Showing papers by "Peter C Gøtzsche published in 2014"

Amphotericin B lipid soluble formulations versus amphotericin B in cancer patients with neutropenia

Abstract: Background Patients with cancer who are treated with chemotherapy or receive a bone marrow transplant have an increased risk of acquiring fungal infections. Such infections can be life-threatening. Antifungal drugs are therefore often given prophylactically to such patients, or when they have a fever. Objectives To compare the benefits and harms of lipid soluble formulations of amphotericin B with conventional amphotericin B in cancer patients with neutropenia. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) Issue 4, 2007, PubMed (November 2007) and the reference lists of articles. We searched the proceedings of the ICAAC (from 1990 to 2007), General Meeting of the ASM (from 1990 to 2007), and the European Congress of Clinical Microbiology and Infectious Diseases (1995 to 2007) and contacted researchers in the field. For the 2011 update we searched PubMed from 1966 to 18 July 2011 and the reference lists of articles. Selection criteria Randomised clinical trials comparing lipid soluble formulations of amphotericin B with conventional amphotericin B. Data collection and analysis The two review authors independently assessed trial eligibility, risk of bias and abstracted data. Main results We found 12 trials (1895 patients). Lipid-based amphotericin B was not more effective than conventional amphotericin B for mortality (relative risk (RR) 0.83, 95% confidence interval (CI) 0.62 to 1.12), but decreased invasive fungal infection (RR 0.65, 95% CI 0.44 to 0.97), nephrotoxicity, defined as a 100% increase in serum creatinine (RR 0.45, 95%CI 0.37 to 0.54), and number of dropouts (RR 0.78, 95%CI 0.62 to 0.97). For the drug used in most patients, AmBisome (3 trials, 1149 patients), there was no significant difference in mortality (RR 0.74, 95% CI 0.52 to 1.07) whereas it tended to be more effective than conventional amphotericin B for invasive fungal infection (RR 0.63, 95% CI 0.39 to 1.01, P = 0.053). AmBisome, amphotericin B in Intralipid (6 trials, 379 patients), amphotericin B colloidal dispersion (ABCD) (2 trials, 262 patients), and amphotericin B lipid complex (ABLC) (1 trial, 105 patients) all decreased the occurrence of nephrotoxicity, but conventional amphotericin B was rarely administered under optimal circumstances. For the 2011 update no additional trials were identified for inclusion. Authors' conclusions It is not clear whether there are any advantages of lipid-based formulations if conventional amphotericin B is administered under optimal circumstances and their high cost prohibits routine use in most settings. There is a need for large trials comparing lipid-based formulations of amphotericin B with conventional amphotericin B given in the same dose, with routine premedication for prevention of infusion-related toxicity, and with supplementation with fluid, potassium and magnesium for prevention of nephrotoxicity.

Benefits and harms in clinical trials of duloxetine for treatment of major depressive disorder: comparison of clinical study reports, trial registries, and publications

Abstract: Objective To determine, using research on duloxetine for major depressive disorder as an example, if there are inconsistencies between protocols, clinical study reports, and main publicly available sources (journal articles and trial registries), and within clinical study reports themselves, with respect to benefits and major harms Design Data on primary efficacy analysis and major harms extracted from each data source and compared Setting Nine randomised placebo controlled trials of duloxetine (total 2878 patients) submitted to the European Medicines Agency (EMA) for marketing approval for major depressive disorder Data sources Clinical study reports, including protocols as appendices (total 13 729 pages), were obtained from the EMA in May 2011 Journal articles were identified through relevant literature databases and contacting the manufacturer, Eli Lilly Clinicaltrialsgov and the manufacturer’s online clinical trial registry were searched for trial results Results Clinical study reports fully described the primary efficacy analysis and major harms (deaths (including suicides), suicide attempts, serious adverse events, and discontinuations because of adverse events) There were minor inconsistencies in the population in the primary efficacy analysis between the protocol and clinical study report and within the clinical study report for one trial Furthermore, we found contradictory information within the reports for seven serious adverse events and eight adverse events that led to discontinuation but with no apparent bias In each trial, a median of 406 (range 177-645) and 166 (100-241) treatment emergent adverse events (adverse events that emerged or worsened after study drug was started) in the randomised phase were not reported in journal articles and Lilly trial registry reports, respectively We also found publication bias in relation to beneficial effects Conclusion Clinical study reports contained extensive data on major harms that were unavailable in journal articles and in trial registry reports There were inconsistencies between protocols and clinical study reports and within clinical study reports Clinical study reports should be used as the data source for systematic reviews of drugs, but they should first be checked against protocols and within themselves for accuracy and consistency

Nystatin prophylaxis and treatment in severely immunodepressed patients

Abstract: Background Nystatin is sometimes used prophylactically in patients with severe immunodeficiency or in the treatment of fungal infection in such patients, although its effect seems to be equivocal. Objectives To study whether nystatin decreases morbidity and mortality when given prophylactically or therapeutically to patients with severe immunodeficiency. Search methods We searched PubMed from 1966 to 7 July 2014 and the reference lists of identified articles. Selection criteria Randomised clinical trials comparing nystatin with placebo, an untreated control group, fluconazole or amphotericin B. Data collection and analysis Data on mortality, invasive fungal infection and colonisation were independently extracted by both authors. A random-effects model was used unless the P value was greater than 0.10 for the test of heterogeneity. Main results We included 14 trials (1569 patients). The drugs were given prophylactically in 12 trials and as treatment in two. Eleven trials were in acute leukaemia, solid cancer, or bone marrow recipients; one in liver transplant patients; one in critically ill surgical and trauma patients; and one in AIDS patients. Nystatin was compared with placebo in three trials, with fluconazole in 10, and amphotericin B in one; the dose varied from 0.8 MIE to 72 MIE daily and was 2 mg/kg/d in a liposomal formulation. The effect of nystatin was similar to that of placebo on fungal colonisation (relative risk (RR) 0.85, 95% confidence interval (CI) 0.65 to 1.13). There was no statistically significant difference between fluconazole and nystatin on mortality (RR 0.75, 95% CI 0.54 to 1.03) whereas fluconazole was more effective in preventing invasive fungal infection (RR 0.40, 95% CI 0.17 to 0.93) and colonisation (RR 0.50, 95% CI 0.36 to 0.68). There were no proven fungal infections in a small trial that compared amphotericin B with liposomal nystatin. The results were very similar if the three studies that were not performed in cancer patients were excluded. For the 2011 and 2014 updates no additional trials were identified for inclusion. Authors' conclusions Nystatin cannot be recommended for prophylaxis or the treatment of Candida infections in immunodepressed patients.

Routine versus selective antifungal administration for control of fungal infections in patients with cancer.

Abstract: BACKGROUND Systemic fungal infection is considered to be an important cause of morbidity and mortality in cancer patients, particularly those with neutropenia. Antifungal drugs are often given prophylactically, or to patients with persistent fever. OBJECTIVES The objective of this review was to assess the effect of antifungal drugs in cancer patients with neutropenia. SEARCH STRATEGY We searched the Cochrane Controlled Trials Register and MEDLINE (November 1999) and the reference lists of articles. We searched the proceedings of the ICAAC, General Meeting of the ASM (from 1990 to 1999), and the 7th European Congress of Clinical Microbiology and Infectious Diseases (1995 to 1999) and contacted researchers in the field. SELECTION CRITERIA Randomised trials of amphotericin B, AmBisome, fluconazole, ketoconazole, miconazole, or itraconazole compared with placebo or no treatment in cancer patients with neutropenia. DATA COLLECTION AND ANALYSIS Two reviewers independently assessed trial eligibility, methodological quality and abstracted data. MAIN RESULTS Twenty-nine trials involving 3875 patients were included. Intravenous amphotericin B reduced total mortality (relative risk 0.72, 95% confidence interval 0.51 to 1.02, P=0.06) based on 8 trials. This borderline result was confirmed by three trials which compared lipid soluble amphotericin B (AmBisome) with smaller doses of standard amphotericin B; the trials demonstrated an effect of AmBisome on mortality, relative risk 0.70 (95% CI 0.50 to 0.99). The risk difference for the two estimates combined is 0.040 (95% CI 0.012 to 0.068) which means that 25 patients (95% CI 15 to 83) would need to be treated with intravenous amphotericin B to avoid one death. In contrast, fluconazole, ketoconazole, miconazole and itraconazole had no effect on mortality. The incidence of invasive fungal infection decreased with administration of amphotericin B (relative risk 0.39, 95% CI 0.20 to 0.76), fluconazole (relative risk 0.39, 95% CI 0.27 to 0.57) and itraconazole (relative risk 0.45, 95% CI 0.20 to 0.99), but not with miconazole or ketoconazole. REVIEWER'S CONCLUSIONS Intravenous amphotericin B is the only antifungal agent which has a documented effect on mortality, and there is not sufficient evidence to judge the relative merits of other antifungal agents. This drug should therefore be preferred for prophylactic or empirical antifungal therapy in cancer patients with neutropenia.

Amphotericin B versus fluconazole for controlling fungal infections in neutropenic cancer patients

Abstract: Background Systemic fungal infection is considered to be an important cause of morbidity and mortality in cancer patients, particularly those with neutropenia. Antifungal drugs are often given prophylactically, or empirically to patients with persistent fever. Objectives To compare the effect of fluconazole and amphotericin B on morbidity and mortality in patients with cancer complicated by neutropenia. Search methods We searched PubMed from 1966 to 7 July 2014 and the reference lists of identified articles. Selection criteria Randomised clinical trials comparing fluconazole with amphotericin B. Data collection and analysis The two review authors independently assessed trial eligibility and risk of bias, and abstracted data. Main results Seventeen trials (3798 patients, 381 deaths) were included. In two large three-armed trials, results for amphotericin B were combined with results for nystatin in a 'polyene' group. Because nystatin is an ineffective drug in these circumstances, this approach creates a bias in favour of fluconazole. Furthermore, most patients were randomised to oral amphotericin B, which is poorly absorbed and poorly documented. There was overlap among the 'polyene' trials but we were unable to obtain any information from the trial authors or from Pfizer, the manufacturer of fluconazole, to clarify these issues. There were no significant differences in effect between fluconazole and amphotericin B, but the confidence intervals were wide. More patients dropped out of the study when they received amphotericin B, but as none of the trials were blinded decisions on premature interruption of therapy could have been biased. Furthermore, amphotericin B was not given under optimal circumstances, with premedication to reduce infusion-related toxicity, slow infusion, and with fluid, potassium and magnesium supplements to prevent nephrotoxicity. The major harms were hepatic impairment and gastrointestinal adverse effects with fluconazole and infusion-related toxicity, renal impairment and gastrointestinal adverse effects with amphotericin B. For the 2011 and 2014 updates no additional trials were identified for inclusion. Authors' conclusions Amphotericin B has been disfavoured in several of the trials through their design or analysis, or both. Since intravenous amphotericin B is the only antifungal agent for which an effect on mortality has been shown, and since it is considerably cheaper than fluconazole, it should be the preferred agent.

Voriconazole versus amphotericin B or fluconazole in cancer patients with neutropenia

Abstract: BACKGROUND Opportunistic fungal infections are a major cause of morbidity and mortality in neutropenic cancer patients and antifungal therapy is used both empirically and therapeutically in these patients. OBJECTIVES To compare the benefits and harms of voriconazole with those of amphotericin B and fluconazole when used for prevention or treatment of invasive fungal infections in cancer patients with neutropenia. SEARCH METHODS Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2014, Issue 1 2014), MEDLINE (to January 2014). Letters, abstracts and unpublished trials were accepted. Contact was made with trial authors and industry. SELECTION CRITERIA Randomised clinical trials comparing voriconazole with amphotericin B or fluconazole. DATA COLLECTION AND ANALYSIS Data on mortality, invasive fungal infection, colonisation, use of additional (escape) antifungal therapy and adverse effects leading to discontinuation of therapy were extracted independently by two review authors. MAIN RESULTS Three trials were included. One trial compared voriconazole to liposomal amphotericin B as empirical treatment of fever of unknown origin (suspected fungal infection) in neutropenic cancer patients (849 patients, 58 deaths). The second trial compared voriconazole to amphotericin B deoxycholate in the treatment of confirmed and presumed invasive Aspergillus infections (391 patients, 98 deaths). The third trial compared fluconazole to voriconazole for prophylaxis of fungal infections in patients receiving allogeneic stem cell transplantation (600 patients, number of deaths not stated). In the first trial, voriconazole was significantly inferior to liposomal amphotericin B according to the trial authors' prespecified criteria. More patients died in the voriconazole group and a claimed significant reduction in the number of breakthrough fungal infections disappeared when patients arbitrarily excluded from the analysis by the trial authors were included. In the second trial, the deoxycholate preparation of amphotericin B was used without any indication of the use of premedication to counter side effects and replacement of electrolytes or use of salt water. This choice of comparator resulted in a marked difference in the duration of treatment on the trial drugs (77 days with voriconazole versus 10 days with amphotericin B) and precluded meaningful comparisons of the benefits and harms of the two drugs. The third trial failed to find a difference in fungal free survival or invasive fungal infections at 180 days when voriconazole was compared to fluconazole. AUTHORS' CONCLUSIONS Liposomal amphotericin B is significantly more effective than voriconazole for empirical therapy of fungal infections in neutropenic cancer patients and should be preferred. For treatment of aspergillosis, there are no trials that have compared voriconazole with amphotericin B given under optimal conditions. For prophylactic fungal treatment in patients receiving allogeneic stem cell transplantation, there was no difference between voriconazole and fluconazole regarding fungal free survival or invasive fungal infections.

General health checks don’t work

Abstract: It’s time to let them go We check our cars regularly, so why shouldn’t we also check our bodies so that we can find and treat abnormalities before they cause too much harm? It seems so easy, but the human body is not a car, and, in contrast to a car, it has self healing properties. Actually, the first thing we know about screening is that it will cause harm in some people. This is why we need randomised trials to find out whether screening does more good than harm before we decide whether to introduce it. Doctors realised this early on and embarked on 16 randomised trials of general health checks between 1963 and 1999. A Cochrane review from 2012 that included 11 940 deaths did not find an effect of general health checks on total mortality (risk ratio 0.99, 95% confidence interval 0.95 to 1.03) or on mortality due to cardiovascular disease (1.03, 0.91 to 1.17) or cancer (1.01, 0.92 to 1.12).1 2 These trials were carried out in Europe and in the United States. The most recent one, the Danish Inter99 trial, which started in 1999, reports its results …

Lead-Time Models Should Not Be Used to Estimate Overdiagnosis in Cancer Screening

Abstract: Lead-time can mean two different things: Clinical lead-time is the lead-time for clinically relevant tumors; that is, those that are not overdiagnosed. Model-based lead-time is a theoretical construct where the time when the tumor would have caused symptoms is not limited by the person’s death. It is the average time at which the diagnosis is brought forward for both clinically relevant and overdiagnosed cancers. When screening for breast cancer, clinical lead-time is about 1 year, while model-based lead-time varies from 2 to 7 years. There are two different methods to calculate overdiagnosis in cancer screening—the excess-incidence approach and the lead-time approach—that rely on two different lead-time definitions. Overdiagnosis when screening with mammography has varied from 0 to 75 %. We have explained that these differences are mainly caused by using different definitions and methods and not by variations in data. High levels of overdiagnosis of cancer have usually been explained by detection of many slow-growing tumors with long lead-times. This theory can be tested by studying if slow-growing tumors accumulate in the absence of screening, which they don’t. Thus, it is likely that the natural history of many subclinical cancers is spontaneous regression.

Comparison of Results from Different Imputation Techniques for Missing Data from an Anti-Obesity Drug Trial

Abstract: Background In randomised trials of medical interventions, the most reliable analysis follows the intention-to-treat (ITT) principle. However, the ITT analysis requires that missing outcome data have to be imputed. Different imputation techniques may give different results and some may lead to bias. In anti-obesity drug trials, many data are usually missing, and the most used imputation method is last observation carried forward (LOCF). LOCF is generally considered conservative, but there are more reliable methods such as multiple imputation (MI). Objectives To compare four different methods of handling missing data in a 60-week placebo controlled anti-obesity drug trial on topiramate. Methods We compared an analysis of complete cases with datasets where missing body weight measurements had been replaced using three different imputation methods: LOCF, baseline carried forward (BOCF) and MI. Results 561 participants were randomised. Compared to placebo, there was a significantly greater weight loss with topiramate in all analyses: 9.5 kg (SE 1.17) in the complete case analysis (N = 86), 6.8 kg (SE 0.66) using LOCF (N = 561), 6.4 kg (SE 0.90) using MI (N = 561) and 1.5 kg (SE 0.28) using BOCF (N = 561). Conclusions The different imputation methods gave very different results. Contrary to widely stated claims, LOCF did not produce a conservative (i.e., lower) efficacy estimate compared to MI. Also, LOCF had a lower SE than MI.

Should journals stop publishing research funded by the drug industry

Abstract: The BMJ no longer publishes research funded by tobacco companies. Richard Smith and Peter Gotzsche say that research funded by drug companies is also flawed and published to encourage sales, but Trish Groves says that the industries are fundamentally different and that moves are afoot to increase integrity

Coding of adverse events of suicidality in clinical study reports of duloxetine for the treatment of major depressive disorder: descriptive study

Abstract: Objective To assess the effects of coding and coding conventions on summaries and tabulations of adverse events data on suicidality within clinical study reports.

Our prescription drugs kill us in large numbers

Abstract: Our prescription drugs are the third leading cause of death after heart disease and cancer in the United States and Europe. Around half of those who die have taken their drugs correctly; the other half die because of errors, such as too high a dose or use of a drug despite contraindications. Our drug agencies are not particularly helpful, as they rely on fake fixes, which are a long list of warnings, precautions, and contraindications for each drug, although they know that no doctor can possibly master all of these. Major reasons for the many drug deaths are impotent drug regulation, widespread crime that includes corruption of the scientific evidence about drugs and bribery of doctors, and lies in drug marketing, which is as harmful as tobacco marketing and, therefore, should be banned. We should take far fewer drugs, and patients should carefully study the package inserts of the drugs their doctors prescribe for them and independent information sources about drugs such as Cochrane reviews, which will make it easier for them to say "no thanks".

“Human guinea pig” asks for animal studies

Abstract: A trial participant whose request for animal data had been rejected turned to Peter Gotzsche for help. It later emerged that the information he requested didn’t exist at the start of the human trial. He describes what happened and says the social contract between patients and corporate sponsors of drug trials is broken

Muscular adverse effects are common with statins.

Abstract: The 2011 Cochrane review of statins for the primary prevention of cardiovascular disease reported a risk ratio of 1.03 for muscle pain—3% more patients developed muscle pain on the drug than on placebo.1 However, industry funded randomised trials are notoriously unreliable …

Time to halt an out of control trial with ineffective oversight

Abstract: Detailed scientific and ethical concerns have repeatedly been raised about the less than robust mammography screening age extension trial.1 2 3 The chief investigator is not medically or scientifically qualified, encourages contamination, ignores questions or obfuscates, and both runs the national programme and chairs the (non-independent) trial steering committee. The eight page study protocol,4 produced only after repeated freedom of information requests, contains two references and has …

Strobe bi̇ldi̇ri̇mi̇: epi̇demi̇yoloji̇de gözlemsel araştirma raporu yaziminin güçlendi̇ri̇lmesi̇ i̇çi̇n bi̇r rehber

Abstract: The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: Guidelines for Reporting Observational Studies Much biomedical research is observational. The reporting of such research is often inadequate, which hampers the assessment of its strengths and weaknesses and of a study's generalisability. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Initiative developed recommendations on what should be included in an accurate and complete report of an observational study. We defined the scope of the recommendations to cover three main study designs: cohort, case-control, and cross-sectional studies. We convened a 2-day workshop in September 2004, with methodologists, researchers, and journal editors to draft a checklist of items. This list was subsequently revised during several meetings of the coordinating group and in email discussions with the larger group of STROBE contributors, taking into account empirical evidence and methodological considerations. The workshop and the subsequent iterative process of consultation and revision resulted in a checklist of 22 items (the STROBE Statement) that relate to the title, , introduction, methods, results, and discussion sections of articles. 18 items are common to all three study designs and four are specific for cohort, case-control, or cross-sectional studies. A detailed Explanation and Elaboration document is published separately and is freely available on the Web sites of PLoS Medicine, Annals of Internal Medicine, and Epidemiology. We hope that the STROBE Statement will contribute to improving the quality of reporting of observational studies.

Authors’ reply to Lauritzen and colleagues, Newton and colleagues, and Mangin

Abstract: As our editorial explained, criticism of a clear negative result cannot turn it positive.1 Lauritzen and colleagues say that the trials in our Cochrane review tested outdated screening tests and treatments.2 3 This is not correct—for example, probably all 14 trials measured blood pressure and six trials tested for diabetes. They also say the trials were old, but if we increase the number of deaths from 11 940 to 15 103 …

Study of study of changes in antidepressant use after FDA warnings is not reliable

Abstract: Lu and colleagues reported that suicide attempts in young people increased after the Food and Drug Administration warned that selective serotonin reuptake inhibitors (SSRIs) can increase suicidal behaviour.1 This makes no sense. The FDA’s meta-analysis of 100 000 patients in placebo controlled randomised trials found that antidepressants increase suicidal behaviour up to about age 40 years,2 and that the risk …

Assessment Bias in Clinical Trials

Abstract: Assessment bias in a clinical trial occurs if bias in the assessment of the outcome exists. It is also called ascertainment bias, diagnostic bias, or detection bias. A major cause of assessment bias is lack of blinding. Other problems relate to differential identification of harmless or false-positive cases of disease, bias in assessment of disease-specific mortality, the use of composite outcomes, competing risks, timing of the assessments, and bias in assessment of harms. Keywords: diagnostic bias; detection bias; lack of blinding; harmless or false positive cases of disease; disease-specific mortality; assessment of harms

Questionable research and marketing of a combination drug for smoker’s lungs

Abstract: However, nowhere in the 15-page trial report was the correct factorial analysis to be found, and the abstract gave the readers the clear impression that the combination was better than any of its components 1 : The hazard ratio for death in the combination-ther- apy group, as compared with the placebo group, was 0.825 (95% confidence interval (CI), 0.681 to 1.002; p ¼ 0.052, adjusted for the interim analyses), corres- ponding to ... a reduction in the risk of death of 17.5%. The mortality rate for salmeterol alone or fluticasone propionate alone did not differ signifi- cantly from that for placebo.