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Showing papers by "Peter C Gøtzsche published in 2016"


Journal ArticleDOI
27 Jan 2016-BMJ
TL;DR: In adults there was no significant increase in all four outcomes, but in children and adolescents the risk of suicidality and aggression doubled, and the harms could not be estimated accurately.
Abstract: Objective To study serious harms associated with selective serotonin and serotonin-norepinephrine reuptake inhibitors. Design Systematic review and meta-analysis. Main outcome measures Mortality and suicidality. Secondary outcomes were aggressive behaviour and akathisia. Data sources Clinical study reports for duloxetine, fluoxetine, paroxetine, sertraline, and venlafaxine obtained from the European and UK drug regulators, and summary trial reports for duloxetine and fluoxetine from Eli Lilly’s website. Eligibility criteria for study selection Double blind placebo controlled trials that contained any patient narratives or individual patient listings of harms. Data extraction and analysis Two researchers extracted data independently; the outcomes were meta-analysed by Peto’s exact method (fixed effect model). Results We included 70 trials (64 381 pages of clinical study reports) with 18 526 patients. These trials had limitations in the study design and discrepancies in reporting, which may have led to serious under-reporting of harms. For example, some outcomes appeared only in individual patient listings in appendices, which we had for only 32 trials, and we did not have case report forms for any of the trials. Differences in mortality (all deaths were in adults, odds ratio 1.28, 95% confidence interval 0.40 to 4.06), suicidality (1.21, 0.84 to 1.74), and akathisia (2.04, 0.93 to 4.48) were not significant, whereas patients taking antidepressants displayed more aggressive behaviour (1.93, 1.26 to 2.95). For adults, the odds ratios were 0.81 (0.51 to 1.28) for suicidality, 1.09 (0.55 to 2.14) for aggression, and 2.00 (0.79 to 5.04) for akathisia. The corresponding values for children and adolescents were 2.39 (1.31 to 4.33), 2.79 (1.62 to 4.81), and 2.15 (0.48 to 9.65). In the summary trial reports on Eli Lilly’s website, almost all deaths were noted, but all suicidal ideation events were missing, and the information on the remaining outcomes was incomplete. Conclusions Because of the shortcomings identified and having only partial access to appendices with no access to case report forms, the harms could not be estimated accurately. In adults there was no significant increase in all four outcomes, but in children and adolescents the risk of suicidality and aggression doubled. To elucidate the harms reliably, access to anonymised individual patient data is needed.

248 citations


Journal ArticleDOI
TL;DR: It is the opinion that augmentation therapy with alpha-1 antitrypsin cannot be recommended and several secondary outcomes were unreported in the largest and most recent trial whose authors had numerous financial conflicts of interest.
Abstract: Background Alpha-1 antitrypsin deficiency is an inherited disorder that can cause chronic obstructive pulmonary disease (COPD). People who smoke are more seriously affected and have a greater risk of dying from the disease. Therefore, the primary treatment is to help people give up smoking. There are now also preparations available that contain alpha-1 antitrypsin, but it is uncertain what their clinical effect is. Objectives To review the benefits and harms of augmentation therapy with intravenous alpha-1 antitrypsin in patients with alpha-1 antitrypsin deficiency and lung disease. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed and ClinicalTrials.gov to 25 March 2016. Selection criteria We included randomised trials of augmentation therapy with alpha-1 antitrypsin compared with placebo or no treatment. Data collection and analysis The two review authors independently selected trials, extracted outcome data and assessed the risk of bias. Main results We included three trials (283 participants in the analyses) that ran for two to three years. All participants were ex- or never-smokers and had genetic variants that carried a high risk of developing COPD. Only one trial reported mortality data (one person of 93 died in the treatment group and three of 87 died in the placebo group). There was no information on harms in the oldest trial. Another trial reported serious adverse events in 10 participants in the treatment group and 18 participants in the placebo group. In the most recent trial, serious adverse events occurred in 28 participants in each group. None of the trials reported mean number of lung infections or hospital admissions. In the two trials that reported exacerbations, there were more exacerbations in the treatment group than in the placebo group, but the results of both trials included the possibility of no difference. Quality of life was similar in the two groups. Forced expiratory volume in one second (FEV1) deteriorated more in participants in the treatment group than in the placebo group but the confidence interval (CI) included no difference (standardised mean difference -0.19, 95% CI -0.42 to 0.05; P = 0.12). For carbon monoxide diffusion, the difference was -0.11 mmol/minute/kPa (95% CI -0.35 to 0.12; P = 0.34). Lung density measured by computer tomography (CT) scan deteriorated significantly less in the treatment group than in the placebo group (mean difference (MD) 0.86 g/L, 95% CI 0.31 to 1.42; P = 0.002). Several secondary outcomes were unreported in the largest and most recent trial whose authors had numerous financial conflicts of interest. Authors' conclusions This review update added one new study and 143 new participants, but the conclusions remain unchanged. Due to sparse data, we could not arrive at a conclusion about the impact of augmentation therapy on mortality, exacerbations, lung infections, hospital admission and quality of life, and there was uncertainty about possible harms. Therefore, it is our opinion that augmentation therapy with alpha-1 antitrypsin cannot be recommended.

94 citations


Journal ArticleDOI
TL;DR: In the orlistat trials, important disparities were identified in the reporting of adverse events between protocols, clinical study reports, and published papers, which seemed to have systematically understated adverse events.
Abstract: Background Little is known about how adverse events are summarised and reported in trials, as detailed information is usually considered confidential. We have acquired clinical study reports (CSRs) from the European Medicines Agency through the Freedom of Information Act. The CSRs describe the results of studies conducted as part of the application for marketing authorisation for the slimming pill orlistat. The purpose of this study was to study how adverse events were summarised and reported in study protocols, CSRs, and published papers of orlistat trials. Methods and Findings We received the CSRs from seven randomised placebo controlled orlistat trials (4,225 participants) submitted by Roche. The CSRs consisted of 8,716 pages and included protocols. Two researchers independently extracted data on adverse events from protocols and CSRs. Corresponding published papers were identified on PubMed and adverse event data were extracted from this source as well. All three sources were compared. Individual adverse events from one trial were summed and compared to the totals in the summary report. None of the protocols or CSRs contained instructions for investigators on how to question participants about adverse events. In CSRs, gastrointestinal adverse events were only coded if the participant reported that they were “bothersome,” a condition that was not specified in the protocol for two of the trials. Serious adverse events were assessed for relationship to the drug by the sponsor, and all adverse events were coded by the sponsor using a glossary that could be updated by the sponsor. The criteria for withdrawal due to adverse events were in one case related to efficacy (high fasting glucose led to withdrawal), which meant that one trial had more withdrawals due to adverse events in the placebo group. Finally, only between 3% and 33% of the total number of investigator-reported adverse events from the trials were reported in the publications because of post hoc filters, though six of seven papers stated that “all adverse events were recorded.” For one trial, we identified an additional 1,318 adverse events that were not listed or mentioned in the CSR itself but could be identified through manually counting individual adverse events reported in an appendix. We discovered that the majority of patients had multiple episodes of the same adverse event that were only counted once, though this was not described in the CSRs. We also discovered that participants treated with orlistat experienced twice as many days with adverse events as participants treated with placebo (22.7 d versus 14.9 d, p-value < 0.0001, Student’s t test). Furthermore, compared with the placebo group, adverse events in the orlistat group were more severe. None of this was stated in the CSR or in the published paper. Our analysis was restricted to one drug tested in the mid-1990s; our results might therefore not be applicable for newer drugs. Conclusions In the orlistat trials, we identified important disparities in the reporting of adverse events between protocols, clinical study reports, and published papers. Reports of these trials seemed to have systematically understated adverse events. Based on these findings, systematic reviews of drugs might be improved by including protocols and CSRs in addition to published articles.

53 citations


Journal ArticleDOI
TL;DR: The primary outcomes of this review were total mortality, overdiagnosis of malignant melanoma, and quality of life/psychosocial consequences.
Abstract: Background Screening for malignant melanoma has the potential to reduce morbidity and mortality from the disease through earlier detection, as prognosis is closely associated with the thickness of the lesion at the time of diagnosis. However, there are also potential harms from screening people without skin lesion concerns, such as overdiagnosis of lesions that would never have caused symptoms if they had remained undetected. Overdiagnosis results in harm through unnecessary treatment and the psychosocial consequences of being labelled with a cancer diagnosis. For any type of screening, the benefits must outweigh the harms. Screening for malignant melanoma is currently practised in many countries, and the incidence of the disease is rising sharply, while mortality remains largely unchanged. Objectives To assess the effects on morbidity and mortality of screening for malignant melanoma in the general population. Search methods We searched the following databases up to May 2018: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trials registries, checked the reference lists of included and other relevant studies for further references to randomised controlled trials (RCTs), used citation tracking (Web of Science) for key articles, and asked trialists about additional studies and study reports. Selection criteria RCTs, including cluster-randomised trials, of screening for malignant melanoma compared with no screening, regardless of screening modality or setting, in any type of population and in any age group where people were not suspected of having malignant melanoma. We excluded studies in people with a genetic disposition for malignant melanoma (e.g. familial atypical mole and melanoma syndrome) and studies performed exclusively in people with previous melanomas. Data collection and analysis We used standard methodological procedures expected by Cochrane. The primary outcomes of this review were total mortality, overdiagnosis of malignant melanoma, and quality of life/psychosocial consequences. Main results We included two studies with 64,391 participants. The first study was a randomised trial of an intervention developed to increase the rate of performance of thorough skin self-examination. The intervention group received instructional materials, including cues and aids, a 14-minute instruction video, and a brief counselling session, and at three weeks a brief follow-up telephone call from a health educator, aimed at increasing performance of thorough skin self-examination. The control group received a diet intervention with similar follow-up. The trial included 1356 people, who were recruited from 11 primary care practices in the US between 2000 and 2001. Participant mean age was 53.2 years and 41.7% were men. This study did not report on any of our primary outcomes or the following secondary outcomes: mortality specific to malignant melanoma, false-positive rates (skin biopsies/excisions with benign outcome), or false-negative rates (malignant melanomas diagnosed between screening rounds and up to one year after the last round). All participants were asked to complete follow-up telephone interviews at 2, 6, and 12 months after randomisation.The second study was a pilot study for a cluster-RCT of population-based screening for malignant melanoma in Australia. This pilot trial included 63,035 adults aged over 30 years. The three-year programme involved community education, an education and support component for medical practitioners, and the provision of free skin screening services. The mean age of people attending the skin screening clinics (which were held by primary care physicians in workplaces, community venues, and local hospitals, and included day and evening sessions) was 46.5 years, and 51.5% were men. The study included whole communities, targeting participants over 30 years of age, but information on age and gender of the whole study population was not reported. Study duration was three years (1998 to 2001), and outcomes were measured at the screening clinics during these three years. There was no further follow-up for any outcomes. The control group received no programme. The ensuing, planned cluster randomised trial in 560,000 adults was never carried out due to lack of funding. At the time of this review, there are no published or unpublished data on our prespecified outcomes available, and no results for mortality outcomes from the pilot study are to be expected.The risk of bias in these studies was high for performance bias (blinding study personnel and participants) and high or unclear for detection bias (blinding of outcome assessment). Risk of bias in the other domains was either unclear or low. We were unable to assess the certainty of the evidence for our primary outcomes as planned due to lack of data. Authors' conclusions Adult general population screening for malignant melanoma is not supported or refuted by current evidence from RCTs. It therefore does not fulfil accepted criteria for implementation of population screening programmes. This review did not investigate the effects of screening people with a history of malignant melanoma or in people with a genetic disposition for malignant melanoma (e.g. familial atypical mole and melanoma syndrome). To determine the benefits and harms of screening for malignant melanoma, a rigorously conducted randomised trial is needed, which assesses overall mortality, overdiagnosis, psychosocial consequences, and resource use.

51 citations


Journal ArticleDOI
16 Aug 2016-BMJ
TL;DR: Evidence for benefits to patients and public health of adaptive pathways is lacking or contradictory, say Courtney Davis and colleagues.
Abstract: Evidence for benefits to patients and public health of adaptive pathways is lacking or contradictory, say Courtney Davis and colleagues

48 citations


Journal ArticleDOI
TL;DR: Antidepressants double the occurrence of events in adult healthy volunteers that can lead to suicide and violence.
Abstract: ObjectiveTo quantify the risk of suicidality and violence when selective serotonin and serotonin-norepinephrine reuptake inhibitors are given to adult healthy volunteers with no signs of a mental d...

44 citations


Journal ArticleDOI
TL;DR: The results showed substantial and lasting effects on sexual behaviour in rats after exposure to an SSRI early in life on important sexual outcomes.
Abstract: Background Sexual dysfunction is a common adverse effect of selective serotonin reuptake inhibitors (SSRIs) and there is a concern that the sexual harms might persist after discontinuation of therapy. Objective To assess whether the use of SSRIs in animals can lead to persistent sexual dysfunction. Methods Systematic review of animal studies measuring sexual behaviour after end of treatment with SSRIs or serotonin norepinephrine reuptake inhibitors. Data sources We searched PubMed and EMBASE. Results We included 14 studies. The general quality of the studies was poor. Only four studies reported use of randomisation and none mentioned allocation concealment. All studies used placebo and were therefore blinded. For rats exposed to SSRIs compared with those exposed to placebo, we found a higher risk of no mounting behaviour (RR = 0.73; 95% CI = 0.62-0.86), no intromission behaviour (RR = 0.74; 95% CI = 0.60-0.92) and no ejaculation behaviour (RR = 0.49, 95% CI = 0.24-1.00). Conclusion Our results showed substantial and lasting effects on sexual behaviour in rats after exposure to an SSRI early in life on important sexual outcomes.

16 citations


Journal ArticleDOI
05 Apr 2016-JAMA
TL;DR: Screening has not reduced total mortality and it is therefore misleading to claim that “screening saves lives” if recommendations are based on poor evidence, rather than the most reliable trials, interventions will continue to be used that lead to much harm, with little or no benefit.
Abstract: Breast Cancer Screening: Benefit or Harm? To the Editor In the systematic review of breast cancer screening, Dr Myers and colleagues1 claimed that our Cochrane review2 showed that breast screening reduces cause-specific mortality by 19%, there was no significant heterogeneity, and our results were similar to those of other reviews. This misrepresents our findings and creates an impression of scientific agreement that does not exist. It is also not correct that our estimate that 10 women were overdiagnosed for each avoided death from breast cancer was based on “all trials.” We documented important methodological differences and pronounced heterogeneity between results of poorly and adequately randomized trials (I2 = 78%). Trials with adequate randomization found little or no benefit (relative risk, 0.90 [95% CI, 0.79-1.02] for adequately randomized trials vs 0.75 [95% CI, 0.67-0.83] for poorly randomized trials).2 Other researchers have expressed similar concerns.3 When study methods provide a compelling explanation for substantial differences in results between studies, the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) handbook4 recommends using the estimates from trials with a lower risk of bias. However, Myers and colleagues did not properly consider the differences in quality of studies when they used GRADE. The doubtful benefit of breast screening at the population level was confirmed in observational studies from Norway and Denmark, the only countries that allow use of contemporary, same-age control groups.2 Observational studies without control groups are less reliable, no matter how well designed, and improved therapy can explain the entire observed mortality reduction over the past decades.5 When the benefit is overestimated, Cancer Intervention and Surveillance Modeling Network models of the balance between benefits and harms become misleading.1 The new American Cancer Society (ACS) guidelines are a step in the right direction but the insights that led to the recommendations are not new and they do not fully adopt the evidence-based approach. Overconfidence in flawed trials, fueled by economic conflicts of interest and good intentions, has led to many women being given diagnoses of breast cancer that they did not need, producing unwarranted fear and psychological stress and exposing them to treatment that can only harm them. Treatment of overdiagnosed, healthy women kills many of them, and total mortality is therefore the proper outcome. Screening has not reduced total mortality,2 and it is therefore misleading to claim that “screening saves lives.” If recommendations are based on poor evidence, rather than the most reliable trials, interventions will continue to be used that lead to much harm, with little or no benefit.

11 citations


Journal ArticleDOI
TL;DR: The recently updated breast cancer screening guidelines are less aggressive than previous versions and clearer about overdiagnosis, but a lack of attention was placed on the differences in effect estimates between trials at high and low risk of bias, and the authors failed to quantify the most serious harm.
Abstract: The recently updated breast cancer screening guidelines from the American Cancer Society are less aggressive than previous versions and clearer about overdiagnosis. However, a lack of attention was placed on the differences in effect estimates between trials at high and low risk of bias, and the authors failed to quantify the most serious harm.

6 citations


Journal ArticleDOI
10 Feb 2016-BMJ
TL;DR: In their systematic review, Amick and colleagues write that reasons for preferring psychotherapy over drugs for depression include concerns about side effects and “perceived ‘addictiveness’’ of drugs.
Abstract: In their systematic review, Amick and colleagues write that reasons for preferring psychotherapy over drugs for depression include concerns about side effects and “perceived ‘addictiveness’” of drugs.1 This addictiveness is not hypothetical, it is very real and affects about half of those treated with antidepressants.2 3 4 The authors do not discuss what is perhaps their most important …

4 citations


Journal ArticleDOI
16 Feb 2016-BMJ
TL;DR: It should surprise no one that the risk factors for serious suicide attempts are similar to those for suicide, and when these authors and other psychiatrists claim that these drugs protect against suicide despite the solid evidence to the contrary, they are wrong.
Abstract: Dubicka and colleagues say that we are likely to harm young people when we point out that antidepressants increase the risk of suicide.1 2 They consider it harmful that some young people will not start taking antidepressants because they think that these drugs do more harm than good. What is harmful is when these authors and other psychiatrists claim that these drugs protect against suicide despite the solid evidence we have to the contrary and the clear warnings from drug agencies. Dubicka and colleagues say that “It is well established that the undertreatment of depression in children and young people is linked to suicide” and refer to an observational study. There are many such studies, but they are all flawed.3 These authors say that our statement that antidepressants doubled the risk of suicide in children and adolescents is incorrect, and they argue that there is a “hugely important difference” between suicides and suicidal behaviour. There isn’t. A suicide starts with a thought about suicide, which leads to preparations for suicide, a suicide attempt, and suicide. It should surprise no one that the risk factors for serious suicide attempts are similar to those for suicide.4 5 Their other arguments are also invalid. There is no need …