Participants' perspectives on safety monitoring in clinical trials.

BACKGROUND: Minimizing the risk to study participants is an essential requirement of ethical research. Respecting the rights of subjects is also paramount, which includes respecting their autonomy by making available important information about the evolving safety profile of an investigational product as the trial progresses. Little is known about what trial participants understand and expect regarding monitoring and communication of serious adverse events during the conduct of a trial in which they have agreed to participate. PURPOSE: To explore understanding and expectations of potential trial participants concerning monitoring and communication of serious adverse events during a clinical trial. METHODS: A professional moderator led four 90-min, in-person focus groups: two groups with individuals who had never participated in a clinical trial and two groups with people who had. After relevant research terms were defined and existing regulations were explained, discussion focused on how participants expected safety to be monitored and communicated during the conduct of a clinical trial. Group comments were video-recorded and transcribed and then analyzed by the investigators. RESULTS: The 27 racially diverse focus group members were largely unaware of existing safeguards and regulations to manage risk in clinical trials. Many people expressed a desire for increased transparency about serious adverse events during the trial as well as shortened reporting deadlines. Focus group members also spontaneously expressed concerns about potential financial conflicts of interest in monitoring and reporting serious adverse events. LIMITATIONS: This was a single-site, qualitative study and is not meant to establish the prevalence of beliefs. CONCLUSIONS: Potential trial participants have limited understanding and a wide range of expectations about how safety monitoring in clinical trials should be managed and communicated. The overall tenor of opinion suggests unease about participant safety and a desire to have more information conveyed by sponsors to investigators and, in some cases, by investigators to participants. Additional study in other regions and settings may be useful to more broadly explore the range of participants' beliefs and expectations. In the meantime, engaging patient advocates in the design of clinical trials and clearly communicating to trial participants the plan for oversight of their safety may help ease the types of concerns expressed in this study.

Use of central institutional review boards for multicenter clinical trials in the United States: a review of the literature.

BACKGROUND: To improve the efficiency of conducting multicenter clinical trials, the Food and Drug Administration, the Office of Human Research Protections, and the Department of Health and Human Services have expressed support for using a centralized institutional review board (IRB) process. However, research institutions differ in their willingness to defer to central IRBs. PURPOSE: We aimed to review and describe peer-reviewed journal articles on the use of central IRBs for multicenter clinical trials in the United States in an effort to inform the policy discussion about central IRBs. METHODS: We used a PubMed search and consulted IRB experts and the bibliographies of other reviews to identify relevant commentaries and empirical studies. RESULTS: Our search identified 33 articles related to the use of central IRBs for multicenter trials in the United States. Of these, 22 were commentary pieces and 11 were empirical studies. LIMITATIONS: Our review was restricted to journal articles about the use of central IRBs for multicenter clinical trials in the United States. CONCLUSIONS: There is limited empirical work on the use of central IRBs for multicenter trials in the United States. Most published studies focused on problems in efficiency associated with redundant local reviews of multicenter studies and the potential benefits of a centralized system. Because the absence of studies on the use of central IRBs may be due to their infrequent use, additional work is needed to generate data on the use of central IRBs and to elucidate and address the concerns that research institutions have about deferring ethical review to a central IRB.

Patient-focused intervention to improve long-term adherence to evidence-based medications: a randomized trial.

BACKGROUND: Nonadherence to cardiovascular medications is a significant public health problem. This randomized study evaluated the effect on medication adherence of linking hospital and community pharmacists. METHODS: Hospitalized patients with coronary artery disease discharged on aspirin, ß-blocker, and statin who used a participating pharmacy were randomized to usual care or intervention. The usual care group received discharge counseling and a letter to the community physician; the intervention group received enhanced in-hospital counseling, attention to adherence barriers, communication of discharge medications to community pharmacists and physicians, and ongoing assessment of adherence by community pharmacists. The primary end point was self-reported use of aspirin, ß-blocker, and statin at 6 months postdischarge; the secondary end point was a ≥ 75% proportion of days covered (PDC) for ß-blocker and statin through 6 months postdischarge. RESULTS: Of 143 enrolled patients, 108 (76%) completed 6-month follow-up, and 115 (80%) had 6-month refill records. There was no difference between intervention and control groups in self-reported adherence (91% vs 94%, respectively, P = .50). Using the PDC to determine adherence to ß-blockers and statins, there was better adherence in the intervention versus control arm, but the difference was not statistically significant (53% vs 38%, respectively, P = .11). Adherence to ß-blockers was statistically significantly better in intervention versus control (71% vs 49%, respectively, P = .03). Of 85 patients who self-reported adherence and had refill records, only 42 (49%) were also adherent by PDC. CONCLUSIONS: The trend toward better adherence by refill records with the intervention should encourage further investigation of engaging pharmacists to improve continuity of care.

Risk of Guillain-Barré syndrome after meningococcal conjugate vaccination.

PURPOSE: A new meningococcal conjugate vaccine (MCV4) was introduced in 2005. Shortly after, case reports of Guillain-Barré syndrome (GBS), a serious demyelinating disease, began to be reported to the Vaccine Adverse Event Reporting System. In 2006, the Centers for Disease Control and Prevention and the Food and Drug Administration requested the evaluation of GBS risk after MCV4 vaccination. We conducted a study to assess the risk of GBS after MCV4 vaccination using health plan administrative and claims data together with the review of primary medical records of potential cases. METHODS: Retrospective cohort study among 12.6 million 11- to 21-year-old members of five US health plans with a total membership of 50 million. Automated enrollment and medical claims data from March 2005 through August 2008 were used to identify the population, the vaccinations administered, and the medical services associated with possible GBS. Medical records were reviewed and adjudicated by a neurologist panel to confirm cases of GBS. The study used distributed data analysis methods that minimized sharing of protected health information. RESULTS: We confirmed 99 GBS cases during 18,322,800 person-years (5.4/1,000,000 person-years). More than 1.4 million MCV4 vaccinations were observed. No confirmed cases of GBS occurred within 6 weeks after vaccination. The upper 95% CI for the attributable risk of GBS associated with MCV4 is estimated as 1.5 cases per 1,000,000 doses. CONCLUSIONS: Among members of five US health plans, MCV4 vaccination was not associated with increased GBS risk.

Characteristics of clinical trials registered in ClinicalTrials.gov, 2007-2010.

CONTEXT: Recent reports highlight gaps between guidelines-based treatment recommendations and evidence from clinical trials that supports those recommendations. Strengthened reporting requirements for studies registered with ClinicalTrials.gov enable a comprehensive evaluation of the national trials portfolio. OBJECTIVE: To examine fundamental characteristics of interventional clinical trials registered in the ClinicalTrials.gov database. METHODS: A data set comprising 96,346 clinical studies from ClinicalTrials.gov was downloaded on September 27, 2010, and entered into a relational database to analyze aggregate data. Interventional trials were identified and analyses were focused on 3 clinical specialties-cardiovascular, mental health, and oncology-that together encompass the largest number of disability-adjusted life-years lost in the United States. MAIN OUTCOME MEASURES: Characteristics of registered clinical trials as reported data elements in the trial registry; how those characteristics have changed over time; differences in characteristics as a function of clinical specialty; and factors associated with use of randomization, blinding, and data monitoring committees (DMCs). RESULTS: The number of registered interventional clinical trials increased from 28,881 (October 2004-September 2007) to 40,970 (October 2007-September 2010), and the number of missing data elements has generally declined. Most interventional trials registered between 2007 and 2010 were small, with 62% enrolling 100 or fewer participants. Many clinical trials were single-center (66%; 24,788/37,520) and funded by organizations other than industry or the National Institutes of Health (NIH) (47%; 17,592/37,520). Heterogeneity in the reported methods by clinical specialty; sponsor type; and the reported use of DMCs, randomization, and blinding was evident. For example, reported use of DMCs was less common in industry-sponsored vs NIH-sponsored trials (adjusted odds ratio [OR], 0.11; 95% CI, 0.09-0.14), earlier-phase vs phase 3 trials (adjusted OR, 0.83; 95% CI, 0.76-0.91), and mental health trials vs those in the other 2 specialties. In similar comparisons, randomization and blinding were less frequently reported in earlier-phase, oncology, and device trials. CONCLUSION: Clinical trials registered in ClinicalTrials.gov are dominated by small trials and contain significant heterogeneity in methodological approaches, including reported use of randomization, blinding, and DMCs.

Monitoring the quality of conduct of clinical trials: a survey of current practices.

BACKGROUND: There is a little empirical evidence to determine which, if any, monitoring practices best achieve the goals of trial monitoring set forth in ICH E6 under the variable circumstances of different clinical trial settings. PURPOSE: The purpose of this project was to describe current methods of monitoring clinical trials and to explore the rationale for the use of those methods. METHODS: An electronic survey of known monitoring practices was developed and sent to over 200 organizations involved in conducting clinical research. The survey collected information on institutional demographics, methods of overall study oversight, use of risk-based monitoring and factors that influence assessments of risk, and details on quality assurance and monitoring practices. RESULTS: Seventy-nine organizations completed the survey; our analysis included the 65 organizations that indicated they perform clinical trials. Data from the survey indicate that a wide variety of monitoring practices are currently being employed. Eighty-three percent of respondents use centrally available data to evaluate site performance, but only 12% of respondents always or frequently used centralized monitoring to replace on-site visits. Eighty-seven percent of respondents indicated that they always performed on-site visits. This varied by type of organization, with 31% of academic coordinating centers/cooperative groups/government organizations always performing on-site monitoring visits versus 84% of other organizations. The rationale for using a specific monitoring approach does not appear to be based on empirical evidence. Fifty-four percent of respondents stated that 'usual practice' determined the frequency with which they conducted on-site monitoring visits. LIMITATIONS: The overall response rate to our survey was only 30%; thus, we may not have captured the full variance of current monitoring practices, and our responding sample may not be representative. CONCLUSION: These findings underscore the necessity of research to provide an evidence base for monitoring practice.

A randomized trial of direct-to-patient communication to enhance adherence to beta-blocker therapy following myocardial infarction.

BACKGROUND: Although beta-blockers are routinely prescribed at hospital discharge after myocardial infarction (MI), patients' adherence has been shown to decline substantially over time. We sought to test the hypothesis that a simple, direct-to-patient intervention can improve adherence to beta-blocker therapy following MI. METHODS: We conducted a cluster randomized controlled trial in 4 geographically dispersed health maintenance organizations testing the hypothesis that a simple direct-to-patient intervention could improve adherence. The study was carried out from June 2004 to March 2005. The primary analyses were based on 836 post-MI patients who were dispensed a beta-blocker prescription after discharge. The intervention consisted of 2 mailings 2 months apart describing the importance of beta-blocker use. The main outcomes were proportion of days covered with beta-blocker therapy and percentage of patients with at least 80% of days covered in the 9 months after the first mailing. Analyses were adjusted for age, sex, total medications dispensed, days between MI and intervention, and intervention site. RESULTS: Over the entire follow-up period, patients in the treatment arm had a mean absolute increase of 4.3% of days covered per month compared with patients in the control arm (a 5.7% relative change from baseline), representing 1.3 extra days (P = .04). Treatment patients were 17% more likely (relative risk, 1.17; 95% confidence interval, 1.02-1.29) to have 80% of days covered. For every 16 patients receiving the intervention, 1 additional patient would become adherent (80% or more days covered per month). CONCLUSION: A low-cost, easily replicable effort to increase adherence can have a demonstrable impact on beta-blocker adherence following MI. Trial Registration clinicaltrials.gov Identifier: NCT00211172.

Scientific evidence underlying the ACC/AHA clinical practice guidelines.

CONTEXT: The joint cardiovascular practice guidelines of the American College of Cardiology (ACC) and the American Heart Association (AHA) have become important documents for guiding cardiology practice and establishing benchmarks for quality of care. OBJECTIVE: To describe the evolution of recommendations in ACC/AHA cardiovascular guidelines and the distribution of recommendations across classes of recommendations and levels of evidence. DATA SOURCES AND STUDY SELECTION: Data from all ACC/AHA practice guidelines issued from 1984 to September 2008 were abstracted by personnel in the ACC Science and Quality Division. Fifty-three guidelines on 22 topics, including a total of 7196 recommendations, were abstracted. DATA EXTRACTION: The number of recommendations and the distribution of classes of recommendation (I, II, and III) and levels of evidence (A, B, and C) were determined. The subset of guidelines that were current as of September 2008 was evaluated to describe changes in recommendations between the first and current versions as well as patterns in levels of evidence used in the current versions. RESULTS: Among guidelines with at least 1 revision or update by September 2008, the number of recommendations increased from 1330 to 1973 (+48%) from the first to the current version, with the largest increase observed in use of class II recommendations. Considering the 16 current guidelines reporting levels of evidence, only 314 recommendations of 2711 total are classified as level of evidence A (median, 11%), whereas 1246 (median, 48%) are level of evidence C. Level of evidence significantly varies across categories of guidelines (disease, intervention, or diagnostic) and across individual guidelines. Recommendations with level of evidence A are mostly concentrated in class I, but only 245 of 1305 class I recommendations have level of evidence A (median, 19%). CONCLUSIONS: Recommendations issued in current ACC/AHA clinical practice guidelines are largely developed from lower levels of evidence or expert opinion. The proportion of recommendations for which there is no conclusive evidence is also growing. These findings highlight the need to improve the process of writing guidelines and to expand the evidence base from which clinical practice guidelines are derived.

Postmarket evaluation of breakthrough technologies.

Cardiovascular procedures performed in the United States have more than tripled in the last decade, a trend that is expected to continue with the aging of the population, coupled with epidemics of obesity and diabetes mellitus. Helping to drive this increase are new medical devices that address conditions previously treated by medication alone. Many of these novel devices receive expedited reviews before Food and Drug Administration (FDA) approval and are rapidly adopted into clinical practice. However, recent high-profile cases involving potentially dangerous defects in widely used medical devices have increased concerns about the adequacy of premarket trials and postmarket surveillance in establishing the safety of these devices. In response to these concerns, the American College of Cardiology and the Duke Clinical Research Institute sponsored a "think tank" of experts representing the industry, regulatory authorities, academic medicine, and professional societies to examine these concerns and propose possible solutions. This group examined case studies including drug-eluting stents and implantable cardioverter-defibrillators. Challenges inherent in the current system, including the difficulty of establishing accurate event rates for medical devices and potential disincentives for the industry to conduct comprehensive monitoring, were discussed. Possible solutions to these problems included improving and enforcing current regulations, considering creative study design strategies that link pre- and postmarket data, declaring postmarket surveillance a public health issue, creating financial incentives for participation in postmarketing studies, using more relevant animal models, encouraging postmortem device retrieval, and aligning professional societies with the FDA to evaluate breakthrough technologies and communicate findings to patients and clinicians.

A distributed research network model for post-marketing safety studies: the Meningococcal Vaccine Study.

PURPOSE: We describe a multi-center post-marketing safety study that uses distributed data methods to minimize the need for covered entities to share protected health information (PHI). Implementation has addressed several issues relevant to creation of a large scale post-marketing drug safety surveillance system envisioned by the FDA's Sentinel Initiative. METHODS: This retrospective cohort study of Guillain-Barré syndrome (GBS) following meningococcal conjugate vaccination incorporates the data and analytic expertise of five research organizations closely affiliated with US health insurers. The study uses administrative claims data, plus review of full text medical records to adjudicate the status of individuals with a diagnosis code for GBS (ICD9 357.0). A distributed network approach is used to create the analysis files and to perform most aspects of the analysis, allowing nearly all of the data to remain behind institutional firewalls. Pooled analysis files transferred to a central site will contain one record per person for approximately 0.2% of the study population, and contain PHI limited to the month and year of GBS onset for cases or the index date for matched controls. RESULTS: The first planned data extraction identified over 9 million eligible adolescents in the target age range of 11-21 years. They contributed an average of 14 months of eligible time on study over 27 months of calendar time. MCV4 vaccination coverage levels exceeded 20% among 17-18-year olds and 16% among 11-13 and 14-16-year-old age groups by the second quarter of 2007. CONCLUSION: This study demonstrates the feasibility of using a distributed data network approach to perform large scale post-marketing safety analyses and is scalable to include additional organizations and data sources. We believe these results can inform the development of a large national surveillance system.

Long-term adherence to evidence-based secondary prevention therapies in coronary artery disease.

BACKGROUND: Studies have examined the use of evidence-based therapies for coronary artery disease (CAD) in the short term and at hospital discharge, but few have evaluated long-term use. METHODS AND RESULTS: Using the Duke Databank for Cardiovascular Disease for the years 1995 to 2002, we determined the annual prevalence and consistency of self-reported use of aspirin, beta-blockers, lipid-lowering agents, and their combinations in all CAD patients and of angiotensin-converting enzyme inhibitors (ACEIs) in those with and without heart failure. Logistic-regression models identified characteristics associated with consistent use (reported on > or =2 consecutive follow-up surveys and then through death, withdrawal, or study end), and Cox proportional-hazards models explored the association of consistent use with mortality. Use of all agents and combinations thereof increased yearly. In 2002, 83% reported aspirin use; 61%, beta-blocker use; 63%, lipid-lowering therapy use; 54%, aspirin and beta-blocker use; and 39%, use of all 3. Consistent use was as follows: For aspirin, 71%; beta-blockers, 46%; lipid-lowering therapy, 44%; aspirin and beta-blockers, 36%; and all 3, 21%. Among patients without heart failure, 39% reported ACEI use in 2002; consistent use was 20%. Among heart failure patients, ACEI use was 51% in 2002 and consistent use, 39%. Except for ACEIs among patients without heart failure, consistent use was associated with lower adjusted mortality: Aspirin hazard ratio (HR), 0.58 and 95% confidence interval (CI), 0.54 to 0.62; beta-blockers, HR, 0.63 and 95% CI, 0.59 to 0.67; lipid-lowering therapy, HR, 0.52 and 95% CI, 0.42 to 0.65; all 3, HR, 0.67 and 95% CI, 0.59 to 0.77; aspirin and beta-blockers, HR, 0.61 and 95% CI, 0.57 to 0.65; and ACEIs among heart failure patients, HR, 0.75 and 95% CI, 0.67 to 0.84. CONCLUSIONS: Use of evidence-based therapies for CAD has improved but remains suboptimal. Although improved discharge prescription of these agents is needed, considerable attention must also be focused on understanding and improving long-term adherence.

Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation.

CONTEXT: Recent studies of drug-eluting intracoronary stents suggest that current antiplatelet regimens may not be sufficient to prevent late stent thrombosis. OBJECTIVE: To assess the association between clopidogrel use and long-term clinical outcomes of patients receiving drug-eluting stents (DES) and bare-metal stents (BMS) for treatment of coronary artery disease. DESIGN, SETTING, AND PATIENTS: An observational study examining consecutive patients receiving intracoronary stents at Duke Heart Center, a tertiary care medical center in Durham, NC, between January 1, 2000, and July 31, 2005, with follow-up contact at 6, 12, and 24 months through September 7, 2006. Study population included 4666 patients undergoing initial percutaneous coronary intervention with BMS (n = 3165) or DES (n = 1501). Landmark analyses were performed among patients who were event-free (no death, myocardial infarction [MI], or revascularization) at 6- and 12-month follow-up. At these points, patients were divided into 4 groups based on stent type and self-reported clopidogrel use: DES with clopidogrel, DES without clopidogrel, BMS with clopidogrel, and BMS without clopidogrel. MAIN OUTCOME MEASURES: Death, nonfatal MI, and the composite of death or MI at 24-month follow-up. RESULTS: Among patients with DES who were event-free at 6 months (637 with and 579 without clopidogrel), clopidogrel use was a significant predictor of lower adjusted rates of death (2.0% with vs 5.3% without; difference, -3.3%; 95% CI, -6.3% to -0.3%; P = .03) and death or MI (3.1% vs 7.2%; difference, -4.1%; 95% CI, -7.6% to -0.6%; P = .02) at 24 months. However, among patients with BMS (417 with and 1976 without clopidogrel), there were no differences in death (3.7% vs 4.5%; difference, -0.7%; 95% CI, -2.9% to 1.4%; P = .50) and death or MI (5.5% vs 6.0%; difference, -0.5%; 95% CI, -3.2% to 2.2%; P = .70). Among patients with DES who were event-free at 12 months (252 with and 276 without clopidogrel), clopidogrel use continued to predict lower rates of death (0% vs 3.5%; difference, -3.5%; 95% CI, -5.9% to -1.1%; P = .004) and death or MI (0% vs 4.5%; difference, -4.5%; 95% CI, -7.1% to -1.9%; P<.001) at 24 months. However, among patients with BMS (346 with and 1644 without clopidogrel), there continued to be no differences in death (3.3% vs 2.7%; difference, 0.6%; 95% CI, -1.5% to 2.8%; P = .57) and death or MI (4.7% vs 3.6%; difference, 1.0%; 95% CI, -1.6% to 3.6%; P = .44). CONCLUSIONS: The extended use of clopidogrel in patients with DES may be associated with a reduced risk for death and death or MI. However, the appropriate duration for clopidogrel administration can only be determined within the context of a large-scale randomized clinical trial.

National evaluation of adherence to beta-blocker therapy for 1 year after acute myocardial infarction in patients with commercial health insurance.

BACKGROUND: Quality measures of evidence-based medications post-myocardial infarction have focused on prescription at hospital discharge. Yet survival benefits of these medications are best realized with sustained therapy. We sought to examine long-term beta-blocker adherence over the first year after myocardial infarction in patients with commercial health insurance and prescription drug benefits. METHODS: This multicenter analysis examined health plan records from members of 11 health plans who had myocardial infarction in 2001, survived at least 1 year, and maintained insurance coverage (N = 17,035). The primary outcome measure was adherence to beta-blockers (defined as prescription claims covering > or = 75% of days) for 360 days post-discharge. We also examined associations with adherence--time from discharge, health plan product (commercial or Medicare + Choice [M + C]), age (35-64 or > or = 65), sex, and region. RESULTS: For 360 days after discharge, only 45% of patients were adherent to beta-blockers, with the biggest drop in adherence between 30 and 90 days. In a multivariable model, statistically significant predictors of lower adherence were participation in M + C product, residence in the Southeast, and age (driven by young participants in M + C and young females in commercial products). CONCLUSIONS: In a population of patients with health insurance and prescription drug coverage, adherence to beta-blocker therapy in the first year after myocardial infarction is poor, indicating that factors other than medication cost are important determinants of long-term adherence. Quality improvement initiatives focused on long-term adherence are needed to realize maximal benefit from medical therapy in post-myocardial infarction patients.

Multifaceted intervention to promote beta-blocker use in heart failure.

BACKGROUND: Despite a survival benefit and guideline recommendation for beta-blockers in left ventricular systolic dysfunction, beta-blockers are underused in clinical practice. METHODS: Medical practices with > or = 15 patients with heart failure (HF) in the Duke Databank for Cardiovascular Disease (DDCD) were identified for a prospective, randomized study using a multifaceted intervention to improve beta-blocker use. Intervention practices received provider education, patient education materials, feedback on beta-blocker use of their patients with HF, and access to telephone consultation with an HF expert. The primary outcome was a comparison between intervention and control practices of the proportion of patients with HF self-reporting beta-blocker use on their first routine DDCD follow-up in the postintervention year. A random effects model was used for the analysis. RESULTS: Post intervention, 2631 patients (1701 in 23 intervention practices and 930 in 22 control practices) completed DDCD follow-up. No significant difference in the proportion of patients with HF reporting beta-blocker use was found in the intervention versus control groups (OR 1.16, 95% CI 0.94-1.43, P = .2), although more patients in the intervention group started a beta-blocker than stopped a beta-blocker during the study period (P = .02). CONCLUSIONS: This multifaceted intervention did not significantly increase the mean proportion of patients taking beta-blockers within practices exposed to the intervention, although favorable trends were observed. Further studies are needed to identify and evaluate strategies for translating evidence into clinical practice to reduce the global health burden associated with HF.

A survey of health care practitioners' knowledge of the QT interval.

OBJECTIVE: To assess health care practitioners' ability to correctly measure the QT interval, and to identify factors and medications that may increase the risk of QT-interval prolongation and torsades de pointes. DESIGN: A cross-sectional analysis of a survey administered between April 2002 and March 2003. PARTICIPANTS AND SETTING: Health care practitioners attending Grand Rounds Conferences at 6 academic institutions in the United States in internal medicine and psychiatry and at 6 community hospitals in the same geographical areas as the academic institutions. INTERVENTION: Anonymous, self-administered questionnaire that included 20 questions on the QT interval. MEASUREMENTS AND MAIN RESULTS: Of approximately 826 attendees, 517 (63%) completed the survey. Of about 608 attendees of internal medicine conferences, 371 (61%) responded, and of about 208 attendees of psychiatry conferences, 146 (67%) responded. Of a total number of 20 questions, the median number of correct answers for the whole group was 10 (interquartile range 7-13). The median number of correct answers for internists was 12 (interquartile range 9-13), for psychiatrists 10 (interquartile range 7-13), and for other specialists 10 (interquartile range 5-13). Respondents who graduated between 1990 and 1999 and academicians performed significantly better overall than other respondents. Of the 517 respondents, 224 (43%) measured the QT interval correctly. Physicians in training and academicians were more likely to measure the QT interval correctly. CONCLUSION: The majority of health care practitioners cannot correctly measure the QT interval and cannot correctly identify factors and medications that can prolong the QT interval. Our findings suggest that greater attention to the QT interval is warranted to ensure safer use of QT prolonging medications.

Case reports of heart failure after therapy with a tumor necrosis factor antagonist.

BACKGROUND: Etanercept and infliximab are U.S. Food and Drug Administration-approved tumor necrosis factor (TNF) antagonists. OBJECTIVE: To describe adverse event reports of heart failure after TNF antagonist therapy. DESIGN: Case series. SETTING: The U.S. Food and Drug Administration's MedWatch program. PATIENTS: 47 patients who developed new or worsening heart failure during TNF antagonist therapy. MEASUREMENTS: Clinical and laboratory reports. RESULTS: After TNF antagonist therapy, 38 patients developed new-onset heart failure and 9 patients experienced heart failure exacerbation. Of the 38 patients with new-onset heart failure, 19 (50%) had no identifiable risk factors. Ten patients younger than 50 years of age developed new-onset heart failure after receiving TNF antagonists. After TNF antagonist therapy was discontinued and heart failure therapy was started in these 10 patients, 3 had complete resolution of heart failure, 6 improved, and 1 died. CONCLUSION: In a fraction of patients, TNF antagonists might induce new-onset heart failure or exacerbate existing disease.

Evaluation of the dofetilide risk-management program.

BACKGROUND: Dose-dependent torsades de pointes has been shown to occur with dofetilide (Tikosyn) and sotalol HCl (Betapace AF); thus, detailed dosing and monitoring recommendations to minimize this risk are included in the product labeling for both drugs. Only dofetilide, however, has a mandated risk-management program that restricts distribution of the drug and requires prescriber education on the drug. We investigated whether this program improved adherence to dosing and monitoring recommendations for dofetilide as compared with sotalol. METHODS: Charts for 47 patients taking dofetilide and 117 patients taking sotalol were reviewed. RESULTS: The recommended starting dose was prescribed more frequently in the dofetilide group than in the sotalol group (79% vs 35%, P <.001). A higher number of patients in the dofetilide group compared with the sotalol group received the recommended baseline tests for potassium (100% vs 82%, P <.001), magnesium (89% vs 38%, P <.001), serum creatinine (100% vs 82%, P <.001), and electrocardiography (94% vs 67%, P <.001). A significantly greater proportion of patients in the dofetilide group received recommended electrocardiograms obtained after the first dose (94% for dofetilide vs 43% for sotalol, P <.001) and subsequent doses (80% for dofetilide vs 3.5% for sotalol, P <.001). CONCLUSION: Better adherence to several dosing and monitoring recommendations in the dofetilide group may be caused by the presence of the risk-management program. However, low usage of dofetilide during the study period may signify an unintended, negative consequence of the risk-management program.

Role of target vessel size and body surface area on outcomes after percutaneous coronary interventions in women.

BACKGROUND: Women have higher mortality rates than men after coronary angioplasty. Differences in target vessel size may partially account for these differences. We set out to explore the effects of sex, body surface area (BSA), and target coronary vessel size on clinical outcomes after angioplasty. METHODS: Data from 5 interventional trials and 1 registry were pooled for analysis (n = 3982). RESULTS: Compared with men, women undergoing angioplasty were older, had lower weights and BSA, more coronary risk factors, and slightly smaller target coronary vessel size (as assessed by reference vessel diameter). The correlation between target vessel size and BSA was poor (r = 0.13). At 6 months, women had higher mortality rates (1.7% vs 0.8%, P =.03) but similar rates of myocardial infarction and repeat revascularization. On univariate analysis, advanced age, smaller BSA, and female sex were associated with increased mortality, but target vessel size was not. Advanced age was the only significant multivariate predictor of mortality. Target vessel size and diabetes were independent predictors of repeat revascularization. CONCLUSIONS: Women have higher unadjusted 6-month mortality rates after angioplasty, owing largely to their more advanced age at the time of intervention. Smaller target vessel size is associated with increased risk of restenosis and repeat revascularization; however, it does not appear to be a predictor for downstream mortality. As such, the fact that women have smaller vessels does not account for their higher 6-month mortality after coronary angioplasty.