Amy Padula

Brief Communication: Better Ways To Question Patients about Adverse Medical Events: A Randomized, Controlled Trial

Context Investigators use diverse methods to assess the adverse events experienced by study participants. Contribution During a 1-month placebo run-in period of a clinical trial, this single-blind substudy randomly assigned 214 men with benign prostatic hyperplasia to 3 groups to test different methods of asking about recent medical problems. Men who completed a checklist about 53 common side effects reported many more problems than participants in the 2 groups that were given different formats of open-ended questions. For example, 77% of the checklist group reported 1 or more medical problems, compared with 13% and 14% of the open-ended groups. Implications Varying the assessment method can cause large differences in reported rates of adverse events. The Editors Currently, there is no standard method for identifying adverse events that occur during a clinical trial. Although regulatory agencies (such as the U.S. Food and Drug Administration) require that studies of new drugs report adverse events in a standard way, they do not specify a standard method for ascertaining these data (1). Consequently, how individual studies identify adverse events varies considerably. For example, early studies of nonsteroidal anti-inflammatory druginduced gastric ulcers reported much lower frequencies of ulcers than more recent studies, mostly because researchers have recently made greater efforts to detect this side effect (2). The implications of this lack of consistent ascertainment methods are substantial; comparisons of rates of reported side effects from 2 or more drugs may not be valid if the methods of collecting adverse events differ. This could impair the ability of patients and physicians to compare the riskbenefit profile of drugs. We therefore conducted a randomized, controlled trial to determine whether different methods of identifying adverse events in a clinical trial would lead to different estimates of the frequency of these events. Methods Study Design The study protocol and all procedures were approved by the Committee on Human Research at the University of California, San Francisco. The study, which took place between April 2002 and April 2005, was a randomized, single-blind, controlled trial that assigned patients to 3 groups to test self-administered methods of assessing medical problems that they experienced while taking a placebo for 1 month. Participants We recruited participants from a larger study that was examining the safety and efficacy of the herb saw palmetto for treatment of benign prostatic hyperplasia (3). The trial, known as the STEP (Saw Palmetto Treatment for Enlarged Prostates) study, required that participants be 50 years of age or older, have moderate to severe symptoms of benign prostatic hyperplasia, and have no serious comorbid illness. All participants in the study gave informed consent; were told that they would be taking placebo at some point during the study; and were assigned to a single-blind, 1-month placebo run-in period. Randomization and Intervention After taking the placebo (referred to as the study medication) for 1 month, patients were randomly assigned to 3 methods of collecting adverse events. All patients were given 1 of 3 self-administered paper forms. The form given to the first group asked an open-ended question: Did you have any significant medical problem since the last study visit? The form given to the second group asked an open-ended question that was more defined: Since the last study visit, have you limited your usual daily activities for more than 1 day because of a medical problem? A checklist accompanied the form given to the third group, which asked a more pointed question: Since the last visit, have you experienced any of the following (checklist attached)? The checklist contained 53 symptoms, grouped by anatomical region. Two of the authors developed the checklist after conducting an unpublished review of checklists that were used in earlier clinical trials performed at the same institution. The checklist did not ask patients to rate the frequency or severity of symptoms and did not ask patients to make a judgment about whether their medical problem was caused by the study medication. Patients in the open-ended question groups who answered yes were asked to identify their medical problem, which was recorded by a study assistant on the same checklist used in the third group. Outcomes and Analysis The primary outcome measure was the difference in the proportion of patients reporting 1 or more adverse events in each group. All patients in the STEP study were included in the current study; therefore, the sample size was not calculated on the basis of the needs of this study. Participants were randomly assigned to the 3 groups in equal proportions by using a computer-generated, random allocation sequence that was prepared before the study began. Study personnel were blinded to the allocation sequence but were aware of group assignments after they were made. Patients were not informed of their group assignment. Persons performing the data analysis were blinded to group assignment. Baseline characteristics of the 3 intervention groups were compared by using analysis of variance for continuous variables and chi-square tests for categorical variables. We also used chi-square tests to compare the number and specific type of adverse events that occurred among groups. All analyses were performed by using Stata, version 8.0 (Stata Corp., College Station, Texas). Role of the Funding Sources The funding organizations had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript. Results We randomly assigned 214 patients to 1 of 3 methods of collecting data on adverse effects. Patients were predominantly healthy, well-educated white men (mean age, 63 years) who were taking a mean of 2.5 medications (Table 1). Baseline characteristics of the patients were similar among the 3 groups. All patients completed the study and the outcome assessment (Figure). Table 1. Baseline Characteristics of Study Participants Figure. Flow diagram showing the distribution of participants at each stage of the study. The group that was assigned to a checklist method reported a significantly greater number of adverse events (238 events) than the first and second groups, which were asked open-ended questions (11 and 14 adverse events, respectively; P< 0.001) (Table 2). A much higher percentage of patients in the checklist group reported 1 or more adverse events (77%) compared with the patients asked each of the 2 different open-ended questions (14% for the first group and 13% for the second group; P< 0.001). For each of the 10 most commonly reported adverse events (Table 2), participants in the checklist group reported a greater number of adverse events (P< 0.001). No serious adverse events occurred during the study period. Table 2. 10 Most Frequently Reported Adverse Events Discussion In this randomized, controlled trial, we found that a checklist method of identifying adverse events dramatically increased the number of reported events compared with 2 types of open-ended questions. Although this finding is intuitive, the magnitude of effect has important implications both for the conduct of clinical trials and for assessment of the riskbenefit profile of drugs and other interventions. It is common practice for physicians and patients to select drugs and other interventions on the basis of their reported rate of side effects. However, if different drugs used for the same indication are examined in clinical trials that use different methods of identifying adverse events, then it is not valid to compare the reported rate of side effects. For example, the reported rates of sexual side effects from selective serotonin reuptake inhibitors range from 2% to 73%; much of this difference is probably attributable to different methods of adverse event collection (4). Similarly, a recent systematic review found that published trials of pharmacologic treatments for rheumatoid arthritis were much more likely to report data on harm than trials of nonpharmacologic treatment (5), highlighting the difficulty of comparing the safety of different treatments for the same condition. The 3 self-administered questions that we used to assess the frequency of adverse events in this study were, by design, limited in scope. The self-administered forms did not ask patients to describe the timing, severity, or frequency of their medical problems, nor did they ask participants or investigators to make a judgment of causality. Other techniques to assess adverse events, such as changes in vital signs, laboratory tests, physical examinations, or more detailed searches for expected adverse events, were not included. The purpose of this simplified approach was to isolate and contrast 3 different initial screening methods of identifying medical problems occurring among participants in a clinical trial. Because all patients in the current study were taking placebo, probably none of the reported adverse events were true side effects of the study medication but were merely symptoms that commonly occur in adults. For example, a previous survey of university students and hospital staff found that 81% of respondents reported some symptom within the past 3 days when prompted by a checklist (6). This highlights the problem that most study participants are likely to have a high prevalence of symptoms that are unrelated to a study drug or intervention, and a checklist method is therefore likely to have very low specificity for detecting true side effects. The wording of the 3 self-administered questions that we used in this study asked about 3 different thresholds of medical problems. One question asked participants if they experienced a significant medical problem, one asked if they limited their usual daily activities fo

Spontaneous bleeding associated with ginkgo biloba: a case report and systematic review of the literature: a case report and systematic review of the literature.

AbstractBACKGROUND:Ginkgo biloba (ginkgo) is a herbal remedy used by over 2% of the adult population in the United States. Several review articles have suggested that ginkgo may increase the risk of bleeding. OBJECTIVE: To report a case of bleeding associated with using ginkgo, to systematically review the literature for similar case reports, and to evaluate whether using ginkgo is causally related to bleeding. DATA SOURCES: We searched MEDLINE, EMBASE, IBIDS, and the Cochrane Collaboration Database from 1966 to October 2004 with no language restrictions. REVIEW METHODS: Published case reports of bleeding events in persons using ginkgo were selected. Two reviewers independently abstracted a standard set of information to assess whether ginkgo caused the bleeding event. RESULTS: Fifteen published case reports described a temporal association between using ginkgo and a bleeding event. Most cases involved serious medical conditions, including 8 episodes of intracranial bleeding. However, 13 of the case reports identified other risk factors for bleeding. Only 6 reports clearly described that ginkgo was stopped and that bleeding did not recur. Bleeding times, measured in 3 reports, were elevated when patients were taking ginkgo. CONCLUSION: A structured assessment of published case reports suggests a possible causal association between using ginkgo and bleeding events. Given the widespread use of this herb and the serious nature of the reported events, further studies are needed. Patients using ginkgo, particularly those with known bleeding risks, should be counseled about a possible increase in bleeding risk.

Spontaneous bleeding associated with Ginkgo biloba

AbstractBACKGROUND:Ginkgo biloba (ginkgo) is a herbal remedy used by over 2% of the adult population in the United States. Several review articles have suggested that ginkgo may increase the risk of bleeding. OBJECTIVE: To report a case of bleeding associated with using ginkgo, to systematically review the literature for similar case reports, and to evaluate whether using ginkgo is causally related to bleeding. DATA SOURCES: We searched MEDLINE, EMBASE, IBIDS, and the Cochrane Collaboration Database from 1966 to October 2004 with no language restrictions. REVIEW METHODS: Published case reports of bleeding events in persons using ginkgo were selected. Two reviewers independently abstracted a standard set of information to assess whether ginkgo caused the bleeding event. RESULTS: Fifteen published case reports described a temporal association between using ginkgo and a bleeding event. Most cases involved serious medical conditions, including 8 episodes of intracranial bleeding. However, 13 of the case reports identified other risk factors for bleeding. Only 6 reports clearly described that ginkgo was stopped and that bleeding did not recur. Bleeding times, measured in 3 reports, were elevated when patients were taking ginkgo. CONCLUSION: A structured assessment of published case reports suggests a possible causal association between using ginkgo and bleeding events. Given the widespread use of this herb and the serious nature of the reported events, further studies are needed. Patients using ginkgo, particularly those with known bleeding risks, should be counseled about a possible increase in bleeding risk.

The Association of Ambient Air Pollution and Traffic Exposures With Selected Congenital Anomalies in the San Joaquin Valley of California

Congenital anomalies are a leading cause of infant mortality and are important contributors to subsequent morbidity. Studies suggest associations between environmental contaminants and some anomalies, although evidence is limited. We aimed to investigate whether ambient air pollutant and traffic exposures in early gestation contribute to the risk of selected congenital anomalies in the San Joaquin Valley of California, 1997-2006. Seven exposures and 5 outcomes were included for a total of 35 investigated associations. We observed increased odds of neural tube defects when comparing the highest with the lowest quartile of exposure for several pollutants after adjusting for maternal race/ethnicity, education, and multivitamin use. The adjusted odds ratio for neural tube defects among those with the highest carbon monoxide exposure was 1.9 (95% confidence interval: 1.1, 3.2) compared with those with the lowest exposure, and there was a monotonic exposure-response across quartiles. The highest quartile of nitrogen oxide exposure was associated with neural tube defects (adjusted odds ratio = 1.8, 95% confidence interval: 1.1, 2.8). The adjusted odds ratio for the highest quartile of nitrogen dioxide exposure was 1.7 (95% confidence interval: 1.1, 2.7). Ozone was associated with decreased odds of neural tube defects. Our results extend the limited body of evidence regarding air pollution exposure and adverse birth outcomes.

A detailed safety assessment of a saw palmetto extract

BACKGROUND Saw palmetto is commonly used by men for lower-urinary tract symptoms. Despite its widespread use, very little is known about the potential toxicity of this dietary supplement. METHODS The Saw palmetto for Treatment of Enlarged Prostates (STEP) study was a randomized clinical trial performed among 225 men with moderate-to-severe symptoms of benign prostatic hyperplasia, comparing a standardized extract of the saw palmetto berry (160 mg twice daily) with a placebo over a 1-year period. As part of this study, detailed data were collected on serious and non-serious adverse events, sexual functioning, and laboratory tests of blood and urine. Between-group differences were assessed with mixed-effects regression models. RESULTS There were no significant differences observed between the saw palmetto and placebo-allocated participants in the risk of suffering at least one serious adverse event (5.4% vs. 9.7%, respectively; p=0.31) or non-serious symptomatic adverse event (34.8% vs. 30.1%, p=0.48). There were few significant between-group differences in sexual functioning or for most laboratory analyses, with only small differences observed in changes over time in total bilirubin (p=0.001), potassium (p=0.03), and the incidence of glycosuria (0% in the saw palmetto group vs. 3.7% in the placebo group, p=0.05). CONCLUSIONS Despite careful assessment, no evidence for serious toxicity of saw palmetto was observed in this clinical trial. Given the sample size and length of this study, however, these data do not rule out potential rare adverse effects associated with the use of saw palmetto.

Ambient Air Pollution and Traffic Exposures and Congenital Heart Defects in the San Joaquin Valley of California

BACKGROUND Congenital anomalies are a leading cause of infant morbidity and mortality. Studies suggest associations between environmental contaminants and some anomalies, although evidence is limited. METHODS We used data from the California Center of the National Birth Defects Prevention Study and the Childrens Health and Air Pollution Study to estimate the odds of 27 congenital heart defects with respect to quartiles of seven ambient air pollutant and traffic exposures in California during the first 2 months of pregnancy, 1997-2006 (n = 822 cases and n = 849 controls). RESULTS Particulate matter < 10 microns (PM10 ) was associated with pulmonary valve stenosis [adjusted odds ratio (aOR)Fourth Quartile  = 2.6] [95% confidence intervals (CI) 1.2, 5.7] and perimembranous ventricular septal defects (aORThird Quartile  = 2.1) [95% CI 1.1, 3.9] after adjusting for maternal race/ethnicity, education and multivitamin use. PM2.5 was associated with transposition of the great arteries (aORThird Quartile  = 2.6) [95% CI 1.1, 6.5] and inversely associated with perimembranous ventricular septal defects (aORFourth Quartile  = 0.5) [95% CI 0.2, 0.9]. Secundum atrial septal defects were inversely associated with carbon monoxide (aORFourth Quartile  = 0.4) [95% CI 0.2, 0.8] and PM2.5 (aORFourth Quartile  = 0.5) [95% CI 0.3, 0.8]. Traffic density was associated with muscular ventricular septal defects (aORFourth Quartile  = 3.0) [95% CI 1.2, 7.8] and perimembranous ventricular septal defects (aORThird Quartile  = 2.4) [95% CI 1.3, 4.6], and inversely associated with transposition of the great arteries (aORFourth Quartile  = 0.3) [95% CI 0.1, 0.8]. CONCLUSIONS PM10 and traffic density may contribute to the occurrence of pulmonary valve stenosis and ventricular septal defects, respectively. The results were mixed for other pollutants and had little consistency with previous studies.

Residential Agricultural Pesticide Exposures and Risk of Neural Tube Defects and Orofacial Clefts Among Offspring in the San Joaquin Valley of California

We examined whether early gestational exposures to pesticides were associated with an increased risk of anencephaly, spina bifida, cleft lip with or without cleft palate (CLP), or cleft palate only. We used population-based data along with detailed information from maternal interviews. Exposure estimates were based on residential proximity to agricultural pesticide applications during early pregnancy. The study population derived from the San Joaquin Valley, California (1997-2006). Analyses included 73 cases with anencephaly, 123 with spina bifida, 277 with CLP, and 117 with cleft palate only in addition to 785 controls. A total of 38% of the subjects were exposed to 52 chemical groups and 257 specific chemicals. There were relatively few elevated odds ratios with 95% confidence intervals that excluded 1 after adjustment for relevant covariates. Those chemical groups included petroleum derivatives for anencephaly, hydroxybenzonitrile herbicides for spina bifida, and 2,6-dinitroaniline herbicides and dithiocarbamates-methyl isothiocyanate for CLP. The specific chemicals included 2,4-D dimethylamine salt, methomyl, imidacloprid, and α-(para-nonylphenyl)-ω-hydroxypoly(oxyethylene) phosphate ester for anencephaly; the herbicide bromoxynil octanoate for spina bifida; and trifluralin and maneb for CLP. Adjusted odds ratios ranged from 1.6 to 5.1. Given that such odds ratios might have arisen by chance because of the number of comparisons, our study showed a general lack of association between a range of agricultural pesticide exposures and risks of selected birth defects.

Ambient polycyclic aromatic hydrocarbons and pulmonary function in children

Few studies have examined the relationship between ambient polycyclic aromatic hydrocarbons (PAHs) and pulmonary function in children. Major sources include vehicular emissions, home heating, wildland fires, agricultural burning, and power plants. PAHs are an important component of fine particulate matter that has been linked to respiratory health. This cross-sectional study examines the relationship between estimated individual exposures to the sum of PAHs with 4, 5, or 6 rings (PAH456) and pulmonary function tests (forced expiratory volume in one second (FEV1) and forced expiratory flow between 25% and 75% of vital capacity) in asthmatic and non-asthmatic children. We applied land-use regression to estimate individual exposures to ambient PAHs for averaging periods ranging from 1 week to 1 year. We used linear regression to estimate the relationship between exposure to PAH456 with pre- and postbronchodilator pulmonary function tests in children in Fresno, California (N=297). Among non-asthmatics, there was a statistically significant association between PAH456 during the previous 3 months, 6 months, and 1 year and postbronchodilator FEV1. The magnitude of the association increased with the length of the averaging period ranging from 60 to 110 ml decrease in FEV1 for each 1 ng/m3 increase in PAH456. There were no associations with PAH456 observed among asthmatic children. We identified an association between annual PAHs and chronic pulmonary function in children without asthma. Additional studies are needed to further explore the association between exposure to PAHs and pulmonary function, especially with regard to differential effects between asthmatic and non-asthmatic children.

Residential agricultural pesticide exposures and risk of selected congenital heart defects among offspring in the San Joaquin Valley of California

BACKGROUND Pesticide exposures are ubiquitous and of substantial public concern. We examined the potential association of congenital heart defects with residential proximity to commercial agricultural pesticide applications in the San Joaquin Valley, California. METHODS Study subjects included 569 heart defect cases and 785 non-malformed controls born from 1997 to 2006 whose mothers participated in a population-based case-control study. Associations with any versus no exposure to physicochemical groups of pesticides and specific chemicals were assessed using logistic regression adjusted for relevant covariates, for 8 heart defect phenotypes that included ≥ 50 cases and pesticide exposures with ≥ 5 exposed cases and controls, which resulted in 235 comparisons. RESULTS 38% of cases and controls were classified as exposed to pesticides within a 500 m radius of mothers address during a 3-month periconceptional window. Adjusted odds ratios (AORs) with 95% CIs excluding 1.0 were observed for 18 comparisons; all were >1 and ranged from 1.9 to 7.1. They included tetralogy of Fallot (n=101 cases) and neonicotinoids; hypoplastic left heart syndrome (n=59) and strobins; coarctation of the aorta (n=74) and pyridazinones; pulmonary valve stenosis (n=53) and bipyridyliums and organophosphates; ventricular septal defects (n=93) and avermectins and pyrethroids; and atrial septal defects (n=132) and dichlorphenoxy acid or esters, organophosphates, organotins, and pyrethroids. No AORs met both of these criteria for d-transposition of the great arteries (n=58) or heterotaxia (n=53). CONCLUSIONS Most pesticides were not associated with increased risk of specific heart defect phenotypes. For the few that were associated, results should be interpreted with caution until replicated in other study populations.

Exposure to Traffic-related Air Pollution During Pregnancy and Term Low Birth Weight: Estimation of Causal Associations in a Semiparametric Model

Traffic-related air pollution is recognized as an important contributor to health problems. Epidemiologic analyses suggest that prenatal exposure to traffic-related air pollutants may be associated with adverse birth outcomes; however, there is insufficient evidence to conclude that the relation is causal. The Study of Air Pollution, Genetics and Early Life Events comprises all births to women living in 4 counties in Californias San Joaquin Valley during the years 2000-2006. The probability of low birth weight among full-term infants in the population was estimated using machine learning and targeted maximum likelihood estimation for each quartile of traffic exposure during pregnancy. If everyone lived near high-volume freeways (approximated as the fourth quartile of traffic density), the estimated probability of term low birth weight would be 2.27% (95% confidence interval: 2.16, 2.38) as compared with 2.02% (95% confidence interval: 1.90, 2.12) if everyone lived near smaller local roads (first quartile of traffic density). Assessment of potentially causal associations, in the absence of arbitrary model assumptions applied to the data, should result in relatively unbiased estimates. The current results support findings from previous studies that prenatal exposure to traffic-related air pollution may adversely affect birth weight among full-term infants.