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Background: Patient navigation programs have been launched nationwide in an attempt to reduce racial/ethnic and socio-demographic disparities in cancer care, but few have evaluated outcomes in the prostate cancer setting. The National Cancer Institute-funded Chicago Patient Navigation Research Program (C-PNRP) aims to implement and evaluate the efficacy of a patient navigation intervention for predominantly low-income minority patients with an abnormal prostate cancer screening test at a Veterans Affairs (VA) hospital in Chicago. Methods/Design: From 2006 through 2010, C-PNRP implemented a quasi-experimental intervention whereby trained social worker and lay health navigators worked with veterans with an abnormal prostate screen to proactively identify and resolve personal and systems barriers to care. Men were enrolled at a VA urology clinic and were selected to receive navigated versus usual care based on clinic day. Patient navigators performed activities to facilitate timely follow-up such as appointment reminders, transportation coordination, cancer education, scheduling assistance, and social support as needed. Primary outcome measures included time (days) from abnormal screening to diagnosis and time from diagnosis to treatment initiation. Secondary outcomes included psychosocial and demographic predictors of non-compliance and patient satisfaction. Dates of screening, follow-up visits, and treatment were obtained through chart audit, and questionnaires were administered at baseline, after diagnosis, and after treatment initiation. At the VA, 546 patients were enrolled in the study (245 in the navigated arm, 245 in the records-based control arm, and 56 in a subsample of surveyed control subjects). Discussion: Given increasing concerns about balancing better health outcomes with lower costs, careful examination of interventions aimed at reducing healthcare disparities attain critical importance. While analysis of the C-PNRP data is underway, the design of this patient navigation intervention will inform other patient navigation programs addressing strategies to improve prostate cancer outcomes among vulnerable populations. [ABSTRACT FROM AUTHOR]

In this article the author discusses an approach to signal detection of adverse events related to drug-drug interactions in typical HIV therapy. It presents the study's findings on how the patients are affected after receiving the unboosted combination of atazanavir and tenofovir, particularly focusing on the annual changes of the cost of medical care. It also looks into the approaches that works best in improving awareness of the provider and action on the part of the patients.

BACKGROUND: Since 1988, millions of patients have received epoetin products intravenously (IV) and subcutaneously. In 1998, epoetin-associated pure red cell aplasia (PRCA) was first reported and causation was attributed to formulations without human serum albumin (HSA), subcutaneous administration, and uncoated rubber stoppers. STUDY DESIGN AND METHODS: Data on erythropoietin (EPO)-associated PRCA were obtained from the Food and Drug Administration (FDA), regulatory authorities in other countries, and the manufacturers of epoetin alfa, epoetin beta, and darbepoetin. The data included information on numbers of PRCA cases and estimated exposure-adjusted incidence rates by EPO product, anemia etiology, administration route, country of PRCA identification, and date reported. RESULTS: In 1999, academicians in Paris identified 12 EPO-treated patients with antibody-mediated PRCA; 11 of these patients were on hemodialysis and had received subcutaneous Eprex (Johnson & Johnson). In 2002, authorities in Europe, Australia, Singapore, and Canada mandated Eprex by IV route to hemodialysis patients, and the relevant manufacturers added Teflon coating to prefilled syringes of Eprex; PRCA cases subsequently decreased by 90 percent. By 2003, 180 Eprex-associated PRCA cases were identified in Europe, Canada, Australia, and Asia, despite improvements in handling. Since 2002, FDA safety databases include information on 59 new cases of antibody-associated PRCA, primarily associated with subcutaneous epoetin alfa and darbepoetin that does not contain HSA. CONCLUSION: Independent actions by regulatory authorities, manufacturers, and academic researchers identified significant numbers of PRCA cases between 1998 and 2003 and characterized the probable etiology. Today, antibody-mediated PRCA is an infrequent class toxicity occurring among some hemodialysis patients on EPOs. [ABSTRACT FROM AUTHOR]

Abstract: Gemtuzumab ozogamicin (GO) was approved for marketing in 2000 by the United States Food and Drug Administration (FDA) for older patients with relapsed acute myeloid leukemia (AML). Four months later, 14 phase II clinical trial participants who received novel GO-containing combination chemotherapy regimens developed an unexpected hepatic toxicity termed sinusoidal obstructive syndrome (SOS) or hepatic veno-occlusive disease (VOD). Investigators associated with the Research on Adverse Drug Events and Reports (RADAR) project reviewed safety reports for GO included in reports of clinical trials and observational studies, interim reports from an FDA mandated Prospective Observational Registry, and the Food and Drug Administration''s Adverse Event Reporting System. Medline searches provided incidence estimates of GO-associated SOS and comparative rates of SOS without GO. SOS is characterized by hyperbilirubinemia, painful hepatomegaly, ascites, and sudden weight gain developing at a median of 10 days following GO administration for patients who did not undergo an allogeneic SCT procedure and 13 days following an allogeneic SCT for patients who had previously received GO. Among adult AML patients who received GO in clinical trials, SOS incidence was 3% at doses ≤6mg/m2 if administered as monotherapy or in combination with non-hepatotoxic agents versus 28% if administered with thioguanine and 15% when administered as monotherapy at a dose of 9mg/m2. Observational studies identified SOS rates between 15% and 40% if an SCT is performed within 3 months of GO administration. The FDA mandated Prospective Observational Registry of patients who receive care at 60 medical centers has identified GO-associated SOS rates of 14% if an SCT is performed and 9% otherwise. Caution is advised when administering GO in routine clinical practice, particularly if administered with other hepatotoxic agents, at doses and schedules more intensive than those approved by the FDA, or within 3 months of a SCT procedure. [Copyright &y& Elsevier]

Because penicillin agents are implicated in granulopoiesis inhibition, healthcare professionals frequently consider discontinuation of such therapy in patients with decreasing white blood cell counts. No systematic review to date has described piperacillin and the patient population at risk for this adverse drug reaction (ADR). This review sought to assess the occurrence of piperacillin-induced neutropenia, describe characteristics of affected patients and assess the reporting modalities that most accurately classify this ADR. Case reports, cohort studies and clinical trials identified by comprehensive searches of PubMed and the US FDA Adverse Event Reporting System (AERS) database were reviewed for patient demographics, duration and dose of piperacillin or piperacillin-tazobactam treatment and the occurrence of neutropenia. Causality assessments were performed. Six published case reports, three cohort studies, 178 clinical trials and two compilations of phase I-III trials were reviewed. Review of case reports was notable in that the duration of β-lactam therapy prior to the noting of leukopenia always exceeded 15 days. No deaths were recorded in this group. Among 13 816 patients enrolled in non-neutropenic fever studies, the occurrence of piperacillin-induced neutropenia was rare: five patients (0.04%) developed neutropenia; none died. The demographics for this group were poorly documented. Through the AERS database, we identified 366 unique cases of piperacillin or piperacillintazobactam-induced haematological abnormalities, including neutropenia (n = 183, 50.0%), leukopenia, (n = 99, 27%), agranulocytosis (n = 58, 15.8%) and others. In 62 cases, patients received between 1 and 14 days of therapy (mean 7.7 + 4.1 days). Overall, there were 82 (22.4%) deaths. Reports of haematological ADRs among patients receiving piperacillin or piperacillin-tazobactam are rare. Report of neutropenia associated with piperacillin usage prior to 15 days of therapy is a novel finding that requires further evaluation. Current reporting methods poorly characterise patient groups at risk. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article related about visual hallucinations in an elderly woman published in a previous issue.

Purpose: The purpose of this study was to gain an understanding of older gynecologic cancer patients’ preferences and opinions related to physical activity during chemotherapy, including interventions to promote physical activity. Methods: Gynecologic cancer patients 60 years or older receiving chemotherapy at a single institution within the last 12 months completed questionnaires and a semi-structured interview asking about their preferences for physical activity interventions aimed at promoting physical activity while receiving treatment. Results: Among the 30 gynecologic cancer patients surveyed and interviewed, a majority agreed with the potential usefulness of a physical activity intervention during chemotherapy (67%) and most reported they would be willing to use an activity tracker during chemotherapy (73%). They expressed a preference for an aerobic activity intervention such as walking, indicated a desire for education from their clinical team on the effects physical activity can have on treatment symptoms, and stated a need for an intervention that could be accessed from anywhere and anytime. Additionally, they emphasized a need for an intervention that considered their treatment symptoms as these were a significant barrier to physical activity while on chemotherapy. Conclusion: In this study of older gynecologic cancer patients receiving chemotherapy, most were open to participating in a virtually accessible and symptom-tailored physical activity intervention to promote physical activity during chemotherapy. [ABSTRACT FROM AUTHOR]

A response by the authors to a letter to the editor about their article related to Charles Bonnet Syndrome is presented.

Background: Prostate cancer disproportionately affects low-income and minority men. This study evaluates the impact of a patient navigation intervention on timeliness of diagnostic resolution and treatment initiation among veterans with an abnormal prostate cancer screen. Methods: Participants were enrolled between 2006 and 2010. The intervention involved a social worker and lay health worker navigation team that assisted patients in overcoming barriers to care. For navigated (n = 245) versus control (n = 245) participants, we evaluated rates of diagnostic resolution and treatment and adjusted for race, age, and Gleason score. Results: Of 490 participants, 68% were African American, 47% were ≥ 65 years old, and 35% had cancer. Among those with an abnormal screen, navigation did not have a significant effect on time to diagnostic resolution compared to controls (median days of 97 versus 111; adj. HR 1.17, 95% CI, 0.96-1.43, p = 0.12). On analysis of the period beyond 80 days, navigated men reached resolution faster than controls (median of 151 days versus 190 days; adj. HR 1.41, 95% CI, 1.07-1.86, p = 0.01). Among those with cancer, navigation did not have a significant effect on time to treatment initiation compared to controls (median of 93 days versus 87 days; adj. HR 1.15, 95% CI, 0.82-1.62, p = 0.41). Conclusion: Our navigation program did not significantly impact the overall time to resolution or treatment for men with prostate cancer compared to controls. The utility of navigation programs may extend beyond targeted navigation times, however, and future studies focusing on other outcomes measures are therefore needed. [ABSTRACT FROM AUTHOR]

Summary: More than half of all serious adverse reactions are identified 7 or more years after a drug receives approval from the US Food and Drug Administration (FDA). In 2002, 9 months after the intravenous bisphosphonate zoledronic acid received regulatory approval for marketing, the FDA received reports of nine patients with cancer, who were treated with zoledronic acid, who unexpectedly developed osteonecrosis of the jaw. During the next 2 years, three oral surgeons described 104 patients with cancer with osteonecrosis of the jaw in the medical literature and identified intravenous bisphosphonate therapy as being common to the care of these patients. In subspecialty medical, radiology, and dental journals, case reports and case series described clinical features of osteonecrosis of the jaw in patients with cancer who were treated with bisphosphonates. Manufacturer-sponsored epidemiological studies reported the first estimates of the incidence of this toxic effect, ranging from 0·1% to 1·8%. By contrast, independent epidemiological efforts from clinicians and the International Myeloma Foundation reported incidence estimates between 5% and 10%. Between 2003 and 2005, warnings about the risks of bisphosphonate-associated osteonecrosis were disseminated by national regulatory agencies, the manufacturers of bisphosphonates, and the International Myeloma Foundation. From 2006, independent clinical recommendations for diagnosis, prevention, and treatment of this toxic effect have been disseminated by manufacturers, national regulatory authorities, the International Myeloma Foundation, and medical specialty organisations. Furthermore, independent efforts by pharmaceutical manufacturers, dental and medical professionals, a non-profit organisation (the International Myeloma Foundation), patients, and regulatory authorities has led to the rapid identification and dissemination of safety information for this serious adverse reaction. Better coordination of safety-related pharmacovigilance initiatives is now needed. [Copyright &y& Elsevier]

In this paper, we examine how the management of prostate cancer lends itself to a disease state management (DSM)–based approach, and propose a framework that emphasizes the patient–provider–caregiver triad in managing the long-term implications of the condition. There is often no clearly superior approach to the management of patients with prostate cancer (eg, watchful waiting and hormonal therapy), and each option entails different trade-offs in quality of life. Ideally, the physician and patient discuss the options, issues, and patient preferences for treatment through the shared decision-making process. A family caregiver such as the spouse of the patient is often involved in the treatment decision and in the long-term management of the cancer experience. In order to develop a DSM program supporting both patient and caregiver, educational, psychosocial, and health care system support needs should be tailored to each phase of cancer treatment/management. To embrace the unique aspects of prostate cancer management, the proposed framework emphasizes communication among the patient–caregiver–provider triad, inclusion of family caregivers in the program, cancer phase–specific support, and psychosocial services as a basis for implementation and evaluation of a DSM program in prostate cancer. (Disease Management 2005;8:235–244) [ABSTRACT FROM AUTHOR]

Recombinant granulocyte colony-stimulating factor (G-CSF) [filgrastim and lenograstim] and pegylated G-CSF (pegfilgrastim) have been shown to reduce the severity and duration of chemotherapy-associated febrile neutropenia (FN) when administered prophylactically to cancer patients receiving chemotherapeutic regimens. The American Society of Clinical Oncology (ASCO) evidence-based clinical guidelines published in 1994, 1996 and 1997 recommended primary prophylaxis with G-CSF for cancer patients. The 2000 ASCO update, with the same recommendation, highlights the importance of economic considerations in decision making for CSFs. This paper reviews the available cost-effectiveness evidence on the use of G-CSF as primary prophylaxis against FN in patients with small cell lung cancer (SCLC). Cost-effectiveness ratios from a healthcare payer perspective supported the use of filgrastim as primary prophylaxis for people with SCLC, on the basis of both clinical and economic benefits, treated with chemotherapeutic regimens that have an FN rate in the range of 40–60%. However, when indirect and patient out-of-pocket costs attributable to severe FN are included, available evidence suggests that the risk threshold may be reduced by more than half. Given that FN rates associated with chemotherapeutic regimens for SCLC are generally <40%, then few circumstances would warrant the use of G-CSFs (filgrastim and lenograstim) under the current rule. However, inclusion of indirect costs would lower the cost-effectiveness threshold. Future cost-effectiveness studies of medications such as pegfilgrastim should attempt to capture the societal perspective by incorporating productivity-related costs and using base-case rates of FN reported in the literature. [ABSTRACT FROM AUTHOR]

• Urologists role-played as patient and provider to learn shared decision-making (SDM) • They used the SHARE approach for prostate cancer screening and treatment decisions • Cases highlighted patient values more prevalent amongst underserved populations • Postworkshop, urologists' knowledge about SDM strategies increased • Urologists unanimously stated that the workshop met its objectives and was valuable. Shared decision-making (SDM) is an approach to patient-centered care that is strongly recommended when counseling patients for screening and treatment of prostate cancer. However, providers report lack of comfort with SDM and particularly in disparate populations. We report our experience designing and piloting an online workshop to educate practicing urologists on SDM in diverse populations. Our objective was to create a valued interactive SDM workshop to help urologists learn to lead SDM discussions with men form underserved populations. Therefore, we tested the hypothesis that urologists would agree or strongly agree that we met our learning objectives on postcourse survey. With the support of the American Urologic Association, we developed a case-based workshop with interactive role-playing to demonstrate and teach integration of SDM into clinical care. Cases were centered around screening and treatment decisions for localized prostate cancer in diverse patients. Brief surveys were used to track success with learning objectives and urologists' satisfaction with the workshop. The session included 14 participants from 6 countries. A postworkshop survey indicated that 100% of respondents (8 of 8) "strongly agreed" that the activity met learning objectives, and 100% rated the session as "good" (1), "very good" (1), or "excellent" (6). Participants' knowledge also improved on shared decision-making concepts and the knowledge was maintained one month after the workshop. We successfully created and piloted an interactive online workshop to improve urologists' comfort using shared decision-making in caring for diverse patient populations. The course met its objectives and participant feedback for the course was positive. Sharing this process and framework for development of this intervention may inform future workshops that can be applied to medical students, residents, and providers. [ABSTRACT FROM AUTHOR]

Purpose: Approximately 18,500 persons are diagnosed with malignant glioma in the United States annually. Few studies have investigated the comprehensive economic costs. We reviewed the literature to examine costs to patients with malignant glioma and their families, payers, and society. Methods: A total of 18 fully extracted studies were included. Data were collected on direct and indirect costs, and cost estimates were converted to US dollars using the conversion rate calculated from the study's publication date, and updated to 2011 values after adjustment for inflation. A standardized data abstraction form was used. Data were extracted by one reviewer and checked by another. Results: Before approval of effective chemotherapeutic agents for malignant gliomas, estimated total direct medical costs in the United States for surgery and radiation therapy per patient ranged from $50,600 to $92,700. The addition of temozolomide (TMZ) and bevacizumab to glioblastoma treatment regimens has resulted in increased overall costs for glioma care. Although health care costs are now less front-loaded, they have increased over the course of illness. Analysis using a willingness-to-pay threshold of $50,000 per quality-adjusted life-year suggests that the benefits of TMZ fall on the edge of acceptable therapies. Furthermore, indirect medical costs, such as productivity losses, are not trivial. Conclusion: With increased chemotherapy use for malignant glioma, the paradigm for treatment and associated out-ofpocket and total medical costs continue to evolve. Larger outof-pocket costs may influence the choice of chemotherapeutic agents, the economic implications of which should be evaluated prospectively. [ABSTRACT FROM AUTHOR]

BACKGROUND Navigators can facilitate timely access to cancer services, but to the authors' knowledge there are little data available regarding their economic impact. METHODS The authors conducted a cost-consequence analysis of navigation versus usual care among 10,521 individuals with abnormal breast, cervical, colorectal, or prostate cancer screening results who enrolled in the Patient Navigation Research Program study from January 1, 2006 to March 31, 2010. Navigation costs included diagnostic evaluation, patient and staff time, materials, and overhead. Consequences or outcomes were time to diagnostic resolution and probability of resolution. Differences in costs and outcomes were evaluated using multilevel, mixed-effects regression modeling adjusting for age, race/ethnicity, language, marital status, insurance status, cancer, and site clustering. RESULTS The majority of individuals were members of a minority (70.7%) and uninsured or publically insured (72.7%). Diagnostic resolution was higher for navigation versus usual care at 180 days (56.2% vs 53.8%; P = .008) and 270 days (70.0% vs 68.2%; P < .001). Although there were no differences in the average number of days to resolution between the 2 groups (110 days vs 109 days; P = .63), the probability of ever having diagnostic resolution was higher for the navigation group versus the usual-care group (84.5% vs 79.6%; P < .001). The added cost of navigation versus usual care was $275 per patient (95% confidence interval, $260-$290; P < .001). There was no significant difference in stage distribution among the 12.4% of patients in the navigation group vs 11% of the usual-care patients diagnosed with cancer. CONCLUSIONS Navigation adds costs and modestly increases the probability of diagnostic resolution among patients with abnormal screening test results. Navigation is only likely to be cost-effective if improved resolution translates into an earlier cancer stage at the time of diagnosis. Cancer 2014;120:570-578. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

People with diabetes are at risk of developing complications that contribute to substantial morbidity and mortality. In 2011, the American Association of Diabetes Educators convened an invitational Reducing Risks Symposium, during which an interdisciplinary panel of 11 thought leaders examined current knowledge about the reduction and prevention of diabetes-related risks and translated evidence into diabetes care and self-management education. Symposium participants reviewed findings from the literature and engaged in a moderated roundtable discussion. This report summarizes the discussion and presents recommendations to incorporate into practice to improve outcomes. The objective of the symposium was to develop practical advice for diabetes educators and other members of the diabetes care team regarding the reduction of diabetes-related risks. Optimal diabetes management requires patients to actively participate in their care, which occurs most effectively with a multidisciplinary team. Diabetes education is an integral part of this team approach because it not only helps the patient understand diabetes, its progression, and possible complications, but also provides guidance and encouragement to the patient to engage in proactive risk-reduction decisions for optimal health. A variety of tools are available to help the diabetes educator develop an individualized, patient-centered plan for risk reduction. More research is needed regarding intervention efficacy, best practices to improve adherence, and quantification of benefits from ongoing diabetes support in risk reduction. Diabetes educators are urged to stay abreast of evolving models of care and to build relationships with health care providers both within and beyond the diabetes care team. ( Population Health Management 2013;16:74-81) [ABSTRACT FROM AUTHOR]

Purpose: To determine whether acute kidney injury (AKI) is identified within the US Food and Drug Administration's Adverse Events and Reporting System (FDA AERS) as an adverse event resulting from bisphosphonate (BP) use in cancer therapy. Methods: A search of the FDA AERS records from January 1998 through June 2009 was performed; search terms were "renal problems" and all drug names for BPs. The search resulted in 2,091 reports. We analyzed for signals of disproportional association by calculating the proportional reporting ratio for zoledronic acid (ZOL) and pamidronate. Literature review of BP-associated renal injury within the cancer setting was conducted. Results: Four hundred eighty cases of BP-associated acute kidney injury (AKI) were identified in patients with cancer. Two hundred ninety-eight patients (56%) were female; mean age was 66 ± 10 years. Multiple myeloma (n = 220, 46%), breast cancer (n = 98, 20%), and prostate cancer (n = 24, 5%) were identified. Agents included ZOL (n = 411, 87.5%), pamidronate (n = 8, 17%), and alendronate (n = 36, 2%). Outcomes included hospitalization (n = 304, 63.3%) and death (n = 68, 14%). The proportional reporting ratio for ZOL was 1.22 (95% CI, 1.13 to 1.32) and for pamidronate was 1.55 (95% CI, 1.25 to 1.65), reflecting a nonsignificant safety signal for both drugs. Conclusion: AKI was identified in BP cancer clinical trials, although a safety signal for BPs and AKI within the FDA AERS was not detected. Our findings may be attributed, in part, to clinicians who believe that AKI occurs infrequently; ascribe the AKI to underlying premorbid disease, therapy, or cancer progression; or consider that AKI is a known adverse drug reaction of BPs and thus under-report AKI to the AERS. [ABSTRACT FROM AUTHOR]

Background: In the United States, hip fracture rates have declined by 30% coincident with bisphosphonate use. However, bisphosphonates are associated with sporadic cases of atypical femoral fracture. Atypical femoral fractures are usually atraumatic, may be bilateral, are occasionally preceded by prodromal thigh pain, and may have delayed fracture-healing. This study assessed the occurrence of bisphosphonate-associated nonhealing femoral fractures through a review of data from the U.S. FDA (Food and Drug Administration) Adverse Event Reporting System (FAERS) (1996 to 2011), published case reports, and international safety efforts.Methods: We analyzed the FAERS database with use of the proportional reporting ratio (PRR) and empiric Bayesian geometric mean (EBGM) techniques to assess whether a safety signal existed. Additionally, we conducted a systematic literature review (1990 to February 2012).Results: The analysis of the FAERS database indicated a PRR of 4.51 (95% confidence interval [CI], 3.44 to 5.92) for bisphosphonate use and nonhealing femoral fractures. Most cases (n = 317) were attributed to use of alendronate (PRR = 3.32; 95% CI, 2.71 to 4.17). In 2008, international safety agencies issued warnings and required label changes. In 2010, the FDA issued a safety notification, and the American Society for Bone and Mineral Research (ASBMR) issued recommendations about bisphosphonate-associated atypical femoral fractures.Conclusions: Nonhealing femoral fractures are unusual adverse drug reactions associated with bisphosphonate use, as up to 26% of published cases of atypical femoral fractures exhibited delayed healing or nonhealing. [ABSTRACT FROM AUTHOR]

Background: In the United States, hip fracture rates have declined by 30% coincident with bisphosphonate use. However, bisphosphonates are associated with sporadic cases of atypical femoral fracture. Atypical femoral fractures are usually atraumatic, may be bilateral, are occasionally preceded by prodromal thigh pain, and may have delayed fracture-healing. This study assessed the occurrence of bisphosphonate-associated nonhealing femoral fractures through a review of data from the U.S. FDA (Food and Drug Administration) Adverse Event Reporting System (FAERS) (1996 to 2011), published case reports, and international safety efforts. Methods: We analyzed the FAERS database with use of the proportional reporting ratio (PRR) and empiric Bayesian geometric mean (EBGM) techniques to assess whether a safety signal existed. Additionally, we conducted a systematic literature review (1990 to February 2012). Results: The analysis of the FAERS database indicated a PRR of 4.51 (95% confidence interval [Cl], 3.44 to 5.92) for bisphosphonate use and nonhealingfemoral fractures. Most cases (n = 317) were attributed to use of alendronate (PRR = 3.32; 95% CI, 2.71 to 4.17). In 2008, international safety agencies issued warnings and required label changes. In 2010, the FDA issued a safety notification, and the American Society for Bone and Mineral Research (ASBMR) issued recommendations about bisphosphonate-associated atypical femoral fractures. Conclusions: Nonhealing femoral fractures are unusual adverse drug reactions associated with bisphosphonate use, as up to 26% of published cases of atypical femoral fractures exhibited delayed healing or nonhealing. [ABSTRACT FROM AUTHOR]

Individuals with type II diabetes have an increased risk of cancer diagnosis (relative risk [RR]=1.12-2.50) and mortality (RR=1.4) compared to normoglycemic individuals. Biologic mechanisms, including mitogenic effects of insulin, hyperglycemia, and increased oxidative stress, as well as behavioral factors (eg, difficulty managing the comorbidity) may explain the elevated risk. To investigate the effects of the comorbidity on disease management, the authors compared diabetes education utilization in individuals with diabetes-cancer co-morbidity to utilization by individuals with diabetes in the absence of cancer. The effect of diabetes education on outcomes was further assessed in the subset of individuals with diabetes-cancer comorbidity. Administrative claims data were used for this analysis. The study population included individuals >60 years of age and members of both commercial and Medicare Advantage health plans from a private national database of payer data, but excluded Medicare fee for service and Medicaid patients. Most of these individuals were eligible to receive reimbursement for diabetes education. Diabetes education utilization was identified using procedure codes. Outcomes were assessed for a 3-year time period. There was little difference in diabetes education utilization between individuals with diabetes in the absence of cancer (3.8% utilization) and those with diabetes-cancer comorbidity (3.5% utilization). Individuals who receive diabetes education are more likely to have multiple HbA1c tests per year, fewer emergency department visits, fewer hospital admissions, and lower care-associated costs (except for outpatient and pharmacy averages). When diabetes coexists with cancer, management of diabetes often lags, making diabetes education an imperative. ( Population Health Management 2013;16:53-57. [ABSTRACT FROM AUTHOR]

Individuals with type II diabetes have an increased risk of cancer diagnosis (relative risk [RR]=1.12-2.50) and mortality (RR=1.4) compared to normoglycemic individuals. Biologic mechanisms, including mitogenic effects of insulin, hyperglycemia, and increased oxidative stress, as well as behavioral factors (eg, difficulty managing the comorbidity) may explain the elevated risk. To investigate the effects of the comorbidity on disease management, the authors compared diabetes education utilization in individuals with diabetes-cancer co-morbidity to utilization by individuals with diabetes in the absence of cancer. The effect of diabetes education on outcomes was further assessed in the subset of individuals with diabetes-cancer comorbidity. Administrative claims data were used for this analysis. The study population included individuals >60 years of age and members of both commercial and Medicare Advantage health plans from a private national database of payer data, but excluded Medicare fee for service and Medicaid patients. Most of these individuals were eligible to receive reimbursement for diabetes education. Diabetes education utilization was identified using procedure codes. Outcomes were assessed for a 3-year time period. There was little difference in diabetes education utilization between individuals with diabetes in the absence of cancer (3.8% utilization) and those with diabetes-cancer comorbidity (3.5% utilization). Individuals who receive diabetes education are more likely to have multiple HbA1c tests per year, fewer emergency department visits, fewer hospital admissions, and lower care-associated costs (except for outpatient and pharmacy averages). When diabetes coexists with cancer, management of diabetes often lags, making diabetes education an imperative. ( Population Health Management 2013;16:53-57. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer disproportionately affects low-income and minority men. This study evaluates the impact of a patient navigation intervention on timeliness of diagnostic resolution and treatment initiation among veterans with an abnormal prostate cancer screen.Methods: Participants were enrolled between 2006 and 2010. The intervention involved a social worker and lay health worker navigation team that assisted patients in overcoming barriers to care. For navigated (n = 245) versus control (n = 245) participants, we evaluated rates of diagnostic resolution and treatment and adjusted for race, age, and Gleason score.Results: Of 490 participants, 68% were African American, 47% were ≥ 65 years old, and 35% had cancer. Among those with an abnormal screen, navigation did not have a significant effect on time to diagnostic resolution compared to controls (median days of 97 versus 111; adj. HR 1.17, 95% CI, 0.96-1.43, p = 0.12). On analysis of the period beyond 80 days, navigated men reached resolution faster than controls (median of 151 days versus 190 days; adj. HR 1.41, 95% CI, 1.07-1.86, p = 0.01). Among those with cancer, navigation did not have a significant effect on time to treatment initiation compared to controls (median of 93 days versus 87 days; adj. HR 1.15, 95% CI, 0.82-1.62, p = 0.41).Conclusion: Our navigation program did not significantly impact the overall time to resolution or treatment for men with prostate cancer compared to controls. The utility of navigation programs may extend beyond targeted navigation times, however, and future studies focusing on other outcomes measures are therefore needed. [ABSTRACT FROM AUTHOR]

Purpose: Pharmaceutical safety is a public health issue. In 2005, the Connecticut Attorney General (AG) raised concerns over adverse drug reactions in off-label settings, noting that thalidomide was approved to treat a rare illness, but more than 90% of its use was off label. A hematologist had reported thalidomide with doxorubicin or dexamethasone was associated with venous thromboembolism (VTE) rates of 25%. We review US Food and Drug Administration (FDA) and manufacturer responses to a citizenpetition filed to address these thalidomide safety issues. Methods: Case study. Results: The AG petitioned the FDA requesting thalidomide related safety actions. Coincidentally, the manufacturer submitted a supplemental New Drug Approval (sNDA), requesting approval to treat multiple myeloma with thalidomide-dexamethasone. FDA safety officers reviewed the petition and the literature and noted that VTE risks with thalidomide were not appropriately addressed in the existing package insert. In the sNDA application, the manufacturer reported thalidomide-associated toxicities for multiple myeloma were primarily somnolence and neurotoxicity, and a proposed package insert did not focus on VTE risks. In October, the FDA informed the Oncology Drug Division that VTE risks with thalidomide were poorly addressed in the existing label. After reviewing this memorandum, an Oncology Drug Division reviewer informed the manufacturer that approval of the sNDA would be delayed until several thalidomide-associated VTE safety actions, including revisions of the package insert, were implemented. The manufacturer and FDA agreed on these actions, and the sNDA was approved. Conclusion: New approaches addressing off-label safety are needed. The conditions that facilitated the successful response to this citizen petition are uncommon. [ABSTRACT FROM AUTHOR]

Thienopyridine-derivatives (ticlopidine, clopidogrel, and prasugrel) are the primary antiplatelet agents. Thrombotic thrombocytopenic purpura (TTP) is a rare drug-associated syndrome, with the thienopyridines being the most common drugs implicated in this syndrome. We reviewed 20 years of information on clinical, epidemiologic, and laboratory findings for thienopyridine-associated TTP. Four, 11, and 11 cases of thienopyridine-associated TTP were reported in the first year ofmarketing of ticlopidine (1989), clopidogrel (1998), and prasugrel (2010), respectively. As of 2011, the FDA received reports of 97 ticlopidine-, 197 clopidogrel-, and 14 prasugrel-associated TTP cases. Severe deficiency of ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) was present in 80% and antibodies to 100% of these TTP patients on ticlopidine, 0% of the patients with clopidogrelassociated TTP (p < 0.05), and an unknown percentage of patients with prasugrel-associated TTP. TTP is associated with use of each of the three thienopyridines, although the mechanistic pathways may differ. [ABSTRACT FROM AUTHOR]

Background Patient navigation (PN) is a method for addressing racial-ethnic and socioeconomically based disparities in cancer-related care. Patient navigators provide logistic and emotional support to underserved patients to facilitate successful completion of diagnostic and treatment care. Yet, little is known about patient satisfaction with the relationship with a navigator due to a dearth of instruments measuring satisfaction. Objective The objective of this study was to validate the Patient Satisfaction with Interpersonal Relationship with Navigator (PSN-I) measure for patients undergoing diagnostic and/or therapeutic cancer care. Methods We administered the PSN-I to 783 participants from the nine different sites of the National Cancer Institute sponsored Patient Navigation Research Program. We evaluated the latent structure and internal consistency of the PSN-I using principal components analysis (PCA) and Cronbach coefficient alpha ( α), respectively. We used correlation analyses to examine divergence and convergence of the PSN-I with the Patient Satisfaction with Cancer-related Care (PSCC), the Rapid Estimate of Adult Literacy in Medicine (REALM) Long Form, and patients' demographics. Results The PCA revealed a coherent set of items that explicates 76.6% of the variance in PSN-I. Reliability assessment revealed high internal consistency ( α ranging from 0.95 to 0.96). The PSN-I had good face validity as well as convergent and divergent validities as indicated by moderate correlations with score on the PSCC (all ps < 0.0001) and non-significant correlations with primary language, marital status, and scores on the REALM Long Form (all ps > 0.05). Conclusion The PSN-I is a valid and suitable measure of satisfaction with a patient navigator for the present sample. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: Although amiodarone is the most commonly prescribed anti-arrhythmic drug, its use is limited by serious toxicities, including optic neuropathy. Current reports of amiodarone-associated optic neuropathy identified from the Food and Drug Administration''s Adverse Event Reporting System and published case reports were reviewed. A total of 296 reports were identified: 214 from the Adverse Event Reporting System, 59 from published case reports, and 23 from adverse events reports for patients enrolled in clinical trials. Mean duration of amiodarone therapy before vision loss was 9 months (range 1-84 months). Insidious onset of amiodarone-associated optic neuropathy (44%) was the most common presentation, and nearly one third were asymptomatic. Optic disk edema was present in 85% of cases. Following drug cessation, 58% had improved visual acuity, 21% were unchanged, and 21% had further decreased visual acuity. Legal blindness (<20/200) was noted in at least one eye in 20% of cases. Close ophthalmologic surveillance of patients during the tenure of amiodarone administration is warranted. [Copyright &y& Elsevier]

We investigated a recent (January 1999 to December 2009) cohort of 95 elderly Hodgkin lymphoma subjects. At diagnosis, me- dian age was 67 years (range, 60-89 years), whereas 61% had significant comorbidity, 26% were unfit, 17% had a geriatric syndrome, and 13% had loss of activities of daily living. Overall response rate to therapy was 85%, whereas incidence of bleomycin lung toxicity was 32% (with associated mortality rate, 25%). With 66-month median follow-up, 2-year and 5-year overall survival were 73% and 58%, respectively (advanced-stage, 63% and 46%, respectively). Most International Prognostic Score factors were not prognostic on univariate analyses, whereas Cox multivariate regression identified 2 risk factors associated with inferior overall survival: (1) age more than 70 years (2.24; 95% CI, 1.1 6-4.33, P = .02) and (2) loss of activities of daily living (2.71; 95% Cl, 1.07-6.84, P = .04). Furthermore, a novel survival model based on number of these risk factors (0, 1, or 2) showed differential 2-year OS of 83%, 70%, and 13%, respectively (P < .0001) and 5-year OS of 73%, 51%, and 0%, respectively (P < .0001). [ABSTRACT FROM AUTHOR]

The article focuses on a conceptual model to evaluate the cost-effectiveness of cancer navigation programs such as the one used by the Patient Navigation Research Program (PNRP), a multicenter study supported by the National Cancer Institute in the U.S. It states that navigation programs improve access to healthcare but their efficiency, efficacy of cancer diagnostic and therapeutic services remain unclear. PNRP examines navigation programs that reduce time to deliver a quality cancer care.

Thrombotic thrombocytopenic purpura (TTP) is a fulminant disease characterized by platelet aggregates, thrombocytopenia, renal insufficiency, neurologic changes, and mechanical injury to erythrocytes. Most idiopathic cases of TTP are characterized by a deficiency of ADAMTS13 (a disintegrin and metalloprotease, with thrombospondin-1-like domains) metalloprotease activity. Ironically, use of anti-platelet agents, the thienopyridine derivates clopidogrel and ticlopidine, is associated with drug induced TTP. Data were abstracted from a systematic review of English-language literature for thienopyridine-associated TTP identified in MEDLINE, EMBASE, the public website of the Food and Drug Administration, and abstracts from national scientific conferences from 1991 to April 2008. Ticlopidine and clopidogrel are the two most common drugs associated with TTP in FDA safety databases. Epidemiological studies identify recent initiation of anti-platelet agents as the most common risk factor associated with risks of developing TTP. Laboratory studies indicate that most cases of thienopyridine-associated TTP involve an antibody to ADAMTS13 metalloprotease, present with severe thrombocytopenia, and respond to therapeutic plasma exchange (TPE); a minority of thienopyridine-associated TTP presents with severe renal insufficiency, involves direct endothelial cell damage, and is less responsive to TPE. The evaluation of this potentially fatal drug toxicity can serve as a template for future efforts to comprehensively characterize other severe adverse drug reactions.Kidney International (2009) 75, S20–S24; doi:10.1038/ki.2008.613 [ABSTRACT FROM AUTHOR]

Background and Objective: The antiretroviral nevirapine can cause severe hepatotoxicity when used 'off-label' for preventing mother-to-child HIV transmission (PMTCT), newborn post-exposure prophylaxis and for pre- and post-exposure prophylaxis among non-HIV-infected individuals. We describe the incidence of hepatotoxicity with short- versus long-course nevirapine-containing regimens in these groups.Methods: We reviewed hepatotoxicity cases among non-HIV-infected individuals and HIV-infected pregnant women and their offspring receiving short- (or=5 days) nevirapine prophylaxis. Sources included adverse event reports from pharmaceutical manufacturers and the US FDA, reports from peer-reviewed journals/scientific meetings and the Research on Adverse Drug events And Reports (RADAR) project. Hepatotoxicity was scored using the AIDS Clinical Trial Group criteria.Results: Toxicity data for 8216 patients treated with nevirapine-containing regimens were reviewed. Among 402 non-HIV-infected individuals receiving short- (n=251) or long-course (n=151) nevirapine, rates of grade 1-2 hepatotoxicity were 1.99% versus 5.30%, respectively, and rates of grade 3-4 hepatotoxicity were 0.00% versus 13.25%, respectively (p<0.001 for both comparisons). Among 4740 HIV-infected pregnant women receiving short- (n=3031) versus long-course (n=1709) nevirapine, rates of grade 1-2 hepatotoxicity were 0.62% and 7.04%, respectively, and rates of grade 3-4 hepatotoxicity were 0.23% versus 4.39%, respectively (p<0.001 for both comparisons). The rates of grade 3-4 hepatotoxicity among 3074 neonates of nevirapine-exposed HIV-infected pregnant women were 0.8% for those receiving short-course (n=2801) versus 1.1% for those receiving long-course (n=273) therapy (p<0.72).Conclusions: Therapy duration appears to significantly predict nevirapine hepatotoxicity. Short-course nevirapine for HIV prophylaxis is associated with fewer hepatotoxic reactions for non-HIV-infected individuals or pregnant HIV-infected women and their offspring, but administration of prophylactic nevirapine for >or=2 weeks appears to be associated with high rates of hepatotoxicity among non-HIV-infected individuals and HIV-infected pregnant mothers. When full highly active antiretroviral therapy (HAART) regimens are not available, single-dose nevirapine plus short-course nucleoside reverse transcriptase inhibitors to decrease the development of HIV viral resistance is an essential therapeutic option for PMTCT and these data support the safety of single-dose nevirapine in this setting. [ABSTRACT FROM AUTHOR]

Background: Cost-related medication non-adherence may be influenced by patients' perceived importance of their medications. Objectives: This exploratory pilot study addresses three related but distinct questions: Do patients perceive different levels of importance among their medications? What factors influence perceptions of medication importance? Is perceived importance associated with perceived worth of medications, and does expense impact on that association? Methods: Study participants included individuals aged >60 years who were taking three or more prescription drugs. Semi-structured, in-person interviews were conducted to measure how patients rated their medications in terms of importance, expense and worth. Factors that influenced medication importance were identified using qualitative analysis. Ordinal logistic regression analyses were employed to examine the association between perceived importance and perceived worth of medications, and the impact of expense on that association. Results: For 143 prescription drugs reported by 20 participants, the weighted mean rating of medication importance was 8.2 (SD 1.04) on a scale from 0 (not important at all) to 10 (most important). Patients considered 38% of these medications to he expensive. The weighted mean rating of worth was 8.4 (SD 1.46) on a scale from 0 (not worth it at all) to 10 (most worth). Three major factors influenced medication importance; drug-related (characteristics, indications, effects and alternatives); patient-related (knowledge, attitudes and health); and external (the media, healthcare and family caregivers, and peers). Regression analyses showed an association between perceived importance and perceived worth for inexpensive medications (odds ratio [OR] 2.23; p = 0.002) and an even greater association between perceived importance and perceived worth for expensive medications (OR 4.29; p < 0.001 ). Discussion: This study provides preliminary evidence that elderly patients perceive different levels of importance for their medications based on factors beyond clinical efficacy. Their perception of importance influences how they perceive their medications" worth, especially for medications of high costs. Understanding how patients perceive medication importance may help in the development of interventions to reduce cost-related non-adherence. [ABSTRACT FROM AUTHOR]

The article discusses research which was conducted to review the mortality and venous thrombembolism (VTE) risks associated with administration of erythropoiesis-stimulating agent (ESA) for treating chemotherapy-associated anemia in patients with nonmyeloid malignancies. The data used included a published overview from the Cochrane Collaboration, MEDLINE and EMBASE databases, the web site of the U.S. Food and Drug Administration and ESA manufacturers and safety advisories. The selection used for review was phase 3 trials comparing ESAs with placebo or standard of care for anemia treatment in cancer patients. Research found that ESA administration to cancer patients is associated with increased risks of VTE and mortality.

Objectives: We sought to describe clinical and laboratory findings for a large cohort of patients with thienopyridine-associated thrombotic thrombocytopenic purpura (TTP). Background: The thienopyridine derivatives, ticlopidine and clopidogrel, are the 2 most common drugs associated with TTP in databases maintained by the U.S. Food and Drug Administration (FDA). Methods: Clinical reports of TTP associated with clopidogrel and ticlopidine were identified from medical records, published case reports, and FDA case reports (n = 128). Duration of thienopyridine exposure, clinical and laboratory findings, and survival were recorded. ADAMTS13 activity (n = 39) and inhibitor (n = 30) were measured for a subset of individuals. Results: Compared with clopidogrel-associated TTP cases (n = 35), ticlopidine-associated TTP cases (n = 93) were more likely to have received more than 2 weeks of drug (90% vs. 26%), to be severely thrombocytopenic (84% vs. 60%), and to have normal renal function (72% vs. 45%) (p < 0.01 for each). Compared with TTP patients with ADAMTS13 activity >15% (n = 13), TTP patients with severely deficient ADAMTS13 activity (n = 26) were more likely to have received ticlopidine (92.3% vs. 46.2%, p < 0.003). Among patients who developed TTP >2 weeks after thienopyridine, therapeutic plasma exchange (TPE) increased likelihood of survival (84% vs. 38%, p < 0.05). Among patients who developed TTP within 2 weeks of starting thienopyridines, survival was 77% with TPE and 78% without. Conclusions: Thrombotic thrombocytopenic purpura is a rare complication of thienopyridine treatment. This drug toxicity appears to occur by 2 different mechanistic pathways, characterized primarily by time of onset before versus after 2 weeks of thienopyridine administration. If TTP occurs after 2 weeks of ticlopidine or clopidogrel therapy, therapeutic plasma exchange must be promptly instituted to enhance likelihood of survival. [Copyright &y& Elsevier]

The article reports on a study which evaluated serious adverse drug reaction (ADR) descriptions in the U.S. Food and Drug Administration (FDA) and Research on Adverse Drug events And Reports (RADAR) databases. The comprehensiveness of notifications sent out by drug manufacturers and the RADAR researchers was also studied. Results indicated that the proactive safety activities of the RADAR researchers are more comprehensive than those performed by drug companies and the FDA.

Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) and granulocyte colony-stimulating factor (G-CSF) promote haematopoietic progenitor cell maturation. We reviewed the findings for healthy volunteers/donors who developed haematological malignancies following PEG-rHuMGDF or G-CSF administration. Information was reviewed for three of 538 volunteers who received PEG-rHuMGDF in clinical trials and two of 200 donors who underwent G-CSF mobilised stem cell harvesting procedures for sibling stem cell transplants. Mantle cell, diffuse large B-cell lymphoma and chronic lymphocytic leukaemia were diagnosed 1–5 years after PEG-rHuMGDF exposure among three volunteers. For one patient, thrombocytopenia due to autoantibodies to PEG-rHuMGDF developed shortly after PEG-rHuMGDF administration and persisted until chemotherapy was administered. All three achieved complete remission, although one patient relapsed. Acute myeloid leukaemia was diagnosed 4 and 5 years after G-CSF mobilisation in two donors who underwent peripheral blood stem cell donation for sibling allogeneic haematopoietic stem cell transplantation. Following intensive chemotherapy, one died from acute leukaemia and the second is in complete remission. Controversy exists over the appropriateness of administering haematopoietic growth factors to healthy individuals. While a causal relationship with haematological malignancies cannot be demonstrated, long-term follow-up among healthy individuals who receive haematopoietic growth factors is needed. [ABSTRACT FROM AUTHOR]

Objectives: We undertook the review of all available cases of hypersensitivity reactions after placement of a drug-eluting stent (DES) and classified potential causes. Background: Six months after the approval of the first DES, the Food and Drug Administration (FDA) reported 50 hypersensitivity reactions after stent placement but later concluded these were due to concomitantly prescribed medications such as clopidogrel. Nevertheless, the FDA continued to receive reports of hypersensitivity. Methods: Reports available from April 2003 through December 2004 for hypersensitivity-like reactions associated with the sirolimus-eluting stent (CYPHER, Cordis Corp., Miami Lakes, Florida) and paclitaxel-eluting stent (TAXUS, Boston Scientific Corp., Natick, Massachusetts) were reviewed. Sources of reports included the FDA’s adverse-device-event database, the published literature, and investigators from the Research on Adverse Drug/Device events And Reports (RADAR) project. Causality was assessed using standardized World Health Organization criteria. Results: Of 5,783 reports identified for the DES in the FDA database, 262 unique events included hypersensitivity symptoms. Of these reports, 2 were certainly and 39 unlikely caused by clopidogrel and 1 was certainly, 9 probably, and 13 unlikely caused by the DES. From all sources, we identified 17 distinct cases that were probably or certainly caused by the stent, of which 9 had symptoms that lasted longer than four weeks. Four autopsies confirmed intrastent eosinophilic inflammation, thrombosis, and lack of intimal healing. Conclusions: The FDA reports and autopsy findings suggest that DES may be a cause of systemic and intrastent hypersensitivity reactions that, in some cases, have been associated with late thrombosis and death. [Copyright &y& Elsevier]

Context In 1998, a multidisciplinary team of investigators initiated RADAR (Research on Adverse Drug events And Reports), a clinically based postmarketing surveillance program that systematically investigates and disseminates information describing serious and previously unrecognized adverse drug and device reactions (ADRs). Objective To describe the structure, operations, and preliminary findings from the RADAR project and related dissemination efforts by pharmaceutical suppliers and the US Food and Drug Administration (FDA). Design After identifying a serious and unexpected clinical event suitable for further investigation, RADAR collaborators postulated clinical hypotheses and derived case series and incidence estimates from physician queries, published and unpublished clinical trials, published case reports, FDA databases, and manufacturer sales figures. Results RADAR investigators identified 16 types of serious ADRs among 1699 patients, of whom 169 (10%) died as a result of the reaction. Initial cases were identified by 7 RADAR investigators, 4 collaborating physicians, 2 attorneys, and by reviewing 3 published reports. Additional sources included queries of occupational health programs and medical directors of interventional cardiology laboratories (3 types of ADRs), published manuscripts and clinical trials (11 types of ADRs), review of medical records at a RADAR site (2 types of ADRs), unpublished clinical trial reports (3 types of ADRs), and reports from attorneys, family members, or patients (4 types of ADRs). Incidence estimates, ranging from 0.4% to 33%, were derived from 5 clinical trial reports, 2 physician queries, and 2 observational databases. Laboratory support for hypotheses included identification of 3 neutralizing antibodies and 3 histopathological findings. ADR reports were disseminated as 8 revised package inserts, 7 “dear doctor” letters, and 9 peer-reviewed articles. Conclusion A new, clinically based, hypothesis-driven approach to postmarketing surveillance may supplement existing regulatory surveillance systems and improve patient safety. [ABSTRACT FROM AUTHOR]

The article presents a study on the activity of ADAMTS13, a disintegrin and metalloprotease with thrombospondin type 1 motifs 13, activity among ticlopidine-associated thrombotic thrombocytopenic purpura (TTP) patients in Japan. The study mentions that ADAMTS13 is involved in peptide bond cleavage between the amino acids Thymine1605 and Metionine1606 in the A2 domain of the von willebrand factor (VWF). The study reported deficient activity of ADAMTS13 in ticlopidine-associated TTP patients.

Thrombotic thrombocytopenic purpura (TTP) is a fulminant disease characterized by platelet aggregates, thrombocytopenia, renal insufficiency, neurologic changes, and mechanical injury to erythrocytes. Most idiopathic cases of TTP are characterized by a deficiency of ADAMTS13 ( a d isintegrin a nd m etalloprotease, with t hrombo s pondin-1-like domains) metalloprotease activity. Ironically, use of anti-platelet agents, the thienopyridine derivates clopidogrel and ticlopidine, is associated with drug induced TTP. Data were abstracted from a systematic review of English-language literature for thienopyridine-associated TTP identified in MEDLINE, EMBASE, the public website of the Food and Drug Administration, and abstracts from national scientific conferences from 1991 to April 2008. Ticlopidine and clopidogrel are the two most common drugs associated with TTP in FDA safety databases. Epidemiological studies identify recent initiation of anti-platelet agents as the most common risk factor associated with risks of developing TTP. Laboratory studies indicate that most cases of thienopyridine-associated TTP involve an antibody to ADAMTS13 metalloprotease, present with severe thrombocytopenia, and respond to therapeutic plasma exchange (TPE); a minority of thienopyridine-associated TTP presents with severe renal insufficiency, involves direct endothelial cell damage, and is less responsive to TPE. The evaluation of this potentially fatal drug toxicity can serve as a template for future efforts to comprehensively characterize other severe adverse drug reactions. [ABSTRACT FROM AUTHOR]

Background: Between 1988 and 1998, antibody-associated pure red-cell aplasia was reported in three patients who had undergone treatment with recombinant human erythropoietin (epoetin). Between 1998 and 2000, 13 such cases were reported from France — 12 in patients who had received the Eprex formulation of epoetin alfa and 1 in a patient who had received Neorecormon (a formulation of epoetin beta); both are products that are marketed outside the United States. Methods: We obtained reports of epoetin-associated pure red-cell aplasia from the Food and Drug Administration and from the manufacturers of Eprex, Epogen (another formulation of epoetin alfa), and Neorecormon. The numbers of case reports and estimates of exposure-adjusted incidence were analyzed according to the product, the cause of anemia, the route of administration, the country in which pure red-cell aplasia was identified, and the date on which pure red-cell aplasia was reported. Results: Between January 1998 and April 2004, 175 cases of epoetin-associated pure red-cell aplasia were reported for Eprex, 11 cases for Neorecormon, and 5 cases for Epogen. Over half these cases had occurred in France, Canada, the United Kingdom, and Spain. Between 2001 and 2003, the estimated exposure-adjusted incidence was 18 cases per 100,000 patient-years for the Eprex formulation without human serum albumin, 6 per 100,000 patient-years for the Eprex formulation with human serum albumin, 1 case per 100,000 patient-years for Neorecormon, and 0.2 case per 100,000 patient-years for Epogen. After procedures were adopted to ensure appropriate storage, handling, and administration of Eprex to patients with chronic kidney disease, the exposure-adjusted incidence decreased by 83 percent worldwide. Conclusions: After the peak incidence of Eprex-associated pure red-cell aplasia was reached in 2001, interventions designed in response to drug-monitoring programs worldwide resulted in a reduction of more than 80 percent in the incidence of pure red-cell aplasia due to Eprex. N Engl J Med 2004;351:1403-8. [ABSTRACT FROM AUTHOR]