Risk of misclassification with a non-fasting lipid profile in secondary cardiovascular prevention.

AIMS: Routinely fasting is not necessary for measuring the lipid profile according to the latest European consensus. However, LDL-C tends to be lower in the non-fasting state with risk of misclassification. The extent of misclassification in secondary cardiovascular prevention with a non-fasting lipid profile was investigated. METHODS AND RESULTS: 329 patients on lipid lowering therapy for secondary cardiovascular prevention measured a fasting and non-fasting lipid profile. Cut-off values for LDL-C, non-HDL-C and apolipoprotein B were set at <1.8mmol/l, <2.6mmol/l and <0.8g/l, respectively. Study outcomes were net misclassification with non-fasting LDL-C (calculated using the Friedewald formula), direct LDL-C, non-HDL-C and apolipoprotein B. Net misclassification <10% was considered clinically irrelevant. Mean age was 68.3±8.5years and the majority were men (79%). Non-fasting measurements resulted in lower LDL-C (-0.2±0.4mmol/l, P<0.001), direct LDL-C (-0.1±0.2mmol/l, P=0.001), non-HDL-C (-0.1±0.4mmol/l, P=0.004) and apolipoprotein B (-0.02±0.10g/l, P=0.004). 36.0% of the patients reached a fasting LDL-C target of <1.8mmol/l with a significant net misclassification of 10.7% (95% CI 6.4-15.0%) in the non-fasting state. In the non-fasting state net misclassification with direct LDL-C was 5.7% (95% CI 2.1-9.2%), 4.0% (95% CI 1.0-7.4%) with non-HDL-C and 4.1% (95% CI 1.1-9.1%) with apolipoprotein B. CONCLUSION: Use of non-fasting LDL-C as treatment target in secondary cardiovascular prevention resulted in significant misclassification with subsequent risk of undertreatment, whereas non-fasting direct LDL-C, non-HDL-C and apolipoprotein B are reliable parameters.

Co-administration of Flt-3 ligand counteracts the actions of thrombopoietin in myelosuppressed rhesus monkeys.

This placebo-controlled study evaluated the efficacy of Flt-3 ligand (FL) combined with TPO in myelosuppressed rhesus monkeys. The monkeys were subjected to 5 Gy total body irradiation (TBI), resulting in 3 weeks of profound pancytopenia, and received either 5 microg/kg of rhesus TPO i.v. on d 1 (n = 4) and 100 microg/kg/d s.c. human FL (n = 4) or FL alone (n = 4) for 14 consecutive days and were compared with results from a concomitant study involving the administration of TPO alone (n = 4) or placebo (carrier; n = 4). The TPO/FL combination was considerably less effective than TPO alone, with a more profound nadir and a slower recovery to thrombocyte counts > 100 x 109/l, approaching recovery patterns of placebo controls. Leucocyte regeneration was similar in all animals. Monkeys treated with FL alone displayed a regeneration of reticulocytes and thrombocytes in the lower range of those of the placebo controls. Recovery of bone marrow (BM) cellularity was slightly accelerated in the TPO/FL-treated monkeys, but was not reflected by an increase in progenitor cells, in contrast to TPO alone. Monkeys treated with FL alone showed a BM reconstitution similar to placebo-treated controls. FL by itself was not effective as a therapeutic agent in this model for myelosuppression. As FL also suppressed BM CD34+ cell reconstitution, we concluded that FL competed with TPO at the level of immature cell differentiation.

New TPO treatment schedules of increased safety and efficacy: pre-clinical validation of a thrombopoiesis simulation model.

Thrombopoietin (TPO) immunogenicity hampers its development as a therapeutic agent for attenuating thrombocytopenia and improving platelet harvest in donors. This work was aimed at validating, in mouse and in monkey experiments, a thrombopoiesis computer-model prediction that platelet counts, similar to those obtained with accepted TPO dose scheduling, can also be achieved by new and safer schedules of significantly reduced doses. To this end we compared, in a two-arm mouse experiment, platelet increases obtained with a single intraperitoneal dosing of recombinant mouse TPO (17.5 microg/kg), with those obtained by the model-suggested protocol of a significantly reduced dose (2 microg/kg on 4 consecutive days). The two TPO regimens generated similar platelet profiles, peaking at ca. 2700 x 10(9)/l platelets. In rhesus monkeys, treated by rhesus monkey recombinant TPO (5 microg/kg on 4 consecutive days), the suggested protocol yielded effective platelet stimulation with significantly reduced immunogenicity. The model's ability to predict individual monkey responses to several new TPO administration protocols was further validated, proving sufficient robustness in providing good predictions with limited input data. The simulation tool could be used for testing the effects of different therapeutic agents on thrombopoiesis. Human trials are warranted for testing the suggested improved TPO protocol, possibly in conjunction with chemotherapy.