Pooling, meta-analysis, and the evaluation of drug safety

BACKGROUND: The "integrated safety report" of the drug registration files submitted to health authorities usually summarizes the rates of adverse events observed for a new drug, placebo or active control drugs by pooling the safety data across the trials. Pooling consists of adding the numbers of events observed in a given treatment group across the trials and dividing the results by the total number of patients included in this group. Because it considers treatment groups rather than studies, pooling ignores validity of the comparisons and is subject to a particular kind of bias, termed "Simpson's paradox." In contrast, meta-analysis and other stratified analyses are less susceptible to bias. METHODS: We use a hypothetical, but not atypical, application to demonstrate that the results of a meta-analysis can differ greatly from those obtained by pooling the same data. In our hypothetical model, a new drug is compared to 1) a placebo in 4 relatively small trials in patients at high risk for a certain adverse event and 2) an active reference drug in 2 larger trials of patients at low risk for this event. RESULTS: Using meta-analysis, the relative risk of experiencing the adverse event with the new drug was 1.78 (95% confidence interval [1.02; 3.12]) compared to placebo and 2.20 [0.76; 6.32] compared to active control. By pooling the data, the results were, respectively, 1.00 [0.59; 1.70] and 5.20 [2.07; 13.08]. CONCLUSIONS: Because these findings could mislead health authorities and doctors, regulatory agencies should require meta-analyses or stratified analyses of safety data in drug registration files

Are concomitant treatments confounding factors in randomized controlled trials on intensive blood-glucose control in type 2 diabetes? a systematic review

International audienceBackgroundOpen-label, randomized controlled trials (RCTs) are subject to observer bias. If patient management is conducted without blinding, a difference between groups may be explained by other factors than study treatment. One factor may come from taking concomitant treatments with an efficacy on the studied outcomes. In type 2 diabetes, some antihypertensive or lipid-lowering drugs are effective against diabetic complications. We wanted to determine if these concomitant treatments were correctly reported in articles of RCTs on type 2 diabetes and if they might have influenced the outcome.MethodsWe performed a systematic review using Medline, Embase, and the Cochrane Library (from January 1950 to July 2010). Open-label RCTs assessing the effectiveness of intensive blood-glucose control in type 2 diabetes were included. We chose five therapeutic classes with proven efficacy against diabetes complications: angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor antagonists (AIIRAs), fibrates, statins, and aspirin. Differences between concomitant treatments were considered statistically significant when p ResultsA total of eight open-label RCTs were included, but only three (37.5%) of them published concomitant treatments. In two studies (ACCORD and ADVANCE), a statistically significant difference was observed between the two groups for aspirin (p = 0.02) and ACEIs (p = 0.02).ConclusionsFew concomitant treatments were published in this sample of open-label RCTs. We cannot completely eliminate an observer bias for these studies. This bias probably influenced the results to an extent that has yet to be determined

Preventing acute decrease in renal function induced by coronary angiography (PRECORD): a prospective randomized trial

SummaryBackgroundInfusion of saline attenuates the decrease in renal function induced by radiographic contrast agents among patients with chronic renal insufficiency.AimThe Preventing Renal alteration in Coronary Disease (PRECORD) trial was a randomized trial to assess the effect on renal function of saline infusion during and after coronary angiography in 201 patients without severe chronic renal insufficiency (serum creatinine<140μmol/L).MethodsAll patients received standard oral hydration: 2000mL of tap water within the 24hours after coronary angiography. Patients were randomized before the procedure to intravenous hydration (1000mL of 0.9% saline infusion) or no additional hydration. The infusion was started in the catheterization laboratory and continued for 24hours. The primary endpoint was the change in calculated creatinine clearance between baseline and 24hours after coronary angiography. The same ionic low osmolar radiographic contrast agent (ioxaglate) was used in all patients.ResultsBoth groups had similar baseline characteristics, including age, serum creatinine, volume of contrast and proportion of patients undergoing ad hoc coronary angioplasty. The overall decrease in serum creatinine clearance 24hours after the procedure was –3.44 (0.68)mL/min. The change in serum creatinine clearance 24hours after the procedure was –2.81 (1.07)mL/min in the infusion group vs –4.09 (0.91)mL/min in the control group (p=0.38).ConclusionRenal function is altered only slightly 24hours after coronary angiography with standard oral hydration alone and is not affected by saline infusion started at the beginning of coronary angiography, even in patients with mild-to-moderate renal dysfunction

Consistency of safety and efficacy of new oral anticoagulants across subgroups of patients with atrial fibrillation.

AIMS: The well-known limitations of vitamin K antagonists (VKA) led to development of new oral anticoagulants (NOAC) in non-valvular atrial fibrillation (NVAF). The aim of this meta-analysis was to determine the consistency of treatment effects of NOAC irrespective of age, comorbidities, or prior VKA exposure. METHODS AND RESULTS: All randomized, controlled phase III trials comparing NOAC to VKA up to October 2012 were eligible provided their results (stroke/systemic embolism (SSE) and major bleeding (MB)) were reported according to age (≤ or &gt;75 years), renal function, CHADS2 score, presence of diabetes mellitus or heart failure, prior VKA use or previous cerebrovascular events. Interactions were considered significant at p &lt;0.05. Three studies (50,578 patients) were included, respectively evaluating apixaban, rivaroxaban, and dabigatran versus warfarin. A trend towards interaction with heart failure (p = 0.08) was observed with respect to SSE reduction, this being greater in patients not presenting heart failure (RR = 0.76 [0.67-0.86]) than in those with heart failure (RR = 0.90 [0.78-1.04]); Significant interaction (p = 0.01) with CHADS2 score was observed, NOAC achieving a greater reduction in bleeding risk in patients with a score of 0-1 (RR 0.67 CI 0.57-0.79) than in those with a score ≥2 (RR 0.85 CI 0.74-0.98). Comparison of MB in patients with (RR 0.97 CI 0.79-1.18) and without (RR 0.76 CI 0.65-0.88) diabetes mellitus showed a similar trend (p = 0.06). No other interactions were found. All subgroups derived benefit from NOA in terms of SSE or MB reduction. CONCLUSIONS: NOAC appeared to be more effective and safer than VKA in reducing SSE or MB irrespective of patient comorbidities. Thromboembolism risk, evaluated by CHADS2 score and, to a lesser extent, diabetes mellitus modified the treatment effects of NOAC without complete loss of benefit with respect to MB reduction

French scientific names of continental molluscs of France: process for establishing a list of reference

In the biodiversity crisis context and with the increasing general awareness on this issue, conservation of small and poorly-known species is hampered by the fact they only have latine names. In order to communicate for biodiversity conservation, having French names is an advantage which is lacking in terrestrial and freshwater molluscs from France. To remedy this problem, we propose a list of French scientific names for this group, i.e. all species and subspecies known from France. We have listed existing names in legal documents, in usage and in the 18th and 19th centuries scientific literature. The resulting list being incomplete, we had to create new French names, following a series of recommendations adapted from similar works dealing with other taxonomic groups. We conclude by dealing with the issue of the legitimacy and validity of such names. The list of French scientific names is given as an appendix and is downloadable from internetDans le contexte de la crise de la biodiversité et de la prise de conscience par le grand public des enjeux environnementaux, la conservation des espèces petites et méconnues est handicapée par le fait que ces espèces ne peuvent être désignées que par leur nom latin. Dans une optique de communication pour la préservation de la biodiversité, disposer de nom français est un atout qui fait défaut pour les mollusques terrestres et d'eau douce de France. Pour remédier à cela, nous proposons une liste de noms scientifiques français pour ce groupe, et présentons les étapes qui ont permis l'établissement de cette liste. Les taxons concernés sont l'ensemble des espèces et sous-espèces de la faune de France, pour lesquelles nous avons recensé les noms existants, dans les textes légaux, dans l'usage et dans la littérature scientifique des XVIIIe et XIXe siècles. La liste de noms obtenue étant insuffisante, nous avons dû créer de nouveaux noms, en suivant une série de recommandations adaptées de travaux similaires menés sur d'autres groupes. Enfin, nous concluons par la question de la validité et de la légitimité d'une telle liste. La liste des noms scientifiques français est fournie en annexe et téléchargeable sur internet

Impact of Aldosterone Antagonists on Sudden Cardiac Death Prevention in Heart Failure and Post-Myocardial Infarction Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND AND OBJECTIVES: Sudden cardiac death (SCD) is a severe burden of modern medicine. Aldosterone antagonist is publicized as effective in reducing mortality in patients with heart failure (HF) or post myocardial infarction (MI). Our study aimed to assess the efficacy of AAs on mortality including SCD, hospitalization admission and several common adverse effects. METHODS: We searched Embase, PubMed, Web of Science, Cochrane library and clinicaltrial.gov for randomized controlled trials (RCTs) assigning AAs in patients with HF or post MI through May 2015. The comparator included standard medication or placebo, or both. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Event rates were compared using a random effects model. Prospective RCTs of AAs with durations of at least 8 weeks were selected if they included at least one of the following outcomes: SCD, all-cause/cardiovascular mortality, all-cause/cardiovascular hospitalization and common side effects (hyperkalemia, renal function degradation and gynecomastia). RESULTS: Data from 19,333 patients enrolled in 25 trials were included. In patients with HF, this treatment significantly reduced the risk of SCD by 19% (RR 0.81; 95% CI, 0.67-0.98; p = 0.03); all-cause mortality by 19% (RR 0.81; 95% CI, 0.74-0.88, p&lt;0.00001) and cardiovascular death by 21% (RR 0.79; 95% CI, 0.70-0.89, p&lt;0.00001). In patients with post-MI, the matching reduced risks were 20% (RR 0.80; 95% CI, 0.66-0.98; p = 0.03), 15% (RR 0.85; 95% CI, 0.76-0.95, p = 0.003) and 17% (RR 0.83; 95% CI, 0.74-0.94, p = 0.003), respectively. Concerning both subgroups, the relative risks respectively decreased by 19% (RR 0.81; 95% CI, 0.71-0.92; p = 0.002) for SCD, 18% (RR 0.82; 95% CI, 0.77-0.88, p &lt; 0.0001) for all-cause mortality and 20% (RR 0.80; 95% CI, 0.74-0.87, p &lt; 0.0001) for cardiovascular mortality in patients treated with AAs. As well, hospitalizations were significantly reduced, while common adverse effects were significantly increased. CONCLUSION: Aldosterone antagonists appear to be effective in reducing SCD and other mortality events, compared with placebo or standard medication in patients with HF and/or after a MI

Greater Response to Placebo in Children Than in Adults: A Systematic Review and Meta-Analysis in Drug-Resistant Partial Epilepsy

In a systematic review of antiepileptic drugs, Philippe Ryvlin and colleagues find that children with drug-resistant partial epilepsy enrolled in trials seem to have a greater response to placebo than adults enrolled in such trials

A systematic review of how homeopathy is represented in conventional and CAM peer reviewed journals

BACKGROUND: Growing popularity of complementary and alternative medicine (CAM) in the public sector is reflected in the scientific community by an increased number of research articles assessing its therapeutic effects. Some suggest that publication biases occur in mainstream medicine, and may also occur in CAM. Homeopathy is one of the most widespread and most controversial forms of CAM. The purpose of this study was to compare the representation of homeopathic clinical trials published in traditional science and CAM journals. METHODS: Literature searches were performed using Medline (PubMed), AMED and Embase computer databases. Search terms included "homeo-pathy, -path, and -pathic" and "clinical" and "trial". All articles published in English over the past 10 years were included. Our search yielded 251 articles overall, of which 46 systematically examined the efficacy of homeopathic treatment. We categorized the overall results of each paper as having either "positive" or "negative" outcomes depending upon the reported effects of homeopathy. We also examined and compared 15 meta-analyses and review articles on homeopathy to ensure our collection of clinical trials was reasonably comprehensive. These articles were found by inserting the term "review" instead of "clinical" and "trial". RESULTS: Forty-six peer-reviewed articles published in a total of 23 different journals were compared (26 in CAM journals and 20 in conventional journals). Of those in conventional journals, 69% reported negative findings compared to only 30% in CAM journals. Very few articles were found to be presented in a "negative" tone, and most were presented using "neutral" or unbiased language. CONCLUSION: A considerable difference exists between the number of clinical trials showing positive results published in CAM journals compared with traditional journals. We found only 30% of those articles published in CAM journals presented negative findings, whereas over twice that amount were published in traditional journals. These results suggest a publication bias against homeopathy exists in mainstream journals. Conversely, the same type of publication bias does not appear to exist between review and meta-analysis articles published in the two types of journals

Incommensurable worldviews? Is public use of complementary and alternative medicines incompatible with support for science and conventional medicine?

Proponents of controversial Complementary and Alternative Medicines, such as homeopathy, argue that these treatments can be used with great effect in addition to, and sometimes instead of, ?conventional? medicine. In doing so, they accept the idea that the scientific approach to the evaluation of treatment does not undermine use of and support for some of the more controversial CAM treatments. For those adhering to the scientific canon, however, such efficacy claims lack the requisite evidential basis from randomised controlled trials. It is not clear, however, whether such opposition characterises the views of the general public. In this paper we use data from the 2009 Wellcome Monitor survey to investigate public use of and beliefs about the efficacy of a prominent and controversial CAM within the United Kingdom, homeopathy. We proceed by using Latent Class Analysis to assess whether it is possible to identify a sub-group of the population who are at ease in combining support for science and conventional medicine with use of CAM treatments, and belief in the efficacy of homeopathy. Our results suggest that over 40% of the British public maintain positive evaluations of both homeopathy and conventional medicine simultaneously. Explanatory analyses reveal that simultaneous support for a controversial CAM treatment and conventional medicine is, in part, explained by a lack of scientific knowledge as well as concerns about the regulation of medical research