Prevalence of apolipoprotein E4 genotype and homozygotes (APOE e4/4) among patients diagnosed with Alzheimer's disease: a systematic review and meta-analysis.

BACKGROUND: Population allele frequencies of apolipoprotein E (APOE) vary by geographic region. The purpose of this study is to summarize and evaluate published estimates for the prevalence of APOE e4 carrier status among the population diagnosed with Alzheimer's disease (AD) by geographic region and country. METHODS: A systematic review of English-language publications from January 1, 1985, through May 31, 2010, was conducted. Studies reporting APOE e4 status for patients diagnosed with AD were included in the analysis; trials and autopsies were excluded. APOE e4 data were pooled, and prevalence and 95% confidence intervals (CIs) were calculated. RESULTS: Pooled estimates for APOE e4 carrier prevalence data were derived from 142 independent samples: 48.7% (95% CI: 46.5-51.0), and from 73 samples for e4/4 (homozygotes): 9.6% (95% CI: 8.4-10.8). The highest estimates were in Northern Europe: 61.3% (95% CI: 55.9-66.7), e4/4 prevalence: 14.1% (95% CI: 12.2-16.0). The lowest estimates were in Asia and Southern Europe. Substantial heterogeneity of these prevalence estimates was observed. CONCLUSIONS: APOE e4 genotype prevalence varies among AD patients by region and within each country. Further exploration is warranted to better understand the substantial heterogeneity of these prevalence estimates.

A systematic review of validated methods for identifying erythema multiforme major/minor/not otherwise specified, Stevens-Johnson Syndrome, or toxic epidermal necrolysis using administrative and claims data.

PURPOSE: The Food and Drug Administration's (FDA) Mini-Sentinel pilot program aims to conduct active surveillance to refine safety signals that emerge for marketed medical products. A key facet of this surveillance is to develop and understand the validity of algorithms for identifying health outcomes of interest (HOIs) from administrative and claims data. This paper summarizes the process and findings of the algorithm review of erythema multiforme and related conditions. METHODS: PubMed and Iowa Drug Information Service searches were conducted to identify citations applicable to the erythema multiforme HOI. Level 1 abstract reviews and Level 2 full-text reviews were conducted to find articles that used administrative and claims data to identify erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis and that included validation estimates of the coding algorithms. RESULTS: Our search revealed limited literature focusing on erythema multiforme and related conditions that provided administrative and claims data-based algorithms and validation estimates. Only four studies provided validated algorithms and all studies used the same International Classification of Diseases code, 695.1. Approximately half of cases subjected to expert review were consistent with erythema multiforme and related conditions. CONCLUSIONS: Updated research needs to be conducted on designing validation studies that test algorithms for erythema multiforme and related conditions and that take into account recent changes in the diagnostic coding of these diseases.

A systematic review of validated methods for identifying anaphylaxis, including anaphylactic shock and angioneurotic edema, using administrative and claims data.

PURPOSE: The Food and Drug Administration's Mini-Sentinel pilot program initially aims to conduct active surveillance to refine safety signals that emerge for marketed medical products. A key facet of this surveillance is to develop and understand the validity of algorithms for identifying health outcomes of interest from administrative and claims data. This article summarizes the process and findings of the algorithm review of anaphylaxis. METHODS: PubMed and Iowa Drug Information Service searches were conducted to identify citations applicable to the anaphylaxis health outcome of interest. Level 1 abstract reviews and Level 2 full-text reviews were conducted to find articles using administrative and claims data to identify anaphylaxis and including validation estimates of the coding algorithms. RESULTS: Our search revealed limited literature focusing on anaphylaxis that provided administrative and claims data-based algorithms and validation estimates. Only four studies identified via literature searches provided validated algorithms; however, two additional studies were identified by Mini-Sentinel collaborators and were incorporated. The International Classification of Diseases, Ninth Revision, codes varied, as did the positive predictive value, depending on the cohort characteristics and the specific codes used to identify anaphylaxis. CONCLUSIONS: Research needs to be conducted on designing validation studies to test anaphylaxis algorithms and estimating their predictive power, sensitivity, and specificity.

A systematic review of validated methods for identifying hypersensitivity reactions other than anaphylaxis (fever, rash, and lymphadenopathy), using administrative and claims data.

PURPOSE: The Food and Drug Administration's Mini-Sentinel pilot program aims to conduct active surveillance to refine safety signals that emerge for marketed medical products. A key facet of this surveillance is to develop and understand the validity of algorithms for identifying health outcomes of interest from administrative and claims data. This article summarizes the process and findings of the algorithm review of hypersensitivity reactions. METHODS: PubMed and Iowa Drug Information Service searches were conducted to identify citations applicable to the hypersensitivity reactions of health outcomes of interest. Level 1 abstract reviews and Level 2 full-text reviews were conducted to find articles using administrative and claims data to identify hypersensitivity reactions and including validation estimates of the coding algorithms. RESULTS: We identified five studies that provided validated hypersensitivity-reaction algorithms. Algorithm positive predictive values (PPVs) for various definitions of hypersensitivity reactions ranged from 3% to 95%. PPVs were high (i.e. 90%-95%) when both exposures and diagnoses were very specific. PPV generally decreased when the definition of hypersensitivity was expanded, except in one study that used data mining methodology for algorithm development. CONCLUSIONS: The ability of coding algorithms to identify hypersensitivity reactions varied, with decreasing performance occurring with expanded outcome definitions. This examination of hypersensitivity-reaction coding algorithms provides an example of surveillance bias resulting from outcome definitions that include mild cases. Data mining may provide tools for algorithm development for hypersensitivity and other health outcomes. Research needs to be conducted on designing validation studies to test hypersensitivity-reaction algorithms and estimating their predictive power, sensitivity, and specificity.

Nurse workload in implementing a tight glycaemic control protocol in a UK hospital: a pilot time-in-motion study.

AIMS AND OBJECTIVES: The cumulative time that critical care nurses spend implementing a tight glycaemic control (TGC) protocol was estimated in a time-in-motion (TiM) study conducted in a hospital in the UK. BACKGROUND: TGC protocols were introduced to the critical care setting to reduce hyperglycaemic events in high-risk patients. The time burden to critical care nurses of implementing such protocols has not yet been studied in the UK. DESIGN: A prospective TiM pilot study was conducted in an eligible UK intensive care unit by four protocol-trained observers over five consecutive weekdays from 3 to 7 November 2008. Three nurses were also interviewed on site to gather their attitudes and perceptions about the benefits of and time associated with administering a TGC protocol. METHODS: Independent observers shadowed nurses, observing when a blood glucose measurement was taken, when each predefined subtask was completed and the duration of each task. Semistructured interviews with nurses were conducted in-person and one-on-one by a trained study member. RESULTS: Considered together, the episodic median duration of all TGC activities was 6·65 min. Across a total shift, nurses devoted approximately 7% of their time to administering a TGC protocol. Nurses perceived that a TGC protocol is beneficial to patient safety and outcomes in a critical care setting but acknowledged that the tasks can be mildly to moderately tedious. CONCLUSIONS: This TiM analysis indicated that the additional responsibility of implementing a TGC protocol represents a substantive commitment of nursing time in a critical care setting. RELEVANCE TO CLINICAL PRACTICE: The episodic data of our pilot study in the UK contributes further evidence that TGC protocols may be arduous to maintain and constitute a substantial investment of nursing time.

Apolipoprotein E ε4 prevalence in Alzheimer's disease patients varies across global populations: a systematic literature review and meta-analysis.

BACKGROUND: The ε4 allele of apolipoprotein E (APOE) is associated with Alzheimer's disease (AD). However, attributable risk due to APOE4 varies by region and by race/ethnicity. METHODS: A literature review and meta-analysis were conducted to estimate the prevalence of APOE4 by geographic area among AD patients. RESULTS: Although estimates varied significantly by study design and case definition, AD patients recruited in Asian and southern European/Mediterranean communities seemed to have significantly lower E4 carrier status estimates (37 and 43%) than those recruited in North America (58%) or northern Europe (64%; all: p < 0.05). CONCLUSIONS: APOE4 genotype frequency varies among AD patients in regional patterns similar to that of the general population. Study level differences may also contribute to the heterogeneity of published estimates of APOE4 in AD cases.

Efficient practices associated with diagnosis, treatment and management of fibromyalgia among primary care physicians.

OBJECTIVES: To describe beliefs and practice patterns of primary care physicians (PCPs) providing fibromyalgia (FM) care, and to characterize differences between PCPs who report being able to provide timely and beneficial care versus the remaining PCPs. METHODS: A mixed-methods approach including surveys followed by semi-structured focus groups among United States-based PCPs in seven cities was used. Post hoc, a composite threshold of timely and beneficial care, defined as PCPs reports of at least one-half of their patients achieving an 'acceptable' quality of life within one to four office visits after diagnosis, was created to compare subgroups. RESULTS: Forty-six per cent of PCPs reported some uncertainty when diagnosing FM. PCPs reported personally treating approximately two-thirds of their patients (63%), and reported an average of three dosage titrations. In a post hoc exploratory analysis, 42.5% of PCPs met a composite threshold of self-reported timely and beneficial FM care. These PCPs reported fewer office visits to confirm an FM diagnosis (2.7 versus 4.0 visits [P<0.01]) and more patients with 'significant improvement' (38% versus 23% [P<0.01]) after six months of treatment compared with the remaining PCPs. CONCLUSIONS: Physicians self-reported an inadequacy in diagnosing, treating and managing patients with FM in current practice. A subset of PCPs, however, perceived an ability to reach a definitive diagnosis and initiate treatment plans relatively sooner than the other respondents. If the perception of this subset can be confirmed with objective clinical outcomes, and these behaviours modelled, steps could be taken to improve FM care within the broader PCP setting.

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.

Topical bovine thrombin: a 21-year review of topical bovine thrombin spontaneous case safety reports submitted to FDA's Adverse Event Reporting System.

PURPOSE: To review topical bovine thrombin spontaneous adverse event (AE) reports that were forwarded to the US Food and Drug Administration's (FDA) Adverse Event Reporting System (AERS) between January 1986 and December 2006. METHODS: Forty-one spontaneous AE reports were summarized for reported AE profile and chronological reporting patterns. Each AE report was adjudicated by a hematologist for the topical bovine thrombin product that was given and the AE(s) that were reported. AEs were grouped as allergic, coagulopathy/bleeding, and all other AEs combined. Grouped AE serial analyses were carried out using successive 3-year time increments between 1986 (the year an AE report was first noted for a bovine thrombin product) and 2006 (the first full year that was available at the time of initiation of the data summary). MAIN OUTCOME MEASURES: The primary outcome measures were every 3-year trend lines for all-AE reports, all reporters, and topical bovine thrombin brand mentions for 2 AE groups of interest (allergic events and coagulopathy/bleeding events). RESULTS: The all-AE spontaneous reporter trend showed a downward appearance for AE reporting activity that started in 1995-1998 and continued through 2004-2006. The all-AE reports trend showed two potential safety signals that could be identified serially: (1) a prominent 1989-1991 peak that was attributable to allergic events (in particular, anaphylaxis), and (2) a small 1995-2000 broad peak that was attributable in part to coagulopathy/bleeding events. Allergic events were predominantly reported with products approved prior to 1995, were not temporally associated with prior medical literature case reports, and continued to be forwarded to the FDA at low levels up to the end of this study in 2006. Coagulopathy/bleeding events were reported only with products approved prior to 1995, were temporally associated with medical literature case reports, and were not forwarded to the FDA after 2000. CONCLUSIONS: Overall, spontaneous AE reporting for topical bovine thrombin occurs at very low levels, and appears to have been decreasing since 1995. The serial reporting patterns for topical bovine thrombin are best explained as a strong safety signal for allergic events with ongoing, low level reporting, and a weak safety signal for coagulopathy/bleeding events that ceased on or before 2000. Although this descriptive trend analysis cannot measure associations or causation, the coagulopathy/bleeding signal may have been prompted by multiple, antecedent published case reports. The subsequent diminishment of signal attributed to thrombin likewise may coincide with lack of such reporting in larger follow-up clinical trials or, alternatively, in the introduction and growing market share of thrombin brands of greater purity. Currently marketed topical bovine thrombin formulations are rarely volunteered as possible causes of adverse events.

A safety review of topical bovine thrombin-induced generation of antibodies to bovine proteins.

BACKGROUND: Topical bovine thrombin has been used to accelerate attainment of hemostasis in the surgical setting for >60 years, and its immunogenicity has been widely reported. Although the development of antibodies is inherent in the introduction of any non-self-therapeutic protein such as bovine-sourced thrombin, there are questions about the relationship between the presence of antibodies to constituents of the therapeutic protein preparation and the occurrence of clinically relevant adverse events (AEs). OBJECTIVE: This review examines the proposed mechanisms for the immunogenicity of topical bovine thrombin preparations and summarizes available evidence from randomized clinical trials, observational studies, and case reports to explore possible relationships between the reported immunogenicity of topical bovine thrombin and the occurrence of AEs. METHODS: A search of MEDLINE (1966-August 2008) for studies published in English was conducted using the Medical Subject Heading terms surgery, antibodies, and hemorrhage, as well as equivalent key words for bovine, adverse events, and thrombin. For inclusion in the review, studies had to report clinical or laboratory safety data for patients exposed to topical bovine thrombin during surgery. RESULTS: The evidence suggests that patients with repeated perioperative exposure to topical bovine thrombin have a 3- to 10-fold greater risk for development of antibodies to topical bovine thrombin than do patients with no history of surgery-related exposure to this agent. Early case reports associated the development of anti-bovine protein antibodies with bleeding and/or thrombotic complications. However, in one prospective, randomized controlled trial comparing topical bovine thrombin with topical recombinant human thrombin, 99.5% of patients in each treatment arm developed postoperative AEs. In an-other, 54% and 55% of patients in the respective treatment arms developed postoperative AEs. In a prospective, randomized controlled trial that compared topical bovine thrombin and plasma-derived human thrombin, 95.5% of patients in each treatment arm developed postoperative AEs. CONCLUSIONS: Repeated perioperative exposure to topical bovine thrombin may increase both the prevalence and titers of antibodies to >or=1 protein contained in nonhomogeneous topical bovine thrombin preparations. However, the evidence reviewed does not support a definitive association between preoperative or postoperative generation of anti-bovine protein antibodies and an increased risk of AEs in surgical patients treated with topical bovine thrombin.

Pregnancy outcomes in women with epilepsy: a systematic review and meta-analysis of published pregnancy registries and cohorts.

PURPOSE: To conduct a systematic review and meta-analysis to quantify the incidence of congenital malformations (CMs) and other pregnancy outcomes as a function of in utero anti-epileptic drug (AED) exposure. METHODS: We performed a systematic literature review to identify all published registries and cohort studies of births from pregnant women with epilepsy (WWE) that reported incidence of CMs. Overall incidences were calculated using a random effects model. RESULTS: The review included 59 studies that met inclusion/exclusion criteria, involving 65,533 pregnancies in WWE and 1,817,024 in healthy women. The calculated incidence of births with CM in WWE [7.08%; 95% CIs 5.62, 8.54] was higher than healthy women [2.28%; CIs 1.46, 3.10]. Incidence was highest for AED polytherapy [16.78%; CIs 0.51, 33.05]. The AED with the highest CM incidence was valproate, which was 10.73% [CIs 8.16, 13.29] for valproate monotherapy. CONCLUSIONS: Results of this systematic literature review suggest that the overall incidence of CMs in children born of WWE is approximately threefold that of healthy women. The risk is elevated for all AED monotherapy and further elevated for AED polytherapy compared to women without epilepsy. The risk was significantly higher for children exposed to valproate monotherapy and to polytherapy of 2 or more drugs when the polytherapy combination included phenobarital, phenytoin, or valproate. Further research is needed to delineate the specific risk for each individual AED and to determine underlying mechanisms including genetic risk factors.

Systematic review to establish the safety profiles for direct and indirect inhibitors of p38 Mitogen-activated protein kinases for treatment of cancer. A systematic review of the literature.

OBJECTIVE: To identify potential tolerability issues for a novel selective p38 Mitogen-activated Protein Kinases (p38MAPK) inhibitor, we performed a systematic review of published studies and abstracts reporting safety outcomes for indirect inhibitors of p38MAPK. METHODS: A systematic review was performed to identify articles and meeting abstracts published between January 1, 1990 and March 31, 2005 that reported safety outcomes in cancer patients. Study, patient, and treatment level data were summarized using descriptive statistics without meta-analyses. RESULTS: Of 2,408 studies identified in the search, only 174 met eligibility criteria. Most studies (90%) involved thalidomide (or analog); only 12 (8%) studied sorafenib and 5 studied anti-tumor necrosis factor antibodies. In 165 treatment arms, 32% involved thalidomide (or analog) monotherapy and 2.4% involved sorafenib. The tolerability profiles of the two agents differed markedly. The most common Grade 3/4 adverse events experienced on thalidomide monotherapy were venous thrombosis (3.1% of patients), weakness/asthenia/fatigue (3.0%), neutropenia (2.7%), peripheral neuropathy/tingling/numbness (2.4%), somnolence/drowsiness/lethargy (2.4%), constipation (2.1%), and infection (2.0%). In contrast, the most common Grade 3/4 toxicities with sorafenib were diarrhea (4.8%), weakness/asthenia/fatigue (4.0%), hand-foot syndrome (3.2%), and leukopenia (2.4%). For both types of inhibitors, abnormal liver function tests were reported in about 3% of patients. CONCLUSIONS: The present review summarizes clinical safety information of anti-cancer drugs with indirect or nonspecific p38MAPK inhibitory activity. Based on our analysis, a novel p38MAPK inhibitor should be monitored for similar neurological, gastrointestinal, and cardiovascular symptoms in Phase I clinical trials.

Real-world effectiveness of anti-TNF switching in psoriatic arthritis: a systematic review of the literature.

Anti-tumor necrosis factors (Anti-TNFs) are a class of biologic disease-modifying anti-rheumatic drugs indicated for the treatment of moderate-to-severe psoriatic arthritis (PsA). Refractory patients are commonly managed by switching from one anti-TNF to another. To assess the evidence on the effectiveness of anti-TNF cycling in PsA patients, a systematic review of the literature was conducted. MEDLINE- and Embase-indexed English-language publications were systematically searched from 1995 to 2015 for studies assessing real-world effectiveness outcomes of anti-TNF cycling in PsA patients. Of 1086 citations identified, 18 studies were included; most conducted in Europe. Six of seven studies testing between lines found significant differences in effectiveness between earlier and subsequent lines of anti-TNF therapy. First-line therapy yielded better results compared with second-line therapy, and significant differences were observed between second- and third-line anti-TNF treatments. In the only study with multivariate regression testing for predictors of response, Danish registry patients were less likely to respond (American College of Rheumatology 20 % or 50 % response) to a second anti-TNF course if safety, rather than lack of effect, caused them to switch (odds ratio [OR] 0.04; p = 0.003 and OR 0.05; p = 0.03, respectively). Effectiveness of anti-TNFs at second line and later is reported in a small number of real-world studies of PsA patients. Subsequent treatment lines may be associated with less response in some measures. More research is needed to quantify the effectiveness of sequential anti-TNF lines in this progressive population' and to compare these effects with responses to drugs with different mechanisms of action.

Synthesis and structure-activity relationships of soluble 7-substituted 3-(3,5-dimethoxyphenyl)-1,6-naphthyridin-2-amines and related ureas as dual inhibitors of the fibroblast growth factor receptor-1 and vascular endothelial growth factor receptor-2 tyrosine kinases.

7-Substituted 3-aryl-1,6-naphthyridine-2,7-diamines and related 2-ureas are inhibitors of fibroblast growth factor receptor-1 (FGFR-1) and vascular endothelial growth factor receptor-2 (VEGFR-2). 3-(3,5-Dimethoxyphenyl) and 3-phenyl analogues were prepared from 7-acetamido-2-tert-butylureas by alkylation with benzyl omega-iodoalkyl ethers, debenzylation, and amination, followed by selective cleavage of the 7-N-acetamide. 3-(2,6-Dichlorophenyl) analogues were prepared from the 7-fluoro-2-amine by displacement with substituted alkylamines, followed by selective acylation of the resulting substituted naphthyridine-2,7-diamines with alkyl isocyanates. The 3-(3,5-dimethoxyphenyl) derivatives were low nanomolar inhibitors of both FGFR and VEGFR and were highly selective (>100-fold) over PDGFR and c-Src. Variations in the base strength or spatial position of the 7-side chain base had only small effects on the potency (<5-fold) or selectivity (<20-fold). The 3-(2,6-dichlorophenyl)-2-urea derivatives were slightly less active against VEGFR and less selective, being more effective against PDGFR (ca. 10-fold) and c-Src (ca. 500-fold). The 3-(3,5-dimethoxyphenyl)-1,6-naphthyridines were generally more potent than the corresponding pyrido[2,3-d]pyrimidines against both VEGFR and FGFR (2- to 20-fold), with only slightly increased PDGFR and c-Src activity. The 3-(3,5-dimethoxyphenyl)-1,6-naphthyridine 2-ureas were also low nanomolar inhibitors of the growth of human umbilical vein endothelial cells (HUVECs) stimulated by serum, FGF, or VEGF, at concentrations that did not affect the growth of representative tumor cell lines, and were more (3- to 65-fold) potent than the corresponding pyrido[2,3-d]pyrimidines.

A multicenter pilot study to estimate the prevalence of bovine and human coagulation antibodies in the general US population.

Antibodies to bovine and human coagulation proteins have been reported to develop in some patients receiving perioperative exposure to topical bovine thrombin. To estimate the prevalence of antihuman and antibovine thrombin and factor V antibodies in the general population, this multicenter pilot study in 278 participants was undertaken. Of the participants, 88% had no detectable antibodies by enzyme-linked immunosorbent assay (ELISA). Cumulatively 22 (7.9%) of 278 of the participants were positive for at least 1 of the antibovine antibodies and only 11 (4%) of 278 were positive for human thrombin antibodies. No participants had antihuman factor V/Va antibodies. Antibodies were found in 21% of participants with no history of surgery, transfusion, or pregnancy. In participants without a surgical history, thus a low likelihood of bovine thrombin exposure, 7.9% (9 of 114) had antibovine antibodies and 3.5% (4 of 114) had human antithrombin antibodies, suggesting that antibodies may arise from contact with antigenic sources other than bovine-derived thrombin.

Hypertriglyceridemia in a pediatric referral practice: experience with 300 patients.

BACKGROUND: Pediatric hypertriglyceridemia is an emerging comorbidity of childhood obesity. METHODS: This study reviewed medical records retrospectively to describe the characteristics and clinical course of 300 at-risk children followed in a pediatric preventive cardiology clinic. RESULTS: Average baseline triglyceride (TG) level was 269 mg/dL (SD 342 mg/dL); 91% had TG levels between 150 and 399 mg/dL. A total of 77% were overweight/obese, 23% had elevated blood pressure, 23% had a family history of high triglycerides, and 11% reported a psychiatric diagnosis (33.3% of those with severe TG elevations). Diet and activity change were the first-line therapies; few were taking lipid-lowering medications (baseline, 5.1%; follow-up, 11.4%). TG levels declined by 23% (average, 88 mg/dL; SD 231), often with a decline or plateau in TG risk category. Children with a lower body mass index (<85% gender- and age-matched percentile) were more likely to improve in TG category than heavier children (70% vs 40%; P ≤ .05).

Safety of multi-targeted kinase inhibitors as monotherapy treatment of cancer: a systematic review of the literature.

PURPOSE: To identify potential safety profiles for small molecule multi-targeted kinase inhibitors for the treatment of advanced cancer. METHODS: A systematic review was performed on published papers and meeting abstracts reporting safety outcomes in cancer patients for selected multi-kinase inhibiting small molecules with mainly anti-angiogenic activity. Specifically, we focused on single agent safety or early phase clinical development studies. RESULTS: Of 1,923 studies identified in a MEDLINE search, 26 primary studies met eligibility criteria. Meeting materials included 7 papers, 6 posters, and 27 abstracts. When grade I-IV safety results of all 23 kinases were summed together, diarrhea, fatigue, nausea, rash, anorexia, vomiting, hand/foot syndrome, and hypertension were common, occurring in greater than 10% of patients. When only grade III and IV events are pooled together, fatigue and hypertension remain relatively common (> 5%). When total adverse events were stratified by kinase or by kinase family, differences in safety profiles emerged. CONCLUSIONS: The results of this systematic review suggest that adverse events are common and varied for patients treated with a multi-kinase inhibitor. However, unlike some systemic cytotoxic therapies, serious and severe adverse events for multikinase inhibitors are less frequent. Sub-analyses by target kinase or kinase family demonstrate that certain groups of multi-kinase inhibitors can be associated with different safety profiles with unique adverse events.

Topical bovine thrombin and adverse events: a review of the literature.

OBJECTIVE: To review published evidence suggesting a link between topical bovine thrombin (TBT) and important adverse events (AEs). RESEARCH DESIGN AND METHODS: English language articles and abstracts were obtained from MEDLINE using combinations of text and MeSH terms for thrombin, bovine thrombin and their trade names. References from summary articles were also retrieved. Published case reports, review articles, and retrospective, prospective or observational studies involving either immunogenicity or AEs were selected for further assessment. Retrieved articles were evaluated separately as AE case reports, quantitative studies of antibodies, or quantitative studies of AEs. MAIN OUTCOME MEASURES: Presence of case causal information, temporal pattern of case report publication, reproducibility of aggregate data findings, and study design features. RESULTS: The major limitations of reviewed publications were insufficient information regarding TBT and other exposures, and designs in which linkage between laboratory immune phenomena and AEs could not be evaluated. While immunogenicity studies did support an increased risk for post-TBT antibodies, there was no consistent evidence that this led to an increased AE risk or severity. Common evidentiary deficiencies included case reports from high incidence environments, studies of combination or mixture products, biased study designs, lack of patient-level exposure data, inadequate control groups and insufficient sample sizes. The best designed study (a randomized, controlled comparison of TBT to a recombinant bovine product) documented post-TBT antibody production, but no important efficacy or AE differences. An examination of publication dates for case reports showed a peak between 1992 and 1994 followed by a substantial drop. Since 1997 the number of published AE case reports has continued to decline. CONCLUSIONS: TBT increases the risk for antibody elevations in patients. A careful review of published evidence does not show that either TBT itself or any associated elevations in anti-bovine antibodies are risk factors for clinically important AEs.

Risk of bleeding in surgical patients treated with topical bovine thrombin sealants: a review of the literature.

BACKGROUND: One of the most anticipated, but potentially serious complications during or after surgery are bleeding events. Among the many potential factors associated with bleeding complications in surgery, the use of bovine thrombin has been anecdotally identified as a possible cause of increased bleeding risk. Most of these reports of bleeding events in association with the use of topical bovine thrombin have been limited to case reports lacking clear cause and effect relationship determination. Recent studies have failed to establish significant differences in the rates of bleeding events between those treated with bovine thrombin and those treated with either human or recombinant thrombin. METHODS: We conducted a search of MEDLINE for the most recent past 10 years (1997-2007) and identified all published studies that reported a study of surgical patients with a clear objective to examine the risk of bleeding events in surgical patients. We also specifically noted the reporting of any topical bovine thrombin used during surgical procedures. We aimed to examine whether there were any differences in the risk of bleeds in general surgical populations as compared to those studies that reported exposure to topical bovine thrombin. RESULTS: We identified 21 clinical studies that addressed the risk of bleeding in surgery. Of these, 5 studies analyzed the use of bovine thrombin sealants in surgical patients. There were no standardized definitions for bleeding events employed across these studies. The rates of bleeds in the general surgery studies ranged from 0.1%-20.2%, with most studies reporting rates between 2.6%-4%. The rates of bleeding events ranged from 0.0%-13% in the bovine thrombin studies with most studies reporting between a 2%-3% rate. CONCLUSION: The risk of bleeds was not clearly different in those studies reporting use of bovine thrombin in all patients compared to the other surgical populations studied. A well-designed and well-controlled study is needed to accurately examine the bleeding risks in surgical patients treated and unexposed to topical bovine thrombin, and to evaluate the independent risk associated with topical bovine thrombin as well as other risk factors.

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.