Bovine thrombin safety reporting: an example of study design and publication bias.

BACKGROUND: Bovine thrombin, a popular hemostat and sealant since 1945, has recently been subjected to clinical trial testing due to reformulations in 1998. We sought to compare adverse event rates of early observational studies with those of later interventional trials. METHODS: A MEDLINE-based literature search in publications that report safety in bovine thrombin exposed surgical patients was extracted and reviewed. RESULTS: In 38 studies, about half were case reports and 31.5% were interventional trials. In case reports, 41% of authors reported severe coagulopathic adverse events. In contrast, whereas blood complications were common in large trials, no association of harm was established for bovine thrombin product exposure and/or immunization. CONCLUSIONS: In this review, later clinical trials failed to reproduce the common and severe coagulopathy predicted by earlier observational studies in bovine exposed patients. This example illustrates that perceptions of safety can change as a function of study design, even for a widely adopted, well established biologic such as thrombin. Caution must be exercised in interpreting evidence from observational studies alone.

Over-the-counter ibuprofen and risk of gastrointestinal bleeding complications: a systematic literature review.

BACKGROUND: Exposure to over-the-counter (OTC) ibuprofen and other OTC non-steroidal anti-inflammatory drugs (NSAIDs) is substantial. Although the literature on gastrointestinal (GI) safety of NSAID therapy is extensive, the risk profiles of OTC and prescription dosing are seldom separated, and few studies provide risks specific to OTC ibuprofen. OBJECTIVE: To conduct a literature review to evaluate the risk of GI bleeding events related to OTC ibuprofen use. METHODS: Published clinical trials, observational studies, and meta-analyses of OTC ibuprofen use, defined as up to 1200 mg/day or stated as 'over the counter,' reporting endpoints of incidence rates and proportions of GI bleeding events (e.g., GI bleeding-related hospitalizations and deaths) were identified via MEDLINE through 2010. Data from these studies were summarized. RESULTS: Twenty studies (nine observational, ten clinical trials, one meta-analysis) reporting incidence rates and proportions of a GI bleeding-related event associated with OTC or OTC-specific doses of ibuprofen were included. The frequency of a GI-related hospitalization was <0.2% for patients on OTC-comparable doses. Incidence rates among those using OTC-comparable doses ranged from 0 to 3.19 per 1000 patient-years. The incidence of a GI bleeding-related event increased with age and the use of concomitant medications, and there was a general, though not always statistically significant, ibuprofen dose-response relationship. The relative risk of any GI bleeding-related event ranged from 1.1 to 2.4 for users of OTC-specific doses of ibuprofen compared to non-users. CONCLUSIONS: Studies reported low incidence of GI bleeding events with use of OTC ibuprofen. Few published studies that specifically investigated OTC ibuprofen use were identified. Varying methodologies and definitions of exposure and outcomes prevented direct comparison of many results. Only studies that used the methods herein described were identified. Further research evaluating the risk of GI bleeding events in patients taking OTC-specific ibuprofen use may be useful.

Costs associated with febrile neutropenia in the US.

BACKGROUND AND OBJECTIVE: Febrile neutropenia (FN) is a potentially life-threatening condition that may develop in cancer patients treated with myelosuppressive chemotherapy and result in considerable costs. This study was designed to estimate US healthcare utilization and costs in those experiencing FN by location of care, tumour type and mortality. METHODS: Cancer patients who received chemotherapy between 2001 and 2006 were identified from the HealthCore Integrated Research Database®, a longitudinal claims database with enrolment, medical, prescription and mortality information covering 12 health plans and more than 20 million US patients. Patients who experienced FN were prospectively matched using propensity score methods within each tumour type of interest (non-Hodgkin's lymphoma, breast, lung, colorectal and ovarian cancer) to those not experiencing FN. Health resource utilization was compared per patient per month for unique prescriptions and visits (inpatient and outpatient) over the length of follow-up. Healthcare total paid costs adjusted to 2009 US dollars per patient per month were examined by FN group (FN vs non-FN, FN died vs FN survived), by source of care (physician office visit, outpatient services, hospitalization and prescriptions) and by tumour type. The number of unique FN-related encounters (inpatient and outpatient) and the number of patients experiencing at least one FN-related encounter were examined. The costs per encounter were tabulated. FN encounters differ from FN episodes in that a single FN episode may include multiple FN encounters (i.e. a patient is seen multiple times [encounters] for treatment of a single FN event [episode]). RESULTS: A total of 5990 patients each were successfully matched between the FN and non-FN (control) groups. Health resource utilization was generally higher in those with FN than in controls. FN patients incurred greater costs (mean ± SD: $US9628 ± 12 517 per patient-month) than non-FN patients ($US8478 ± 12 978). Chemotherapy comprised the majority of costs for both FN (33.5%) and non-FN (40.6%) patients. The largest cost difference by categorical source of care was for hospitalization (p < 0.001). FN patients who died had the highest mean total costs compared with FN surviving patients ($US21 214 ± 25 596 per patient-month vs $US8227 ± 8850, respectively). Follow-up time for those surviving was, on average, 6.6 months longer. Hospitalization accounted for 53.1% of costs in those experiencing mortality with FN, while chemotherapy accounted for the majority of costs (37.1%) in surviving FN patients. A total of 6574 patients with at least one FN encounter experienced a total of 55 726 unique FN-related encounters, 90% of which were outpatient in nature. The majority of FN-related encounters (79%) occurred during the first chemotherapy course. The average costs for FN encounters were highest for inpatient encounters, $US22 086 ± 43 407, compared with $US985 ± 1677 for outpatient encounters. CONCLUSIONS: The occurrence of FN in cancer patients receiving chemotherapy results in greater healthcare resource utilization and costs, with FN patients who die accounting for the greatest healthcare costs. Most FN patients experience at least one outpatient FN encounter, and the total cost of treatment for FN continues to be high.

Risk of mortality in patients with cancer who experience febrile neutropenia.

BACKGROUND: Febrile neutropenia (FN) is a serious and potentially life-threatening condition that may develop in patients with cancer who receive myelosuppressive chemotherapy. The risk of mortality from FN is not well characterized in current clinical practice. METHODS: Patients with cancer who were receiving chemotherapy in clinical practice were identified from a large US healthcare claims database, and mortality was confirmed using the National Death Index. Patients with FN had their propensity scores matched within tumor types of interest (non-Hodgkin lymphoma and breast, lung, colorectal, and ovarian cancers) to patients who did not experience FN. Study endpoints of overall mortality (anytime during follow-up), early mortality (during the first 12 months of the first chemotherapy course), and hospitalization were examined using univariate and multivariate techniques. RESULTS: Matched FN and control groups each included 5990 patients, and the average follow-up for both groups was 17.6 months. Crude incidence rates of early mortality were significantly higher for patients with FN compared with controls for all tumor types. Proportional hazards regression demonstrated a significant increase in the risk of overall and early mortality in patients with FN compared with controls (hazard ratio [HR], 1.15 [95% confidence interval, 1.02-1.29] and HR, 1.35 [95% confidence interval, 1.09-1.67], respectively). CONCLUSIONS: The adjusted risk of mortality in patients who experienced FN was at least 15% higher than in comparably matched patients without FN, supporting the inference that infectious complications because of neutropenia resulting from myelosuppressive chemotherapy are clinically important.

Exogenous bovine thrombin as a biomarker of exposure and outcome.

Bovine thrombin has been used for more than 60 years as a surgical hemostat and sealant. Rare postsurgical events have been attributed to antibovine thrombin immunoglobulins cross-reacting with human homologs. In a literature review of 37 papers reporting safety outcomes in surgical patients, we extracted each paper for a quantitative measurement of bovine thrombin exposure and coagulopathic outcomes. We found that 59.5% of papers documented the commercial source of bovine thrombin and only 19% provided an estimate of exposure in units. Conventional tests for hypocoagulation were common (86%); however, only 9% of papers confirmed this inhibition as an isolated antibody. In addition, only 9% of papers cited a specific biomarker for thrombosis.