Systematic review and meta-analysis

Publication bias in clinical research

Background
People who are prescribed self-administered medications typically take less than half the prescribed doses. Efforts to assist patients with adherence to medications might improve the benefits of prescribed medications, but also might increase their adverse effects.

Objectives
To update a review summarizing the results of randomized controlled trials (RCTs) of interventions to help patients follow prescriptions for medications for medical problems, including mental disorders but not addictions.

Search methods
We updated searches of The Cochrane Library, MEDLINE, CINAHL, EMBASE, International Pharmaceutical Abstracts (IPA), PsycINFO (all via OVID) and Sociological Abstracts (via CSA) in January 2007 with no language restriction. We also reviewed bibliographies in articles on patient adherence and articles in our personal collections, and contacted authors of relevant original and review articles.

Selection criteria
Articles were selected if they reported an unconfounded RCT of an intervention to improve adherence with prescribed medications, measuring both medication adherence and treatment outcome, with at least 80% follow-up of each group studied and, for long-term treatments, at least six months follow-up for studies with positive initial findings.

Data collection and analysis
Study design features, interventions and controls, and results were extracted by one review author and confirmed by at least one other review author. We extracted adherence rates and their measures of variance for all methods of measuring adherence in each study, and all outcome rates and their measures of variance for each study group, as well as levels of statistical significance for differences between study groups, consulting authors and verifying or correcting analyses as needed. The studies differed widely according to medical condition, patient population, intervention, measures of adherence, and clinical outcomes. Therefore, we did not feel that quantitative analysis was scientifically justified; rather, we conducted a qualitative analysis.

Main results
For short-term treatments, four of ten interventions reported in nine RCTs showed an effect on both adherence and at least one clinical outcome, while one intervention reported in one RCT significantly improved patient adherence, but did not enhance the clinical outcome. For long-term treatments, 36 of 83 interventions reported in 70 RCTs were associated with improvements in adherence, but only 25 interventions led to improvement in at least one treatment outcome. Almost all of the interventions that were effective for long-term care were complex, including combinations of more convenient care, information, reminders, self-monitoring, reinforcement, counseling, family therapy, psychological therapy, crisis intervention, manual telephone follow-up, and supportive care. Even the most effective interventions did not lead to large improvements in adherence and treatment outcomes.

Authors' conclusions
For short-term treatments several quite simple interventions increased adherence and improved patient outcomes, but the effects were inconsistent from study to study with less than half of studies showing benefits. Current methods of improving adherence for chronic health problems are mostly complex and not very effective, so that the full benefits of treatment cannot be realized. High priority should be given to fundamental and applied research concerning innovations to assist patients to follow medication prescriptions for long-term medical disorders.

Interventions for enhancing medication adherence.

Quality health care rests fundamentally on the achievements of biomedical research. All health outcomes are improved by sound science: health status can be turned around by transplantation when someone's life is in jeopardy due to a diseased organ; social functioning can be improved by shock wave lithotripsy that -leads to faster recovery; and satisfaction can beenhanced when children with moderate or severe asthma receive appropriate anti-inflammatory treatment. To improve the quality of health care that patients actually receive, both biomedical research production and especially its introduction into clinical practice need to be examined.

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Managing Clinical Knowledge for Health Care Improvement

These parameters were developed by the Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma & Immunology; the American College of Allergy, Asthma and Immunology; and the Joint Council of Allergy, Asthma and Immunology. The American Academy of Allergy, Asthma & Immunology (AAAAI) and the American College of Allergy, Asthma and Immunology (ACAAI) have jointly accepted responsibility for establishing "The diagnosis and Management of Rhinitis: An Updated Practice Parameter." This is a complete and comprehensive document at the current time. The medical environment is a changing environment, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single individual, including those who served on the Joint Task Force, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or ACAAI should be directed to the Executive Offices of the AAAAI, the ACAAI, and the Joint Council of Allergy, Asthma and Immunology. These parameters are not designed for use by pharmaceutical companies in drug promotion.

The diagnosis and management of rhinitis: An updated practice parameter

Background. Cyclosporine (CsA) therapy must often be continued during pregnancy to maintain maternal health in such conditions as organ transplantation and autoimmune disease. This meta-analysis was performed to determine whether CsA exposure during pregnancy is associated with an increased risk of congenital malformations, preterm delivery, or low birthweight. Methods. Various health science databases were searched to identify relevant articles. Articles selected for inclusion in the study were required to be free of any apparent selection bias and report outcomes in at least 10 newborns exposed to CsA in utero, specifically commenting on the presence or absence of congenital malformations. Article selection and data extraction were performed by two independent reviewers, with adjudication in cases of disagreement. To assess risks of CsA exposure, a summary odds ratio was calculated. Prevalence of malformations was calculated as a rate for all cyclosporine-exposed live births and for the subgroups identified. Ninety-five percent confidence intervals were constructed for both the odds ratio and prevalence rates. Results. Fifteen studies (6 with control groups of transplant without use of cyclosporine; total patients: 410) met the inclusion criteria for major malformations, 10 for preterm delivery (4 with control groups; total patients: 379) and 5 for low birth weight (1 with control groups; total number of patients: 314). The calculated odds ratio of 3.83 for malformations did not achieve statistical significance (CI 0.75‐19.6). The overall prevalence of major malformations in the study population (4.1%) also did not vary substantially from that reported in the general population. OR for prematurity [1.52 (CI 1.00 ‐2.32)] did not reach statistical significance although the overall prevalence rate was 56.3%. The OR for low birth weight [1.5 (CI 0.95‐ 2.44 based on 1 study)]. Conclusions. CsA does not appear to be a major human teratogen. It may be associated with increased rates of prematurity. More research is needed to evaluate whether cyclosporine increases teratogenic risk.

Pregnancy outcome after cyclosporine therapy during pregnancy: a meta-analysis.

Active and passive smoking have been associated with an array of adverse effects on health. The development of valid and accurate scales of measurement for exposures associated with health risks constitutes an active area of research. Tobacco smoke exposure still lacks an ideal method of measurement. A valid estimation of the risks associated with tobacco exposure depends on accurate measurement. However, some groups of people are more reluctant than others to disclose their smoking status and exposure to tobacco. This is particularly true for pregnant women and parents of young children, whose smoking is often regarded as socially unacceptable. For others, recall of tobacco exposure may also prove difficult. Because relying on self-report and the various biases it introduces may lead to inaccurate measures of nicotine exposure, more objective solutions have been suggested. Biomarkers constitute the most commonly used objective method of ascertaining nicotine exposure. Of those available, cotinine has gained supremacy as the biomarker of choice. Traditionally, cotinine has been measured in blood, saliva, and urine. Cotinine collection and analysis from these sources has posed some difficulties, which have motivated the search for a more consistent and reliable source of this biomarker. Hair analysis is a novel, noninvasive technique used to detect the presence of drugs and metabolites in the hair shaft. Because cotinine accumulates in hair during hair growth, it is a unique measure of long-term, cumulative exposure to tobacco smoke. Although hair analysis of cotinine holds great promise, a detailed evaluation of its potential as a biomarker of nicotine exposure, is needed. No studies have been published that address this issue. Because the levels of cotinine in the body are dependent on nicotine metabolism, which in turn is affected by factors such as age and pregnancy, the characterization of hair cotinine should be population specific. This review aims at defining the sensitivity, specificity, and clinical utilization of different methods used to estimate exposure to cigarette smoking and environmental tobacco smoke.

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Methods for quantification of exposure to cigarette smoking and environmental tobacco smoke: focus on developmental toxicology.

Prospective multicentre study of pregnancy outcome after lithium exposure during first trimester.

To determine the relative risk for major malformations associated with antihistamine (H1 blockers) exposure in the first trimester of pregnancy, a literature search of all studies examining the association between antihistamines and major malformations for the period 1960 to 1991 was conducted, followed by meta-analysis. Odds ratio was calculated using the Mantel-Haenszel method. Twenty-four controlled studies met the inclusion criteria with more than 200,000 participating women. The summary odds ratio of major malformations associated with antihistamines taken during the first trimester was 0.76 (95% CI: 0.60-0.94). This analysis indicates that H1 blockers used mainly for morning sickness during the first trimester do not increase the teratogenic risk in humans and may, in fact, be associated with a protective effect. More study is needed to verify the possibility that by preventing vomiting, antihistamines may ensure better metabolic conditions to the fetus and thus may reduce some birth defects. Alternatively, it is possible that pregnancies characterized by vomiting are associated with better outcome due to other reasons, such as hormonal status or placental function. Women suffering from morning sickness which is not controlled by nonpharmacological methods can safely use antihistamines.

Pregnancy Outcome Following First Trimester Exposure to Antihistamines: Meta-Analysis

Background: The World Health Organization predicts that by 2012, depression will be the number one disease in the world. Thus, many women who become pregnant will require treatment with antidepressants. We are aware that women and their health care providers remain hesitant to prescribe and take these drugs during pregnancy, despite evidence of the relative safety.

Tom Einarson

Papers

Pregnancy outcome after cyclosporine therapy during pregnancy: a meta-analysis.

Methods for quantification of exposure to cigarette smoking and environmental tobacco smoke: focus on developmental toxicology.

Prospective multicentre study of pregnancy outcome after lithium exposure during first trimester.

Pregnancy Outcome Following First Trimester Exposure to Antihistamines: Meta-Analysis

Use of antidepressants by pregnant women: evaluation of perception of risk, efficacy of evidence based counseling and determinants of decision making.