Patrick Mismetti

Étude booster : évaluation comparative d’un nouveau concept de compression élastique dans l’insuffisance veineuse chronique légère et modérée

BACKGROUND Evaluate a new progressive concept of compression stockings in comparison with degressive compression stockings class 2 in patients with mild venous insufficiency without permanent oedema (class 1 of Porters classification or C0s-C1s-C2s CEAPs classification). METHODS The aim of this randomised, double-blind french, multicenter trial was to compare the efficacy and convenience of the new ES compared to conventional ES in patients with mild venous insufficiency for whom elastic compression by knee stockings was indicated. The primary endpoint was leg heaviness after 15 days of wearing ES. Secondary endpoints were discomfort and compliance. RESULTS A total of 130 patients were included (progressive ES: 64; conventional ES: 66). Mean age was 43 years, 68% were women. Disappearance or major improvement of leg heaviness was observed in 73% of patients wearing progressive ES and 62.5% of those wearing conventional ES (difference = -10.5% [95% CI -26.7; +5.6]). This result met pre-specified statistical criteria for non-inferiority and was confirmed by per-protocol analysis. Ease of putting on ES and comfort were significantly better with progressive ES (p<0.0001), as was compliance (p=0.016). INTERPRETATION AND CONCLUSIONS The Booster study is the first randomised, double-blind, multicentre trial evaluating a new concept of compression in mild venous insufficiency. The progressive ES is as efficient as degressive ES but it observance is better. This promising new concept deserves to be evaluated in other settings.

Investigation of drug–drug interactions between clopidogrel and fluoxetine

Drug–drug interactions may contribute to the variability of the response of clopidogrel. Several hypotheses have been proposed concerning the potential modification of clopidogrel pharmacokinetics and pharmacodynamics by fluoxetine. This open‐label crossover study assessed the effect of fluoxetine on the pharmacological activity of clopidogrel in healthy volunteers. Eight healthy male volunteers received a single 600‐mg loading dose of clopidogrel followed by 20 mg of fluoxetine on 4 days and then 20 mg of fluoxetine plus 600 mg of clopidogrel on the fifth day. Eleven blood samples were withdrawn after clopidogrel administration to determine plasma concentrations of clopidogrel active metabolite (CAM) and platelet function. Platelet aggregation was measured by light transmittance aggregometry (LTA) and platelet reactivity index by flow cytometric vasodilator‐stimulated phosphoprotein (VASP) analysis. The areas under the curve and maximum plasma concentrations of CAM were, respectively, 20.6 and 25.3% lower after co‐administration of fluoxetine compared with administration of clopidogrel alone. The percentage maximum platelet aggregation values in the presence of 5 μm and 10 μm adenosine diphosphate, measured by LTA, were, respectively, 13.9 and 22.4% lower after fluoxetine co‐administration. The platelet reactivity index measured by the flow cytometric VASP method was 36.8% lower when clopidogrel was administered in conjunction with fluoxetine.

Is there really a relationship between the plasma concentration of the active metabolite of clopidogrel and the results of platelet function tests

patients with heterozygous defects of the receptor. Our results might also be relevant to the use of the VASP phosphorylation assay for monitoring individual response to clopidogrel, which has been recommended for identifying patients who are poor responders to the drug [2]. The VASP phosphorylation assay has been used for this purpose in many studies [10,11], but the cut-off value for the identification of patients who are poor responders or resistant to the drug has not been clearly identified yet. Fromour observation that the assay is insensitive to mild defects of P2Y12, it can be concluded that clopidogreltreated patients who display a normal PRI with the VASP phosphorylation assay should also not be considered resistant to clopidogrel, because they may have a high percentage of their platelet receptors inhibited by the drug.

TFPI resistance related to inherited or acquired protein S deficiency

BACKGROUND Protein S (PS) is an essential component of the protein C pathway and PS deficiency can explain a poor response to activated protein C. It has recently been shown that PS also acts as a cofactor of Tissue Factor Pathway Inhibitor (TFPI). OBJECTIVES In the present study, we investigated whether PS deficiency could be responsible for a poor response to TFPI. PATIENTS/METHODS Thirty-one patients with inherited PS deficiency, seven pregnant women and 36 controls were enrolled in the study. We measured the plasma response to added TFPI using a two-step diluted prothrombin time (dPT) assay. The response of the different plasmas to the anticoagulant activity of TFPI was expressed as TFPI Normalised Ratio (TFPI NR). RESULTS The median TFPI NR was statistically significantly lower in patients with inherited PS deficiency (0.5) than in controls (1.0) (p<0.0001). It was statistically significantly lower in patients with type I inherited PS deficiency (0.47) compared to patients with type III inherited PS deficiency (0.58) (p=0.018). In contrast, it did not differ between patients with and without thrombosis. Median TFPI NR values were statistically significantly lower during pregnancy (0.54) than 3 months after delivery (0.71) (p=0.016). TFPI NR values correlated well with PS activity values (R(2)=0.681) whatever the nature of the PS deficiency. CONCLUSIONS Our findings confirm that PS deficiency results in a poor anticoagulant response to TFPI, demonstrating again the cofactor role of PS in TFPI activity.

Méthodologie des essais cliniques : une perspective critique

Tous les cliniciens savent ce qu’est un essai randomise realise en double aveugle, et connaissent en fait les grands principes methodologiques de l’essai therapeutique. On oublie par contre plus facilement pourquoi il est important de suivre ces grands principes, et en quoi un essai peut presenter des resultats potentiellement biaises du fait d’une methodologie non adequate. Quel biais d’evaluation peut-on rencontrer dans des etudes realisees en ouvert par exemple, quelles precautions prendre ? C’est aussi l’occasion de reviser un peu l’interpretation des statistiques, a partir d’exemples realises dans l’asthme. Les risques relatifs ou odds ratio n’auront plus de secret pour vous, tout en vous epargnant des formules mathematiques. Nous verrons enfin des donnees plus actuelles, en presentant la methodologie des essais d’equivalence ou de non-inferiorite s’attachant a demonter non pas qu’un traitement est meilleur qu’un autre, mais qu’il fait au moins aussi bien.