Ymkje Anna de Vries

Reporting Bias in Clinical Trials Investigating the Efficacy of Second-Generation Antidepressants in the Treatment of Anxiety Disorders: A Report of 2 Meta-analyses

IMPORTANCE Studies have shown that the scientific literature has overestimated the efficacy of antidepressants for depression, but other indications for these drugs have not been considered. OBJECTIVE To examine reporting biases in double-blind, placebo-controlled trials on the pharmacologic treatment of anxiety disorders and quantify the extent to which these biases inflate estimates of drug efficacy. DATA SOURCES AND STUDY SELECTION We included reviews obtained from the US Food and Drug Administration (FDA) for premarketing trials of 9 second-generation antidepressants in the treatment of anxiety disorders. A systematic search for matching publications (until December 19, 2012) was performed using PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials. DATA EXTRACTION AND SYNTHESIS Double data extraction was performed for the FDA reviews and the journal articles. The Hedges g value was calculated as the measure of effect size. MAIN OUTCOMES AND MEASURES Reporting bias was examined and classified as study publication bias, outcome reporting bias, or spin (abstract conclusion not consistent with published results on primary end point). Separate meta-analyses were conducted for the 2 sources, and the effect of publication status on the effect estimates was examined using meta-regression. RESULTS The findings of 41 of the 57 trials (72%) were positive according to the FDA, but 43 of the 45 published article conclusions (96%) were positive (P < .001). Trials that the FDA determined as positive were 5 times more likely to be published in agreement with that determination compared with trials determined as not positive (risk ratio, 5.20; 95% CI, 1.87 to 14.45; P < .001). We found evidence for study publication bias (P < .001), outcome reporting bias (P = .02), and spin (P = .02). The pooled effect size based on the published literature (Hedges g, 0.38; 95% CI, 0.33 to 0.42; P < .001) was 15% higher than the effect size based on the FDA data (Hedges g, 0.33; 95% CI, 0.29 to 0.38; P < .001), but this difference was not statistically significant (β = 0.04; 95% CI, -0.02 to 0.10; P = .18). CONCLUSIONS AND RELEVANCE Various reporting biases were present for trials on the efficacy of FDA-approved second-generation antidepressants for anxiety disorders. Although these biases did not significantly inflate estimates of drug efficacy, reporting biases led to significant increases in the number of positive findings in the literature.

Influence of baseline severity on antidepressant efficacy for anxiety disorders: meta-analysis and meta-regression

BACKGROUND Antidepressants are established first-line treatments for anxiety disorders, but it is not clear whether they are equally effective across the severity range. AIMS To examine the influence of baseline severity of anxiety on antidepressant efficacy for generalised anxiety disorder (GAD), social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD) and panic disorder. METHOD Fifty-six trials of second-generation antidepressants for the short-term treatment of an anxiety disorder were included. Baseline and change scores were extracted for placebo and treatment groups in each trial. Mixed effects meta-regression was used to investigate the effects of treatment group, baseline severity and their interaction. RESULTS Increased baseline severity did not predict greater improvement in drug groups compared with placebo groups. Standardised regression coefficients of the interaction term between baseline severity and treatment group were 0.04 (95% CI -0.13 to 0.20, P = 0.65) for GAD, -0.06 (95% CI -0.20 to 0.09, P = 0.43) for SAD, 0.04 (95% CI -0.07 to 0.16, P = 0.46) for OCD, 0.16 (95% CI -0.22 to 0.53, P = 0.37) for PTSD and 0.002 (95% CI -0.10 to 0.10, P = 0.96) for panic disorder. For OCD, baseline severity did predict improvement in both placebo and drug groups equally (β = 0.11, 95% CI 0.05 to 0.17, P = 0.001). CONCLUSIONS No relationship between baseline severity and drug-placebo difference was found for anxiety disorders. These results suggest that if the efficacy of antidepressants is considered clinically relevant, they may be prescribed to patients with anxiety regardless of symptom severity.

Bias in the reporting of harms in clinical trials of second-generation antidepressants for depression and anxiety: A meta-analysis

Previous research has shown that reporting bias has inflated the apparent efficacy of antidepressants. We investigated whether apparent safety was also affected. We included 133 trials, involving 31,296 patients, of second-generation antidepressants for the treatment of major depressive disorder (MDD) or anxiety disorders, obtained from Food and Drug Administration (FDA) reviews. We extracted data on overall discontinuation, discontinuation due to adverse events, and serious adverse events (SAEs). Meta-analysis was used to compare discontinuation rates between FDA reviews and matching journal articles, while SAEs were compared qualitatively. The odds ratio for overall discontinuation, comparing drug to placebo, was 1.0 for both sources, while that for discontinuation due to adverse events was 2.4 for both sources. Seventy-seven of 97 (79%) journal articles provided incomplete information on SAEs; sixty-one (63%) articles made no mention of SAEs at all. Of 21 articles which could be compared to the FDA, only 6 (29%) had full reporting without discrepancies. Nine (43%) articles reported a discrepant number of SAEs. Descriptions were absent or discrepant in 6 (29%) additional articles, even for important SAEs such as suicide attempts. In conclusion, reporting bias has not affected average discontinuation rates over trials. However, SAE reporting is not only very poor, with over half of articles failing to discuss SAEs altogether, but discrepancies between the FDA and articles were common and often led to a more favorable drug-placebo comparison. These findings suggest that journal articles are an unreliable source of data on SAEs in antidepressant trials.

Retraction of biased journal articles

We hope that Le Noury and colleagues’ re-analysis of Study 329 will lead to the long overdue retraction of the 2001 paper.1 Study 329 may be the most infamous example of biased reporting within psychiatry, but this practice is widespread. We examined the reporting of antidepressant trials submitted to the …

Initial severity and antidepressant efficacy for anxiety disorders, obsessive-compulsive disorder, and posttraumatic stress disorder : An individual patient data meta-analysis

It has been suggested that antidepressant benefits are smaller for mild than severe depression. Because antidepressants are also used for anxiety disorders, obsessive‐compulsive disorder (OCD), and posttraumatic stress disorder (PTSD), we examined the influence of severity for these disorders.

Predicting antidepressant response by monitoring early improvement of individual symptoms of depression: Individual patient data meta-analysis

Background Improvement in depression within the first 2 weeks of antidepressant treatment predicts good outcomes, but non-improvers can still respond or remit, whereas improvers often do not. Aims We aimed to investigate whether early improvement of individual depressive symptoms better predicts response or remission. Method We obtained individual patient data of 30 trials comprising 2184 placebo-treated and 6058 antidepressant-treated participants. Primary outcome was week 6 response; secondary outcomes were week 6 remission and week 12 response and remission. We compared models that only included improvement in total score by week 2 (total improvement model) with models that also included improvement in individual symptoms. Results For week 6 response, the area under the receiver operating characteristic curve and negative and positive predictive values of the total improvement model were 0.73, 0.67 and 0.74 compared with 0.77, 0.70 and 0.71 for the item improvement model. Model performance decreased for week 12 outcomes. Of predicted non-responders, 29% actually did respond by week 6 and 43% by week 12, which was decreased from the baseline (overall) probabilities of 51% by week 6 and 69% by week 12. In post hoc analyses with continuous rather than dichotomous early improvement, including individual items did not enhance model performance. Conclusions Examining individual symptoms adds little to the predictive ability of early improvement. Additionally, early non-improvement does not rule out response or remission, particularly after 12 rather than 6 weeks. Therefore, our findings suggest that routinely adapting pharmacological treatment because of limited early improvement would often be premature.

Poor Guideline Adherence In The Initiation Of Antidepressant Treatment In Children And Adolescents In The Netherlands : Choice Of Antidepressant And Dose

Background: Type 2 diabetes mellitus (T2DM) has been suggested as a risk factor for liver, pancreatic, and colorectal cancer. T2DM patients show higher incidences of these cancers compared to the non-diabetic (non-DM) population. Current evidence, however, is inconsistent with respect to the incidences of other gastrointestinal (GI) malignancies. Objectives: To determine incidence rates (IRs) of all GI cancers in patients with and without T2DM. Methods: A retrospective cohort study was conducted using the UK Clinical Practice Research Datalink (CPRD) during 1988-2012. A T2DM cohort of antidiabetic drug users was matched to a non-DM reference cohort, by age, sex, and practice. Crude incidence rates (IRs) per 100,000 person-years (105 py) and 95% confidence intervals (CI) were calculated, stratified by age, sex, and calendar period. IRs were compared using the normal theory test. Results: 333,438 T2DM subjects and 333,438 non- DM subjects were analyzed, with a total duration of follow-up of >3.6 million py and 10,977 observed GI cancer cases. Overall, IRs of any GI cancer (IR 330 vs. 276 per 105 py), liver cancer (IR 26 vs. 8.9 per 105 py), pancreatic cancer (IR 65 vs. 31 per 105 py), and colon cancer (IR 119 vs. 109 per 105 py) were significantly higher in the T2DM cohort compared to the non-DM cohort, whereas the IR of esophageal cancer was significantly lower (IR 41 vs. 47 per 105 py, pBackground: Progressive multifocal leukencephalopathy (PML) is a rare, often fatal viral disease, which affects the white matter of the brain. It is caused by John Cunningham (JC) polyomavirus, whi ...The article investigates the special features of state control over international transfer of special-purpose and dual-use goods. It was established what international organizations was created in the international community to determine the principles of control over international transfer of special-purpose and dual-use goods, as well as the question of Ukraines joining the circle of member-states of such organizations. The structure of the system of export control bodies in Ukraine was defined, as well as the main powers of the State Service of Export Control of Ukraine in the sphere of control over international transfer of goods. The essence and the concept of goods over which international transfer state export control is carried out in accordance with the Ukrainian legislation were revealed, as well as special aspects of the procedure of state control over their international transfer.Background: Different antiplatelet regimens are used for secondary prevention after ischemic stroke (IS)/transient ischemic attack (TIA), but studies on the relative effectiveness and safety of each regimen in daily practice are lacking. Objectives: To assess the relative effectiveness and safety of several antiplatelet regimens as secondary prevention in patients after an IS/TIA in clinical practice. Methods: A cohort study was conducted using the Clinical Practice Research Datalink. Patients aged ≥ 18 years with a first diagnosis of IS/TIA in 1998- 2013 were identified. Antiplatelet exposure was categorized into aspirin-dipyridamole, aspirin-only, clopidogrel-only, aspirin-clopidogrel, other regimens, and no-antiplatelet exposure. The primary effectiveness outcome was a composite endpoint of nonfatal IS, nonfatal myocardial infarction (MI), or cardiovascular (CV) death; and the safety outcome was major bleeding. Time-dependent Cox regression analysis was used to assess the association between antiplatelet regimens and CV effectiveness and major bleeding outcomes. Results: We followed 20,552 IS/TIA patients for a median duration of 2.3 years. There were 5,714 composite events during follow-up. All regimens were effective in reducing the primary effectiveness outcome compared to no-antiplatelet exposure. Aspirin-only, clopidogrel-only, aspirin-clopidogrel and other regimens were significantly (p <0.05) less effective compared to aspirin-dipyridamole (HR: 1.35, 1.12, 1.40, and 1.27, respectively), adjusted for age, sex, lifestyle factors, disease history and CV comedications. All other regimens were also significantly (p <0.05) associated with a higher relative risk of major bleeding compared to aspirin-dipyridamole (HR: 1.21, 1.32, 1.78, and 1.37, respectively), adjusted for age, sex, alcohol use, liver and renal disease, major bleeding history and comedications. Conclusions: Compared to aspirin-dipyridamole, all other antiplatelet regimens are less effective in reducing the risk of nonfatal IS, nonfatal MI or CV death, and associated with a higher risk of major bleeding in patients with IS/TIA.Characteristics of Patients at Initiation of Treatment for Primary Chronic Immune ThrombocytopeniaBackground: Guidelines for cardiovascular secondary prevention are based on evidence from relatively old clinical trials and need to be evaluated in daily clinical practice. Objectives: To evaluate effectiveness of the recommended drug classes after an acute coronary syndrome (ACS) for secondary prevention of cardiovascular diseases and all-cause mortality. Methods: This cohort study used data from a representative sample of the French national healthcare insurance system database (EGB). Patients hospitalised for an incident ACS between 2006 and 2011, and aged ≥ 20 years at time of ACS were included in the study. Patients non-exposed to any of the four recommended drug classes (beta-blockers, antiplatelet agents, statins, and angiotensin-converting-enzyme inhibitors, ACEI, or angiotensin II receptor blockers, ARB) in the first 3 months following ACS or who died during this period were not included in the cohort. Exposure status was determined daily during follow-up. Effectiveness of the four therapeutic classes in preventing the composite outcome ACS, transient ischemic attack, ischemic stroke, or all-cause-death was estimated using a time-dependent Cox proportional hazards model, which was adjusted for time-fixed confounders measured at baseline (general characteristics and characteristics of the initial ACS) and time-dependent confounders during follow-up (co-morbidities and co-medications). Results: Of the 2874 patients included in the study, 33.9% were women and the median age was 67 years (interquartile range, IQR: 56-77). The median time of follow-up was 3.6 years (IQR: 2.2-5.3). The risk of the composite outcome decreased with use of antiplatelet agents (adjusted hazard ratio (aHR) 0.76, 95% confidence interval (CI) 0.63; 0.91), use of statins (aHR 0.71, 95%CI 0.57; 0.87), and use of ACEI/ARB (aHR 0.67, 95%CI 0.57; 0.80). Use of beta-blockers was not associated with a lower risk of the composite outcome (aHR, 0.90, 95%CI 0.74; 1.09]). Conclusions: Use of antiplatelet agents, statins, and ACEI/ARB after an ACS, but not beta-blockers, was associated with a lower risk of cardiovascular morbidity and all-cause mortality.Abstracts of the 32nd International Conference on Pharmacoepidemiology & Therapeutic Risk Management, The Convention Centre Dublin, Dublin, Ireland August 25–28, 2016Background: Cough and angioedema are adverse events associated with especially angiotensinconverting enzyme (ACE) inhibitors but also reported with angiotensin receptor blockers (ARBs) and aliskiren, a direct renin inhibitor (DRI). Susceptibility of developing cough/angioedema with ACE inhibitors depends on ethnicity, which is not documented in spontaneous reporting systems of drug safety. Objectives: To assess the impact of ethnicity on the occurrence of cough/angioedema with renin angiotensin system (RAS) inhibitors using information reported to the the World Health Organization database (VigiBase). Methods: A case/non-case study was performed in VigiBase. Cases were defined as reports of cough/angioedema and non-cases were all reports of other adverse events. The reporting countries were divided into three categories: black African countries, East Asian countries and other countries. Logistic regression analysis was used to assess the association between reporting of cough/angioedema with each class of RAS inhibitors stratified by country group and to control for confounding. Results: The reporting of cough with ACE inhibitors was significantly higher in East Asian countries than black African countries and other countries (adjusted reporting odds ratios (RORs): 256, 95%CI (236-278), 48.9, 95%CI (42.7-56.1) and 35.4, 95%CI (34.8- 35.9), respectively. The reporting of angioedema with ACE inhibitors was significantly higher in black African countries than East Asian countries and other countries (adjusted RORs: 55.3, 95%CI (45.5-67.2), 5.29, 95%CI(3.89-7.21) and 16.5, 95%CI (16.1- 16.8), respectively. There was no difference in reporting of cough/angioedema with ARBs and DRI between black African countries, East Asian countries and other countries. Conclusions: Our results by grouping countries according to ethnicity in VigiBase are consistent with previous results in the literature suggesting that the occurrence of cough with ACE inhibitors is higher in East Asian patients and the occurrence of angioedema with ACE inhibitors is higher in black patients. These findings indicate that ethnicity should be included as scientific parameter in pharmacovigilance.An Automatized Model for Sequential Monitoring of Effectiveness of New Drugs using Dronedarone as ExampleGeneral Pharmacological Treatments Preceding A Primary Chronic Immune Thrombocytopenia DiagnosisBackground: Several studies showed a bidirectional association between type 2 diabetes and psychiatric disorders in adults. There is limited information available about the association of type 1 diabetes (T1D) and psychiatric disorders in children and adolescents. Objectives: To assess the extent of psychiatric medication use before and after the onset of T1D in children and adolescents compared with a reference cohort without T1D. Methods: A population-based cohort study was conducted in the Dutch PHARMO Record Linkage System. All children and adolescents <19 years) with at least two insulin dispensings between 1999 and 2009 were identified as a T1D cohort (N=925) and matched with an up to four times larger diabetes-free reference cohort (N=3591) by age and sex. The period prevalences of psychiatric medication use (psycholeptics (ATC N05) and psychoanaleptics (ATC N06)) were calculated by dividing the number of patients with at least one dispensing by the number of patients available in the cohort during that time. Prevalences were calculated from 5 years before until 5 years after the onset of T1D (the index date in both cohorts) and stratified by age, sex, medication subgroup, and before/after the onset of T1D. Results: The mean age of the study participants was 10.1 years and 51% were boys. The 5-year prevalence of psychiatric medication use before the index date was significantly higher in the T1D cohort than in the reference cohort (7.2 vs. 4.7%, respectively, p=0.002). The same pattern was observed for the period after developing T1D (10.4 vs. 7.9% in the T1D and reference cohort respectively, p=0.015). In both cohorts adolescents (15-19 years) and boys had higher prevalences of psychiatric medication use. This increased prevalence of psychiatric medication use both before and after the index date in T1D cohort was mainly driven by an increased use of psycholeptics (mainly anxiolytics). Conclusions: Children with T1D were more likely to use psychiatric medication in the years before and after the onset of type 1 diabetes. This increased use was mainly driven by psycholeptics both before and after onset of T1D.