Publications

CASE: Opioids are commonly prescribed for pain, and are often connected to mental status adverse events. Delirium is a side effect associated with narcotic analgesics, with a higher incidence in the elderly. This report describes an elderly male that received a total knee arthroplasty and received morphine post-operatively. On post-operative day 2, morphine was discontinued due to mental status changes and switched to oxycodone/acetaminophen. Twenty-four hours after administering oxycodone, the patient's mental status declined. After the patient returned to baseline he was transferred to rehabilitation and re-challenged with oxycodone/acetaminophen. The re-challenge was inadvertent due to inadequate documentation of the adverse event and lack of understanding by the health care team of delirium associated with opioids. A similar rapid decline in mental status occurred.

CONCLUSION: Clinicians should be cognizant of narcotic analgesics inducing mental status changes, even with an alternative. Detailed documentation of adverse events should occur to avoid accidental re-challenges.

STUDY OBJECTIVES: The primary objective was to evaluate the change in publication rate of noninferiority trials over a 20-year interval (1989-2009). Secondary objectives were to analyze the frequency of noninferiority trials by therapeutic category, the frequency of noninferiority trial publication by journal, the impact factors of the publishing journals, any potential special advantages of the study drug over the control, the funding sources of the trials, pharmaceutical industry affiliation of the authors, and the use of ghostwriters in the creation of manuscripts.

DESIGN: Retrospective literature review of 583 articles.

DATA SOURCES: PubMed (January 1989-December 2009) and EMBASE (first quarter 1989-fourth quarter 2009) databases.

MEASUREMENTS AND MAIN RESULTS: A total of 583 articles of the results of randomized controlled clinical trials with a noninferiority study design that evaluated drug therapies, published in English, between 1989 and 2009, were included in the analysis. A consistent increase was noted in their yearly publication rates, with no trials published in 1989 versus 133 in 2009. One hundred twenty-six articles (21.6%) were in the therapeutic category of infectious diseases, followed by 78 (13.4%) in cardiology. Among the journals identified, The New England Journal of Medicine had the highest publication rate of trials with a noninferiority design, with 29 (5.0%) of the identified trials published in this journal. The median impact factor of the journals publishing noninferiority trials was 4.807 (interquartile range 3.064-7.5). The most common advantage of the study drug over the control was reduced duration of treatment or reduced pill burden (80 studies [22.9%]). A total of 425 trials (72.9%) listed the pharmaceutical industry as the only funding source. Among 369 trials with authors employed by the pharmaceutical industry, 101 (17.3%) disclosed an acknowledgment to an individual, other than those listed as authors, who contributed to writing the manuscript and who was affiliated with a medical information company and/or a pharmaceutical company (i.e., potential ghostwriters).

CONCLUSION: The publication of noninferiority trials increased during the 20 years from 1989 until 2009, particularly in the therapeutic areas of infectious diseases and cardiology. Because of this growth, clinicians and researchers need to be familiar with the caveats of the noninferiority study design to appropriately interpret and design these clinical studies.

OBJECTIVE: To report an incident of rapid development of profound hypotension, differing from the time described in previous reports, during the infusion of rituximab chemotherapy in a patient without prior exposure to the drug.

CASE SUMMARY: An 84-year-old white male with Rai stage IV chronic lymphocytic leukemia was prescribed rituximab 375 mg/m(2) by intravenous infusion. Rituximab 50 mg/h was initiated after premedication with acetaminophen, diphenhydramine, dexamethasone, and ondansetron 3 days into his hospital course. Five minutes after the infusion had begun, he experienced a significant decrease in blood pressure to 76/45 mm Hg, and the infusion was stopped. After 30 minutes, the blood pressure returned to normal. Rechallenge with rituximab 25 mg/h was attempted, but the blood pressure again declined and the patient experienced chills and rigors. The infusion was discontinued, and the symptoms resolved 1 hour later.

DISCUSSION: Infusion-related adverse reactions associated with rituximab are reported at a higher rate than with other monoclonal antibodies. Hypotension with rituximab has been reported to occur 30 minutes to 2 hours after initiation of the infusion. In contrast, severe hypotension in our patient occurred within 5 minutes after the infusion was started in a patient with no previous exposure to the drug. While many studies hypothesize that cytokine release from lymphocytes and tumor cell agglutination might contribute to severe infusion-related reactions with rituximab, the mechanism of action is not yet known. Use of the Naranjo probability scale indicated that the hypotension was probably associated with rituximab administration.

CONCLUSIONS: Awareness of the rapidity of this adverse effect in patients who have not received prior treatment with monoclonal antibodies is important during chemotherapy treatment.

OBJECTIVES: To evaluate faculty members' and students' perceptions of study strategies and materials.

METHODS: Focus groups were conducted with course directors and first- and second-year students to generate ideas relating to use of course materials, technology, class attendance, and study strategies for mastering class concepts.

RESULTS: Students and faculty members differed in their opinions about the utility of textbooks and supplemental resources. The main learning method recommended by students and faculty members was repeated review of course material. Students recommended viewing classroom lectures again online, if possible. Course directors reported believing that class attendance is important, but students based their opinions regarding the importance of attendance on their perceptions of lecture and handout quality. Results did not differ by campus or by student group (first-year vs. second-year students).

CONCLUSIONS: Students and faculty members have differing opinions on the process that could influence learning and course design. Faculty members should understand the strategies students are using to learn course material and consider additional or alternative course design and delivery techniques based on student feedback.

BACKGROUND: Bacterial resistance presents a constant challenge in the treatment of hospitalized patients, particularly with Gram-negative infections. Carbapenems have an important role in the treatment of resistant nosocomial organisms. Doripenem, a recently approved carbapenem, has shown efficacy in clinical trials, but there is little published data on utilization in a general patient population.

OBJECTIVE: The clinical utilization of doripenem in a general adult inpatient population was evaluated during a carbapenem formulary conversion.

SETTING: A 706-bed acute care tertiary hospital serving an urban community.

METHODS: After formulary conversion to doripenem, the first 100 patients to receive doripenem were included in the analysis. Baseline characteristics were recorded for each patient, along with indication for treatment, prescribing physician, dose and frequency of doripenem and duration of treatment. Patients were monitored for adverse reactions to doripenem. Bacterial culture results were recorded. For positive cultures, doripenem susceptibility was determined by Etest. Patients were followed until discontinuation of antibiotic therapy, discharge or death to determine treatment outcomes. Successful treatment was defined as clinical or microbiological cure, while patients with infection-related mortality or requiring subsequent antibiotics for the index infection were considered treatment failure.

MAIN OUTCOME MEASURES: Clinical utilization of doripenem, including indications and doses used.

RESULTS: Doripenem treatment was recorded in 102 patients. The most common indications for treatment were pneumonia and sepsis. The majority of doripenem orders were written by Infectious Disease or Pulmonology Services. Forty-nine patients were treated successfully with doripenem and six patients experienced treatment failure. The remainder of patients were not evaluable by predefined outcomes criteria. Adverse events were reported in eight patients and included acute renal failure, Clostridium difficile-associated diarrhea and seizures. Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa were the most common organisms in culture results. Doripenem demonstrated in vitro activity against 81% of all organisms and susceptibility results had >90% correlation with meropenem and imipenem susceptibilities.

CONCLUSION: In our limited sample size, doripenem was safe and effective against various types of infections in a general inpatient population with similar bacterial susceptibilities to other cabapenems. Doripenem was utilized for appropriate indications, but doses were frequently outside the manufacturers labeling. Adverse events were uncommon, and no serious adverse events were directly associated with doripenem treatment.

BACKGROUND: Medication nonadherence is a common problem among the elderly.

OBJECTIVE: To conduct a systematic review of the published literature describing potential nonfinancial barriers to medication adherence among the elderly.

METHODS: The PubMed and PsychINFO databases were searched for articles published in English between January 1998 and January 2010 that (1) described "predictors," "facilitators," or "determinants" of medication adherence or that (2) examined the "relationship" between a specific barrier and adherence for elderly patients (ie, ≥65 years of age) in the United States. A manual search of the reference lists of identified articles and the authors' files and recent review articles was conducted. The search included articles that (1) reviewed specific barriers to medication adherence and did not solely describe nonmodifiable predictors of adherence (eg, demographics, marital status), (2) were not interventions designed to address adherence, (3) defined adherence or compliance and specified its method of measurement, and (4) involved US participants only. Nonsystematic reviews were excluded, as were studies that focused specifically on people who were homeless or substance abusers, or patients with psychotic disorders, tuberculosis, or HIV infection, because of the unique circumstances that surround medication adherence for each of these populations.

RESULTS: Nine studies met inclusion criteria for this review. Four studies used pharmacy records or claims data to assess adherence, 2 studies used pill count or electronic monitoring, and 3 studies used other methods to assess adherence. Substantial heterogeneity existed among the populations studied as well as among the measures of adherence, barriers addressed, and significant findings. Some potential barriers (ie, factors associated with nonadherence) were identified from the studies, including patient-related factors such as disease-related knowledge, health literacy, and cognitive function; drug-related factors such as adverse effects and polypharmacy; and other factors including the patient-provider relationship and various logistical barriers to obtaining medications. None of the reviewed studies examined primary nonadherence or nonpersistence.

CONCLUSION: Medication nonadherence in the elderly is not well described in the literature, despite being a major cause of morbidity, and thus it is difficult to draw a systematic conclusion on potential barriers based on the current literature. Future research should focus on standardizing medication adherence measurements among the elderly to gain a better understanding of this important issue.

OBJECTIVE: To conduct a meta-analysis of the association between depression and medication adherence among patients with chronic diseases. Poor medication adherence may result in worse outcomes and higher costs than if patients fully adhere to their medication regimens.

DATA SOURCES: We searched the PubMed and PsycINFO databases, conducted forward searches for articles that cited major review articles, and examined the reference lists of relevant articles.

STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTIONS: We included studies on adults in the United States that reported bivariate relationships between depression and medication adherence. We excluded studies on special populations (e.g., substance abusers) that were not representative of the general adult population with chronic diseases, studies on certain diseases (e.g., HIV) that required special adherence protocols, and studies on interventions for medication adherence.

STUDY APPRAISAL AND SYNTHESIS METHODS: Data abstracted included the study population, the protocol, measures of depression and adherence, and the quantitative association between depression and medication adherence. Synthesis of the data followed established statistical procedures for meta-analysis.

RESULTS: The estimated odds of a depressed patient being non-adherent are 1.76 times the odds of a non-depressed patient, across 31 studies and 18,245 participants. The association was similar across disease types but was not as strong among studies that used pharmacy records compared to self-report and electronic cap measures.

LIMITATIONS: The meta-analysis results are correlations limiting causal inferences, and there is some heterogeneity among the studies in participant characteristics, diseases studied, and methods used.

CONCLUSIONS: This analysis provides evidence that depression is associated with poor adherence to medication across a range of chronic diseases, and we find a new potential effect of adherence measurement type on this relationship. Although this study cannot assess causality, it supports the importance that must be placed on depression in studies that assess adherence and attempt to improve it.

BACKGROUND: Cost-related underuse of medications is common among older adults, who seldom discuss medication costs with their physicians. Some older adults may use free drug samples or industry-sponsored patient assistance programs (PAP) in hopes of lowering out-of-pocket costs, although the long-term effect of these programs on drug spending is unclear.

OBJECTIVE: To examine older adults' use of industry-sponsored strategies to reduce out-of-pocket drug costs and the association between doctor-patient communication and use of these programs.

DESIGN: Cross-sectional analysis of a 2006 nationally representative survey of Medicare beneficiaries.

PARTICIPANTS: 14,322 community-dwelling Medicare beneficiaries age ≥65.

MAIN MEASURES: We conducted bivariate and multivariate analyses of the association between receipt of free samples and participation in PAPs with sociodemographic characteristics, health status, access to care, drug coverage, medication cost burden, and doctor-patient communication.

KEY RESULTS: 51.4% of seniors reported receiving at least one free sample over the last 12 months and 29.2% reported receiving free samples more than once. In contrast, only 1.3% of seniors reported participating in an industry-sponsored PAP. Higher income respondents were more likely to report free sample receipt than low-income respondents (50.8% vs. 43.8%, p < 0.001) and less likely to report participating in a PAP (0.42% vs. 2.2%, p < 0.001). In multivariate analyses, those who reported talking to their doctor about the cost of their medications had more than twice the odds of receiving samples as those who did not (OR 2.17, 95% CI 1.95-2.42).

CONCLUSIONS: In 2006, over half of seniors in Medicare received free samples, but only 1.3% reported receiving any medications from a patient assistance program. Doctor-patient communication is strongly associated with use of these programs, which has important implications for clinical care regardless of whether these programs are viewed as drivers of prescription costs or a remedy for them.