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BACKGROUND: Although prothrombin complex concentrate (PCC) is often used to counteract vitamin K antagonist (VKA) therapy, evidence regarding the optimal dose for this indication is lacking. In Dutch hospitals, either a variable dose, based on body weight, target INR (international normalised ratio) and initial INR, or a fixed dose is used. AIM/OBJECTIVES: In this observational, pilot study, the efficacy and feasibility of the fixed dose strategy compared to the variable dosing regimen, is investigated. MATERIALS AND METHODS: Consecutive patients receiving PCC (Cofact®, Sanquin, Amsterdam) for VKA reversal because of a major non-cranial bleed or an invasive procedure were enrolled in two cohorts. Data were collected prospectively in the fixed dose group, cohort 1, and retrospectively in the variable dose regimen, cohort 2. Study endpoints were proportion of patients reaching target INR and successful clinical outcome. RESULTS: Cohort 1 consisted of 35 and cohort 2 of 32 patients. Target INR was reached in 70% of patients in cohort 1 versus 81% in cohort 2 (P = 0·37). Successful clinical outcome was seen in 91% of patients in cohort 1 versus 94% in cohort 2 (P = 1·00). Median INR decreased from 4·7 to 1·8 with a median dosage of 1040 IU factor IX (F IX) in cohort 1 and from 4·7 to 1·6 with a median dosage of 1580 IU F IX in cohort 2. CONCLUSION: This study suggests that a fixed dose of 1040 IU of F IX may be an effective way to rapidly counteract VKA therapy in our patient population and provides a basis for future research.

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INTRODUCTION: Prothrombin complex concentrate (PCC) is recommended for emergency reversal of oral coumarin anticoagulation. Recently, recombinant factor VIIa (rFVIIa) has also been investigated for this purpose, although no direct comparison of PCC and rFVIIa has been reported. This study was designed to compare the effectiveness of PCC and rFVIIa for reversal of both acute and sustained coumarin anticoagulation. MATERIALS AND METHODS: In the acute model, rats received 2.5 mg.kg(-1) phenprocoumon, and reversal of anticoagulation by 4.88 mL.kg(-1) saline, 100 microg.kg(-1) rFVIIa (NovoSeven) or 50 U.kg(-1) PCC (Beriplex P/N) was assessed at 16 h. For the sustained model, a second phenprocoumon dose was administered at 24 h and anticoagulation reversal evaluated at 48 h. Study endpoints were activated partial thromboplastin time (aPTT), prothrombin time (PT) and tail tip bleeding. RESULTS: Acute anticoagulation raised median PT to 4.3 fold the normal level. This elevation was nearly completely reversed both by rFVIIa and PCC. aPTT increase was minor. Effects of sustained anticoagulation were more severe and pervasive, with aPTT, PT and blood loss increasing to 7.7, 51 and 30 fold the control levels, respectively. In the sustained model, rFVIIa substantially reduced and PCC fully normalized PT. In this model, PCC also diminished aPTT (p<0.01), fully normalized blood loss (p<0.01) and shortened bleeding time (p=0.008), while rFVIIa was without significant effect on these endpoints. CONCLUSIONS: In a sustained anticoagulation animal model designed to simulate standard long-term oral coumarin therapy in patients, PCC was more effective than rFVIIa in restoring hemostatic function.

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QUESTION UNDER STUDY: To investigate the effectiveness of a single adjusted dose of oral vitamin K to temporarily reverse oral anticoagulation with phenprocoumon (Marcoumar) for heart catheterisation. METHODS: Patients under stable oral anticoagulation with phenprocoumon routinely scheduled for heart catheterizstion were given a single adjusted dose of oral vitamin K a day prior to the intervention. The customary anticoagulation scheme was kept unchanged with the exception of taking the double usual dose of phenprocoumon the evening after the intervention. The primary outcome was the achieved international normalised ratio (INR) immediately before the intervention. Secondary outcomes were the INR after one and four weeks, changes in phenprocoumon and coagulation factors II and VII and adverse events. RESULTS: 38 patients at a median age of 71 (63-74) years scheduled for heart catheterisation were included. The median INR changed from 2.2 (1.9-2.6) the day before to 1.5 (1.4-1.7) immediately before the intervention. An INR < or =1.5 respectively < or =1.8 was achieved in 61% and 95% of the patients. The INR values after one respectively four weeks were comparable to preintervention values. No thromboembolic or bleeding adverse events occurred during the study. CONCLUSION: A single adjusted oral dose of vitamin K given a day prior to heart catheterisation combined with a doubled phenprocoumon dose on the procedure day seems to be an easy applicable, safe and effective way to temporary reverse oral anticoagulation with phenprocoumon.

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The elimination, distribution and anticoagulant activities of the enantiomers of phenprocoumon were studied in rats following enzyme induction by phenobarbital (pretreatment with 75 mg . kg-1 for 4 days) and enzyme inhibition by chloramphenicol (100 mg . kg-1 h prior to the injection of phenprocoumon and then 50 mg . kg-1 every 12 h). Pretreatment with phenobarbital increased the rate of elimination and decreased the total anticoagulant effect per dose of both enantiomers. It also caused a slight reduction of the liver/plasma concentration ratio of the enantiomers due to the increase of the liver weight and a significant enhancement of the synthesis rate of prothrombin complex activity in non-anticoagulated rats. Chloramphenicol decreased the rate of elimination and enhanced the total anticoagulant effect per dose of both enantiomers. The distribution between plasma and liver remained unaffected. Thus, in rats neither the induction of the phenprocoumon metabolism by phenobarbital nor its inhibition by chloramphenicol appears to be stereoselective.

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The effect of cyclamate on the anticoagulant activity of phenprocoumon was investigated in rats after single oral doses of phenprocoumon, cyclamate, or phenprocoumon/cyclamate. By means of high pressure liquid chromatrography [HPLC] the change of the concentration of phenprocoumon per unit time in sera was determined. The anticoagulant acitivity of phenprocoumon was determined by the extension of the prothromin-time (Quick-test). It was found that cyclamate gives rise to an elevated of phenprocoumon in the blood, and a reduction of the anticoagulanting potency.

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The effect of cholestyramine (12 gm/day divided into 3 doses) on the pharmacokinetics and pharmacodynamics of a single intravenouse dose (30 mg) of phenprocoumon was studied in 6 normal subjects. Cholestyramine treatment led to an increase in the rate of elimination of phenprocoumon in all. Total clearance increased 1.5- to 2-fold. The total anticoagulant effect per dose was considerably reduced during treatment with cholestyramine. Binding studies in vitro showed that phenprocoumon is strongly bound to cholestyramine and that at a given cholestyramine concentration the percentage of phenprocoumon bound remained constant over a large concentration range of phenprocoumon. The results suggest that phenprocoumon undergoes extensive enterohepatic recycling in man which can be effectively interrupted by cholestyramine.

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The interaction of benzodiazepine derivatives with phenprocoumon (Marcumar) was investigated after a single dose of the combination of phenprocoumon/diazepoxide (Librium), phenprocoumon/diazepam (Valium) and phenprocoumon/nitrazepam (Mogadan) had been applied to rats. By means of the high pressure liquid chromatography (HPLC) the change of concentration of these pharmaceutical agents per unit time in serum was determined and related to the corresponding change of prothrombin-time. Hence it can be concluded that the benzodiazepine derivatives influence the distribution of phenprocoumon in the organism.

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