Confounding by Indication in Epidemiologic Studies of Commonly Used Analgesics

Confounding by indication is a bias frequently encountered in observational epidemiologic studies of drug effects. Because the allocation of treatment in observational studies is not randomized and the indication for treatment may be related to the risk of future health outcomes, the resulting imbalance in the underlying risk profile between treated and comparison groups can generate biased results. Confounding by indication is often present in studies of drugs that are not widely prescribed, because the indications for their use are narrow and not likely to be present in comparison groups; however, this bias is also observed in the study of widely used over-the-counter and prescription drugs, as exemplified by studies of analgesics. In this article we review examples from the published literature to demonstrate how confounding by indication can affect the findings of pharmacoepidemiologic studies relating analgesic use to various health outcomes.

[1]  W. J. Johnson,et al.  Conservative management of chronic renal failure. , 1966, The Medical clinics of North America.

[2]  Alasdair Breckenridge,et al.  Meyler's Side Effects of Drugs , 1976 .

[3]  H. Jick Effects of aspirin and acetaminophen in gastrointestinal hemorrhage. Results from the Boston Collaborative Drug Surveillance Program. , 1981, Archives of internal medicine.

[4]  E. Sito,et al.  Distribution of prostaglandins in gastric and duodenal mucosa of healthy subjects and duodenal ulcer patients: effects of aspirin and paracetamol. , 1981, Gut.

[5]  K. Ivey Gastrointestinal effects of antipyretic analgesics. , 1983, The American journal of medicine.

[6]  J. Hinson Reactive metabolites of phenacetin and acetaminophen: a review , 1983, Environmental health perspectives.

[7]  D. Spiegelhalter,et al.  Analgesic intake and the risk of acute upper gastrointestinal bleeding. , 1983, The American journal of medicine.

[8]  R. Hicks Effect of promoters on incidence of bladder cancer in experimental animal models. , 1983, Environmental health perspectives.

[9]  V. Siskind The need for randomization in the study of intended effects. , 1985, Statistics in medicine.

[10]  Stephen B. Gruber,et al.  Clinical Epidemiology: The Architecture of Clinical Research , 1986, The Yale Journal of Biology and Medicine.

[11]  S. Shapiro,et al.  Major upper gastrointestinal tract bleeding. Relation to the use of aspirin and other nonnarcotic analgesics. , 1988, Archives of internal medicine.

[12]  D. Piper,et al.  Smoking, nonsteroidal anti-inflammatory drugs, and acetaminophen in gastric ulcer. A study of associations and of the effects of previous diagnosis on exposure patterns. , 1988, American journal of epidemiology.

[13]  R. Doll,et al.  An overview of the British and American aspirin studies. , 1988, The New England journal of medicine.

[14]  Final report on the aspirin component of the ongoing Physicians' Health Study. , 1989, The New England journal of medicine.

[15]  R. Collins,et al.  Aspirin and other antiplatelet agents in the secondary and primary prevention of cardiovascular disease. , 1989, Circulation.

[16]  D. Elliott Preventing Upper Gastrointestinal Bleeding in Patients Receiving Nonsteroidal Antiinflammatory Drugs , 1990, DICP : the annals of pharmacotherapy.

[17]  Alfred O. Berg,et al.  Clinical Guidelines And Primary Care Guidelines For The Diagnosis And Management Of Asthma , 2012 .

[18]  The implication of analgesics in human kidney disease , 1993 .

[19]  Walker,et al.  Collaborative overview of randomised trials of antiplatelet therapy Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients , 1994 .

[20]  T V Perneger,et al.  Risk of kidney failure associated with the use of acetaminophen, aspirin, and nonsteroidal antiinflammatory drugs. , 1994, The New England journal of medicine.

[21]  M. Stampfer,et al.  Observational studies of drug safety , 1996, The Lancet.

[22]  Analgesics and chronic renal disease. , 1996, Current opinion in nephrology and hypertension.

[23]  B. Barrett Acetaminophen and adverse chronic renal outcomes: an appraisal of the epidemiologic evidence. , 1996, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[24]  S Shapiro,et al.  Confounding by indication? , 1997, Epidemiology.

[25]  M Maclure,et al.  Case–crossover and case–time–control designs as alternatives in pharmacoepidemiologic research , 1997, Pharmacoepidemiology and drug safety.

[26]  S. Shapiro,et al.  A Review of Epidemiologic Studies of Nonnarcotic Analgesics and Chronic Renal Disease , 1998, Medicine.

[27]  J. McCray,et al.  Clinical Endoscopic Evaluation of the Gastroduodenal Tolerance to (R)‐ Ketoprofen, (R)‐ Flurbiprofen, Racemic Ketoprofen, and Paracetamol: A Randomized, Single‐Blind, Placebo‐Controlled Trial , 1998, Journal of clinical pharmacology.

[28]  W. Chow,et al.  Analgesic use and chronic renal failure: a critical review of the epidemiologic literature. , 1998, Kidney international.

[29]  B. Stricker,et al.  Confounding by indication: an example of variation in the use of epidemiologic terminology. , 1999, American journal of epidemiology.

[30]  W. Blot,et al.  Over the counter non-steroidal anti-inflammatory drugs and risk of gastrointestinal bleeding. , 2000, Journal of epidemiology and biostatistics.

[31]  Blot Wj,et al.  Over the counter non-steroidal anti-inflammatory drugs and risk of gastrointestinal bleeding. , 2000 .

[32]  J. Sterne,et al.  Frequent paracetamol use and asthma in adults , 2000, Thorax.

[33]  J. Manson,et al.  Self-selected posttrial aspirin use and subsequent cardiovascular disease and mortality in the physicians' health study. , 2000, Archives of internal medicine.

[34]  A. Feinstein,et al.  Relationship between nonphenacetin combined analgesics and nephropathy: a review. Ad Hoc Committee of the International Study Group on Analgesics and Nephropathy. , 2000, Kidney international.

[35]  P. Burney,et al.  Paracetamol sales and atopic disease in children and adults: an ecological analysis. , 2000, The European respiratory journal.

[36]  P. Donnan,et al.  The multiple propensity score for analysis of dose–response relationships in drug safety studies , 2001, Pharmacoepidemiology and drug safety.

[37]  P. Donnan,et al.  Propensity score methods in drug safety studies: practice, strengths and limitations , 2001, Pharmacoepidemiology and drug safety.

[38]  L. Signorello,et al.  Acetaminophen, aspirin, and chronic renal failure. , 2001, The New England journal of medicine.

[39]  L. Crofford Rational use of analgesic and antiinflammatory drugs. , 2001, The New England journal of medicine.

[40]  S. Gabriel,et al.  Adverse gastrointestinal effects of NSAIDs: consequences and costs. , 2001, Best practice & research. Clinical gastroenterology.

[41]  S. Hernández-Díaz,et al.  Relative Risk of Upper Gastrointestinal Complications among Users of Acetaminophen and Nonsteroidal Anti-Inflammatory Drugs , 2001, Epidemiology.

[42]  Catherine Sudlow,et al.  Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients , 2002, BMJ : British Medical Journal.

[43]  J. Olsen,et al.  A population-based cohort study of mortality among adults prescribed paracetamol in Denmark. , 2003, Journal of clinical epidemiology.

[44]  A. M. Walker,et al.  Observation and inference. An introduction to the methods of epidemiology , 1991, Cancer Causes & Control.