT choices over all three probability levels. The majority chose ACT for high and medium risk and one third switched from ACT to No ACT in the low-risk condition. This switch was statistically significant.
                Hypothetical treatment decisions against ACT occur only when the probability of recurrence is low and the benefit of ACT is small. This finding for patients with past experience of ACT is similar to those reported for other oncological patient groups still in treatment. We compared the effects of controlled-release and immediate-release morphine preparations in adult patients with moderate-to-severe cancer pain and report methodologic approaches to pain evaluation. The study consisted of a two-phase randomized crossover trial preceded by a titration phase; all phases were conducted under double-blind conditions. To evaluate pain intensity, a visual analogue scale (VAS) and the Present Pain Intensity scale of the McGill Pain Questionnaire were used. Additional morphine solution for breakthrough pain was used as an outcome measure. Pain was evaluated nine times daily, which permitted correlation of pain scores with the pharmacokinetic patterns of the test drugs. Side effects were rated once daily, using a scale from 0 to 3. To assess the relative importance of side effects, a toxicity index was designed based on both the intensity and duration of each side effect. The overall VAS pain scores during treatment with controlled-release and immediate-release morphine were 1.3 (SD = 0.1) and 1.4 (SD = 0.2), respectively. Use of supplemental morphine solution for breakthrough pain expressed as the percentage of the daily dose of the test drug was 5.5% for the controlled-release drug and 10.9% for the immediate-release drug. Differences in pain scores, side effects, and supplemental morphine requirement between the two groups were not significant. We discuss methodologic issues in double-blind clinical trials of analgesics, in particular the validity of "Patient Preference" as an outcome measure and problems related to the titration phase. To determine whether the use of verbal descriptors suggested by the European Union (EU) such as "common" (1-10% frequency) and "rare" (0.01-0.1%) effectively conveys the level of risk of side effects to people taking a medicine.
                Randomised controlled study with unconcealed allocation.
                120 adults taking simvastatin or atorvastatin after cardiac surgery or myocardial infarction.
                Cardiac rehabilitation clinics at two hospitals in Leeds, UK.
                A written statement about one of the side effects of the medicine (either constipation or pancreatitis). Within each side effect condition half the patients were given the information in verbal form and half in numerical form (for constipation, "common" or 2.5%; for pancreatitis, "rare" or 0.04%).
                The estimated likelihood of the side effect occurring. Other outcome measures related to the perceived severity of the side effect, its risk to health, and its effect on decisions about whether to take the medicine.
                The mean likelihood estimate given for the constipation side effect was 34.2% in the verbal group and 8.1% in the numerical group; for pancreatitis it was 18% in the verbal group and 2.1% in the numerical group. The verbal descriptors were associated with more negative perceptions of the medicine than their equivalent numerical descriptors.
                Patients want and need understandable information about medicines and their risks and benefits. This is essential if they are to become partners in medicine taking. The use of verbal descriptors to improve the level of information about side effect risk leads to overestimation of the level of harm and may lead patients to make inappropriate decisions about whether or not they take the medicine. Corticosteroids decrease side effects after noncardiac elective surgery. We designed this randomized, double-blinded, placebo-controlled study to test the hypothesis that standard doses of dexamethasone (4 mg x2) would reduce postoperative nausea, vomiting, and pain, decrease the incidence of atrial fibrillation (AF), and improve appetite after cardiac surgery, thereby facilitating the recovery process. A total of 300 patients undergoing coronary revascularization surgery were enrolled in this clinical study. The anesthetic management was standardized in all patients. Dexamethasone (4 mg/mL) or saline (1 mL) was administered after the induction of anesthesia and a second dose of the same study drug was given on the morning after surgery. The incidence of AF was determined by analyzing the first 72 h of continuously recorded electrocardiogram records after cardiac surgery. The patients were assessed at 24- and 48-h intervals after surgery, as well as at the time of hospital discharge, to determine the incidence and severity of postoperative side effects (e.g., nausea, vomiting, pain) and patient satisfaction scores. Dexamethasone significantly reduced the need for antiemetic rescue medication on the first postoperative day (30% versus 42%), and the incidences of nausea (15% versus 26%) and vomiting (5% versus 16%) on the second postoperative day (P < 0.05). In addition, dexamethasone significantly reduced the percentage of patients with a depressed appetite on the second postoperative day. However, the corticosteroid failed to decrease the incidence of AF (27% versus 32%) or the total dosage of opioid analgesic medication administered in the postoperative period. We conclude that dexamethasone (8 mg in divided doses) was beneficial in reducing emetic symptoms and improving appetite after cardiac surgery. However, this dose of the corticosteroid does not seem to have antiarrhythmic or analgesic-sparing properties.
                Dexamethasone (8 mg IV) was beneficial in reducing emetic symptoms and increasing appetite after cardiac surgery. However, this dose of the corticosteroid failed to decrease postoperative pain or the incidence of new-onset atrial fibrillation.
The conclusion is that the choice of drug must be made based on consideration of drug-specific side effect properties.