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Meta-analysis in medicine has mainly used data from randomized trials, but in pharmacoepidemiology, evidence from observational studies is also relevant. This chapter addresses conceptual and methodological issues for meta-analysis, especially for observational studies. The clinical problems to be addressed by pharmacoepidemiologic research are usu...
Introduced in the 1950s, acetaminophen is one of the most widely used antipyretics and analgesics worldwide. In 1999, the International Agency for Research on Cancer (IARC) reviewed the epidemiologic studies of acetaminophen and the data were judged to be “inadequate” to conclude that it is carcinogenic. In 2019 the California Office of Environment...
Introduction:
Famotidine has been posited as a potential treatment for coronavirus disease 2019 (COVID-19). We compared the incidence of COVID-19 outcomes (i.e., death and death or intensive services use) among hospitalized famotidine users vs proton pump inhibitors (PPIs) users, hydroxychloroquine users, or famotidine nonusers separately.
Method...
Many observational studies explore the association between acetaminophen and cancer, but known limitations such as vulnerability to channeling, protopathic bias, and uncontrolled confounding hamper the interpretability of results. To help understand the potential magnitude of bias, we identify key design choices in these observational studies and s...
IntroductionObservational studies estimating severe outcomes for paracetamol versus ibuprofen use have acknowledged the specific challenge of channeling bias. A previous study relying on negative controls suggested that using large-scale propensity score (LSPS) matching may mitigate bias better than models using limited lists of covariates.Objectiv...
Objective: Observational evidence suggests that patients with type 2 diabetes mellitus (T2DM) are at increased risk for acute pancreatitis (AP) versus those without T2DM. A small number of AP events were reported in clinical trials of the sodium glucose co-transporter 2 inhibitor canagliflozin, though no imbalances were observed between treatment g...
Following publication of the original article [1], we have been notified of a few mistakes:
The revised edition of the Handbook offers the only guide on how to conduct, report and maintain a Cochrane Review.
The second edition of The Cochrane Handbook for Systematic Reviews of Interventions contains essential guidance for preparing and maintaining Cochrane Reviews of the effects of health interventions. Designed to be an accessible resou...
Metaanalysis can be regarded as a “state‐of‐the‐art” review of available data, employing statistical methods to combine data, typically in conjunction with a thorough and systematic qualitative review, which will usually include searching the literature. There are multiple reasons why a pharmacoepidemiologist might be interested in conducting a met...
Background
The randomised controlled trial is widely considered to be the gold standard study for comparing the effectiveness of health interventions. Central to its design is a calculation of the number of participants needed (the sample size) for the trial. The sample size is typically calculated by specifying the magnitude of the difference in t...
Purpose:
To compare the incidence of diabetic ketoacidosis (DKA) among patients with type 2 diabetes mellitus (T2DM) who were new users of sodium glucose co-transporter 2 inhibitors (SGLT2i) versus other classes of antihyperglycemic agents (AHAs).
Methods:
Patients were identified from four large US claims databases using broad (all T2DM patient...
Objectives:
Data Abstraction Assistant (DAA) is a software for linking items abstracted into a data collection form for a systematic review to their locations in a study report. We conducted a randomized cross-over trial that compared DAA-facilitated single-data abstraction plus verification ("DAA verification"), single data abstraction plus verif...
Observational evidence suggests that patients with type 2 diabetes mellitus (T2DM) are at increased risk of AP. A small number of AP events were reported in clinical trials of the SGLT2 inhibitor CANA, with no imbalances noted between treatment groups. This observational study evaluated the risk of AP among new users of CANA vs. 6 classes of other...
Introduction: Diabetic ketoacidosis (DKA) is a serious acute metabolic complication of diabetes. Rare DKA events have occurred in patients taking sodium glucose co-transporter 2 inhibitors (SGLT2i). This study evaluated the risk of DKA in patients with type 2 diabetes mellitus (T2DM) taking SGLT2i versus other antihyperglycemic agents (AHAs) in cli...
Randomised controlled trials are considered to be the best method to assess comparative clinical efficacy and effectiveness, and can be a key source of data for estimating cost effectiveness. Central to the design of a randomised controlled trial is an a priori sample size calculation, which ensures that the study has a high probability of achievin...
Background
A key step in the design of a RCT is the estimation of the number of participants needed in the study. The most common approach is to specify a target difference between the treatments for the primary outcome and then calculate the required sample size. The sample size is chosen to ensure that the trial will have a high probability (adeq...
Table S1. Crude Incidence Rate (Per 1000 Patient‐years) of HHF and BKLE Amputation in the Subpopulation With Established Cardiovascular Disease for New Users of: (1) Canagliflozin, (2) Empagliflozin or Dapagliflozin (Other SGLT2i), (3) All Non‐SGLT2i, and (4) Select Non‐SGLT2i (DPP‐4i, GLP‐1 Receptor Agonist, or Other AHA) During the On‐treatment a...
Background
A key step in the design of a randomised controlled trial is the estimation of the number of participants needed. The most common approach is to specify a target difference in the primary outcome between the randomised groups and then estimate the corresponding sample size. The sample size is chosen to provide reassurance that the trial...
The aim of this document is to provide practical guidance on the choice of target difference used in the sample size calculation of a randomised controlled trial (RCT). Guidance is provided with a definitive trial, one that seeks to provide a useful answer, in mind and not those of a more exploratory nature. The term “target difference” is taken th...
Aims
Sodium glucose co‐transporter 2 inhibitors (SGLT2i) are indicated for treatment of type 2 diabetes mellitus (T2DM); some SGLT2i have reported cardiovascular benefit, and some have reported risk of below‐knee lower extremity (BKLE) amputation. This study examined the real‐world comparative effectiveness within the SGLT2i class and compared with...
Sodium glucose co-transporter 2 inhibitors (SGLT2i) are indicated for treatment of T2DM; some SGLT2i have reported a CV benefit and some reported a risk of BKA. U.S. claims databases were analyzed using a prespecified protocol to examine CANA-associated effects on BKA and hospitalization for heart failure (HHF) vs. other SGLT2i and non-SGLT2i. Anal...
Table S1. Procedure Codes for Amputation Events.
Table S2. Condition and Procedure Codes for High CV Risk*.
Table S3. Distribution of BKLE Amputation Procedures.
Importance
While guidance on statistical principles for clinical trials exists, there is an absence of guidance covering the required content of statistical analysis plans (SAPs) to support transparency and reproducibility.
Objective
To develop recommendations for a minimum set of items that should be addressed in SAPs for clinical trials, develop...
Aims:
To examine the incidence of amputation in patients with type 2 diabetes mellitus (T2DM) treated with sodium glucose co-transporter 2 inhibitors (SGLT2i) overall, and canagliflozin specifically, compared with non-SGLT2i antihyperglycemic agents (AHAs).
Materials and methods:
Patients with T2DM newly exposed to SGLT2i or non-SGLT2i AHAs were...
Publications of hypertension-related meta-analyses (MAs) have increased exponentially in the past 25 years and now average 8/month. Theoretically, this is facilitating evidence-based management of patients. However, some practitioners and authors of guidelines have questioned the quality of published MAs. By extending a prior review, we have assess...
Introduction:
Over-the-counter analgesics such as paracetamol and ibuprofen are among the most widely used, and having a good understanding of their safety profile is important to public health. Prior observational studies estimating the risks associated with paracetamol use acknowledge the inherent limitations of these studies. One threat to the...
Background
A key step in the design of a randomised controlled trial (RCT) is the estimation of the number of participants needed. By far the most common approach is to specify a target difference and then estimate the corresponding sample size; this sample size is chosen to provide reassurance that the trial will have high statistical power to det...
Aims:
To estimate and compare incidence of diabetes ketoacidosis (DKA) among patients with type 2 diabetes who are newly treated with SGLT2 inhibitors (SGLT2i) versus non-SGLT2i antihyperglycemic agents (AHAs) in actual clinical practice.
Methods:
A new-user cohort study design using a large insurance claims database in the US. DKA incidence was...
Background
Data abstraction, a critical systematic review step, is time-consuming and prone to errors. Current standards for approaches to data abstraction rest on a weak evidence base. We developed the Data Abstraction Assistant (DAA), a novel software application designed to facilitate the abstraction process by allowing users to (1) view study a...
BACKGROUND: Use of antipsychotics to treat behavioural symptoms of dementia has been associated with increased risks of mortality and stroke. Little is known about individual patient characteristics that might be associated with bad or good outcomes. AIMS: We examined the risperidone clinical trial data to look for individual patient characteristic...
Medical Publishing Insights & Practices (MPIP)-A partnership among pharmaceutical companies and the International Society for Medical Publication Professionals-aims to identify ways to improve transparency and credibility in publishing the results of industry sponsored research. This article provides guidance from MPIP on clinically relevant and mo...
Objectives:
Doubling on average every 6 years, hypertension-related meta-analyses are now published twice weekly and are often considered the highest level of evidence for clinical practice. However, some hypertension specialists and guideline authors view meta-analyses with skepticism. This article evaluates the quality of hypertension-related me...
A key challenge in Benefit-Risk (B-R) assessment of a medication is the multitude of data sources and the changing quality and relevance of these sources during the medication lifecycle. At the time of regulatory approval, B-R assessment is largely based on data from controlled clinical trials and preclinical studies. Following approval, data infor...
Background:
Use of antipsychotics to treat behavioural symptoms of dementia has been associated with increased risks of mortality and stroke. Little is known about individual patient characteristics that might be associated with bad or good outcomes.
Aims:
We examined the risperidone clinical trial data to look for individual patient characteris...
Background:
Standard recommendations for oral hygiene practices have focused on mechanical methods (toothbrushing and interdental cleaning). Published evidence indicates antimicrobial mouthrinses provide oral health benefits beyond mechanical methods alone. The purpose of this meta-analysis was to evaluate the combined effectiveness of mechanical...
Accurate representation of study findings is crucial to preserve public trust. The language used to describe results could affect perceptions of the efficacy or safety of interventions. We sought to compare the adjectives used in clinical trial reports of industry-authored and non-industry-authored research.
We included studies in PubMed that were...
Premature discontinuation and other forms of noncompliance with treatment assignment can complicate causal inference of treatment effects in randomized trials. The intent-to-treat analysis gives unbiased estimates for causal effects of treatment assignment on outcome, but may understate potential benefit or harm of actual treatment. The correspondi...
The CONSORT statement is used worldwide to improve the reporting of randomised controlled trials. Kenneth Schulz and colleagues describe the latest version, CONSORT 2010, which updates the reporting guideline based on new methodological evidence and accumulating experience Introduction Randomised controlled trials, when appropriately designed, cond...
Heterogeneity (variation in true effect sizes and in factors that might influence those effect sizes) is inherent in meta-analysis, not a problem to be solved. It includes clinical components (eg, diversity in patient populations or interventions) and statistical components (eg, random differences). There are statistical approaches to try to quanti...
Randomized controlled trials can provide estimates of how a treatment affects the risk of adverse events free from the biases inherent in observational studies. The focus of this chapter is on evaluation of adverse events in clinical trials during development, and stems from the premise that if potential harms are identified early in the drug devel...
Purpose
Venous thromboembolism is a common complication after major orthopedic surgery. When prescribing anticoagulant prophylaxis, clinicians weigh the benefits of thromboprophylaxis against bleeding risk and other adverse events. Previous benefit–risk analyses of the REgulation of Coagulation in ORthopaedic surgery to prevent Deep vein thrombosis...
Sharing data from clinical trials could assist with the advancement of science and medicine, potentially providing a better understanding of both the benefits and risks of medicines and other treatments. Sharing data also allows for questions to be addressed at the meta-analysis level that cannot be addressed within individual studies.
In this arti...
Threats to the validity of observational studies on the effects of interventions raise questions about the appropriate role of such studies in decision making. Nonetheless, scholarly journals in fields such as medicine, education, and the social sciences feature many such studies, often with limited exploration of these threats, and the lay press i...
Systematic reviews should build on a protocol that describes the rationale, hypothesis, and planned methods of the review; few reviews report whether a protocol exists. Detailed, well-described protocols can facilitate the understanding and appraisal of the review methods, as well as the detection of modifications to methods and selective reporting...
Back pain outcomes may be improved and costs lowered through risk-stratified care, but relative performance of alternative item sets for predicting back pain outcomes has not been well characterized. We compared alternative prognostic item sets based on STarT Back and Chronic Pain Risk screeners in a cohort of patients initiating primary care for b...
Critics of systematic reviews have argued that these studies often fail to inform clinical decision making because their results are far too general, that the data are sparse, such that findings cannot be applied to individual patients or for other decision making. While there is some consensus on methods for investigating statistical and methodolo...
Clinical studies that use observational databases to evaluate the effects of medical products have become commonplace. Such studies begin by selecting a particular database, a decision that published papers invariably report but do not discuss. Studies of the same issue in different databases, however, can and do generate different results, sometim...
Background:
In acute coronary syndrome (ACS), antithrombotic therapies prevent thrombotic events, but also increase bleeding risk. Knowledge is limited about how patients and physicians balance these benefits and risks.
Objective:
To quantify US patient and physician preferences for outcomes associated with antithrombotic therapies in ACS.
Meth...
An accurate means of identifying patients at high risk for chronic disabling pain could lead to more cost-effective care, with more intensive interventions targeted to those likely to benefit most. The Chronic Pain Risk Score is a tool developed to predict risk for chronic pain. The aim of this study was to examine whether its predictive ability co...
A post hoc analysis of the risperidone (RIS)/paliperidone (Pali) clinical trials database comprising 64 studies was conducted. Risk of sudden death, cardiovascular (CV), and cerebrovascular events during RIS or Pali treatment was estimated. Treatment emergent CV adverse events were identified using 7 prespecified Standardised MedDRA Queries as foll...
The ClinicalTrials.gov web site provides a convenient interface to look up study results, but it does not allow downloading data in a format that can be readily used for quantitative analyses.
To develop a system that automatically downloads study results from ClinicalTrials.gov and provides an interface to retrieve study results in a spreadsheet f...
Unlabelled:
ClinicalTrials.gov is a registry and results database of federally and privately supported clinical trials conducted worldwide. We sought to answer: what are the characteristics of pain trials; how frequently are these trials stopped and why; what is the magnitude of attrition due to lack of efficacy or adverse events; and whether the...
High quality protocols facilitate proper conduct, reporting, and external review of clinical trials. However, the completeness of trial protocols is often inadequate. To help improve the content and quality of protocols, an international group of stakeholders developed the SPIRIT 2013 Statement (Standard Protocol Items: Recommendations for Interven...
The protocol of a clinical trial serves as the foundation for study planning, conduct, reporting, and appraisal. However, trial protocols and existing protocol guidelines vary greatly in content and quality. This article describes the systematic development and scope of SPIRIT (Standard Protocol Items:Recommendations for Interventional Trials) 2013...
Background:
Meta-analyses of clinical trial safety data have risen in importance beyond regulatory submissions. During drug development, sponsors need to recognize safety signals early and adjust the development program accordingly, so as to facilitate the assessment of causality. Once a product is marketed, sponsors add postapproval clinical tria...
Aim:
This was a retrospective cohort study of type 2 diabetes patients, to evaluate the association between initial metformin or sulphonylurea treatment and cancer incidence.
Methods:
Patients identified in the UK Clinical Practice Research Datalink (CPRD), previously General Practice Research Database, during 1995-2008 who were initially stabil...
Little is known about the prevalence of opioid shoppers in clinical practices and the relation between prescriber characteristics and the risk of having opioid shoppers.
Describe the prevalence of opioid shoppers in prescribers' practices. Assess the relation between prescribers' characteristics and patient opioid shopping behavior.
Retrospective c...
To compare placebo responses in neuropathic pain syndromes.
Systematic literature review and meta-analysis.
Randomized placebo-controlled trials assessing pain intensity or pain relief in any neuropathic pain syndrome published since 1995 with ≥5days follow-up.
Placebo response.
Pain intensity and responder rates (proportion reporting ≥50% pain rel...
Meta-analysis can be regarded as a "state-of-the-art" literature review, employing statistical methods to combine data in conjunction with a thorough and systematic qualitative review. There are a number of reasons why a pharmacoepidemiologist might be interested in conducting a meta-analysis. These include the study of uncommon adverse (or favorab...
The purpose of comparative effectiveness research (CER) is to assist consumers, clinicians, purchasers, and policy makers to make informed decisions that will improve health care at both the individual and population levels. There is an ongoing discussion as to what types of evidence are appropriate to inform CER and how best to interpret various f...
Registration of randomized clinical trials has become standard practice and is enforced through publication policies and governmental regulations. However, the registration of observational studies remains controversial. In this commentary, we propose that a compromise can be reached on which observation should be registered based on study design a...
To evaluate whether selective serotonin re-uptake inhibitor (SSRI) exposure influences the risk of myocardial infarction (MI) in patients with depression.
This study included 693 patients with MI (cases) and 2772 controls. Conditional logistic regression was used to calculate the odds ratio (OR).
SSRI exposure may be associated with a reduced MI ri...
N-of-1 clinical trials have the potential to contribute to individual patient management and to the accrual of important information about populations. Incorporating these studies into clinical practice will require creative thinking so as to maintain rigor without excessive disruption of routine care.
Pain intensity is commonly reported using a 0-10 Numeric Rating Scale in pain clinical trials. Analysis of the change on the Pain Intensity Numerical Rating Scale as a proportion has most consistently correlated with clinically important differences reported on the patient's global impression of change. The correlation of data from patients with br...
Cancer patients often develop the potentially debilitating condition of anaemia. Numerous controlled studies indicate that erythropoiesis-stimulating agents (ESAs) can raise haemoglobin levels and reduce transfusion requirements in anaemic cancer patients receiving chemotherapy. To evaluate recent safety concerns regarding ESAs, we carried out a me...
Electronic health databases have become extremely valuable resources for pharmaco-epidemiological and translational research, as noted in the recent Perspective article, Beyond debacle and debate: developing solutions in drug safety (Nature Rev. Drug Discov. 8, 775–779; 2009
ABSTRACT : Population stratification (PS) represents a major challenge in genome-wide association studies. Using the Genetic Analysis Workshop 16 Problem 1 data, which include samples of rheumatoid arthritis patients and healthy controls, we compared two methods that can be used to evaluate population structure and correct PS in genome-wide associa...
We used data reduction and clustering methods to identify five phenotypically homogeneous groups of study participants with similar profiles for cardiovascular disease risk factors. We constructed both qualitative (binary subgroup membership) and quantitative traits (probability of subgroup membership) for each individual. The Cluster 1 comprised i...