Most reported thromboembolic AEs followed the use of rFVIIa for unlabeled indications and occurred in arterial and venous systems, often resulting in serious morbidity and mortality. Analysis of the relationship between AEs and rFVIIa is hindered by concomitant medications, preexisting medical conditions, confounding by indication, and inherent limitations of passive surveillance. Randomized controlled trials are needed to establish the safety and efficacy of rFVIIa in patients without hemophilia.

The most common adverse events reported in association with the Carticel technique involved graft failure, delamination, and tissue hypertrophy.

The characteristics of the currently available platelet function assays (platelet aggregation, serotonin release, and flow cytometry) and enzyme-linked immunosorbent assays that quantitate antiheparin-platelet factor 4 antibody titers were studied using sera collected from clinically diagnosed heparin-induced thrombocytopenia patients, patients without heparin-induced thrombocytopenia, patients with platelet immune disorders other than heparin-induced thrombocytopenia, and normal individuals. The platelet aggregation assay was less sensitive than the serotonin release assay, which was less sensitive than the enzyme-linked immunosorbent assay (p < 0.001). Yet heparin-induced thrombocytopenia was identified by platelet aggregation assay in cases where the serotonin release assay and/or the enzyme-linked immunosorbent assay were negative. Patients with heparin-induced thrombocytopenia and thrombosis were more often positive than heparin-induced thrombocytopenia patients without thrombosis (p < 0.05). Positive platelet aggregation assay and serotonin release assay results were generally associated with a higher antibody titer; however, a minimum critical titer could not be identified. Over a 30-day period the percentage of positive responses did not change significantly even though clinical symptoms corrected in most heparin-induced thrombocytopenia patients. Multiple testing over several days enhanced the chance of detecting a positive, and combined results of the three assays further enhanced the positive response (p < 0.005). In patients without heparin-induced thrombocytopenia, false-positive results were obtained with the enzyme-linked immunosorbent assay. These data demonstrate that there is no direct correlation between the positive responses of these assays, that clinically positive patients can be missed by all assays, and the presence of antibody alone does not determine clinical heparin-induced thrombocytopenia. With these limitations, the combination of aggregation, serotonin release, and enzyme-linked immunosorbent assay testing with multiple samples offers the best chance of identifying a positive heparin-induced thrombocytopenia patient. Caution is advised for all assays as none is optimal.

A synthetic selective inhibitor of factor Xa, the pentasaccharide SR90107A/Org31540 is in clinical development for the prophylaxis of postsurgical deep vein thrombosis. Another synthetic pentasaccharide with even more sustained inhibition of factor Xa, SanOrg34006, has also been developed. Both of these agents were tested in comparison to unfractionated heparin and a low molecular weight heparin (enoxaparin) for their relative platelet activation potential in heparin-induced thrombocytopenia assays. Sera from patients (n = 30) with heparin-induced thrombocytopenia were pooled and validated for heparin-dependent aggregation responses. Using heparin-platelet factor 4 Sepharose columns, antibodies to heparin-platelet factor 4 were purified from the same pool. The effects of heparin, enoxaparin, SR90107A/Org31540, and San-Org34006 were evaluated in a platelet aggregation assay using platelet donors (n = 10). At comparable concentrations, heparin and enoxaparin consistently produced platelet activation, whereas both pentasaccharides failed to produce a response at a concentration up to 100 micrograms/mL (approximately 50 microM). Similarly, in the 14C-serotonin release and flow cytometric assays, heparin and enoxaparin produced positive responses (n = 30), whereas the two pentasaccharides consistently failed to produce any effect. These observations suggest that the two pentasaccharides with highly selective anti-Xa activity are devoid of generating antiheparin-platelet factor 4 antibody, do not produce heparin-induced thrombocytopenic responses and may inhibit active heparin-induced thrombocytopenia antibody platelet activation.

ObjectiveTo assess the potential association of selected antiretrovirals (ARVs), including efavirenz, with suicidality.DesignRetrospective analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS), by performing a Multi-Item Gamma Poisson Shrinker (MGPS) disproportionality analysis.MethodsMGPS disproportionality analysis, a technique to identify associations between drugs and adverse events, was performed using cumulative data from the FAERS database collected up to August 2012. This method yields an Empirical Bayesian Geometric Mean score and corresponding 90% confidence interval (EB05, EB95). EB05 scores ≥2 were pre-defined as a signal for a potential drug-event association. The FAERS database includes spontaneous adverse-event reports from consumers and healthcare professionals. All FAERS reports of suicidality (including suicidal ideation, suicide attempt and completed suicide or a composite of these) in patients taking efavirenz (as single agent or in fixed-dose combination), atazanavir, darunavir, etravirine, nevirapine and raltegravir were identified. A number of parallel analyses were performed to assess the validity of the methodology: fluoxetine and sertraline, antidepressants with a known association with suicidality, and raltegravir, an ARV with rhabdomyolysis and myopathy listed as “uncommon” events in the US-prescribing information.ResultsA total of 29,856 adverse event reports were identified among patients receiving efavirenz, atazanavir, darunavir, etravirine, nevirapine and raltegravir, of which 457 were reports of suicidality events. EB05 scores observed for the composite suicidality term for efavirenz (EB05=0.796), and other ARVs (EB05=0.279–0.368), were below the pre-defined threshold. Fluoxetine and sertraline gave EB05 scores for suicidality >2. Raltegravir gave EB05 scores >2 for myopathy and rhabdomyolysis.ConclusionsThe pre-determined threshold for signals for suicidality, including suicidal ideation, suicide attempt, completed suicide and a composite suicidality endpoint, was not exceeded for efavirenz and other ARVs in this analysis. Efavirenz has been associated with suicidality in clinical trials. Further studies that adjust for confounding factors are needed to better understand any potential association with ARVs and suicidality.