Safety assessment of new antithrombotic agents: lessons from the EXTEND study on ximelagatran.

BACKGROUND: Ximelagatran, the first oral direct thrombin inhibitor, was shown to be an effective antithrombotic agent but was associated with potential liver toxicity after prolonged administration. OBJECTIVES AND METHODS: The aim of the EXTEND study was to assess safety and efficacy of extended administration (35 days) of ximelagatran or enoxaparin for the prevention of venous thromboembolism after elective hip replacement and hip fracture surgery. A follow-up period, including assessment of liver enzymes (in particular alanine aminotransferase; ALAT), until post-operative day 180 was planned, with visits at days 56 and 180. RESULTS: Randomization and administration of study drugs were stopped following a report of serious liver injury occurring 3 weeks after completion of ximelagatran treatment. At the time of study termination, 1158 patients had been randomized and 641 had completed the 35-day treatment; with 303 ximelagatran and 265 enoxaparin patients remaining in the study through to the day 56 follow-up visit. Overall, 58 patients showed an ALAT increase to >2x upper limit of normal: 31 treated with enoxaparin, 27 with ximelagatran. Three ximelagatran patients also showed symptoms potentially related to liver toxicity. Eleven ximelagatran patients showed an ALAT increase after study treatment ended. The clinical development of ximelagatran was terminated and the drug withdrawn from the market. Evaluation of the relative efficacy of the two treatments as specified in the protocol was impossible due to the premature termination of the study. CONCLUSIONS: Prolonged administration of ximelagatran was associated with an increased risk of liver toxicity. In a substantial proportion of patients, ALAT increase occurred after treatment withdrawal. The findings seen with ximelagatran should be considered when designing studies with new antithrombotic agents.

[Autologous blood transfusion]. / Transfusion sanguine autologue.

Autologous blood transfusion techniques are the principal means of reducing allogeneic blood exposure. Those techniques were developed in order to prevent the risk of contamination by viruses, mainly HVB, HCV and HIV. However that risk has become so small that all studies show an exorbitant cost/efficiency ratio. Autologous blood transfusion would therefore be of no interest in terms of public health but a recent experimental study suggested a possible transmission of the BSE agent through blood. Until the matter is settled, the precaution principle means we should prefer alternative techniques to allogeneic blood whenever possible, hence a renewed interest in autologous transfusion.

[Preoperative strategy for homologous blood salvage and peri-operative erythropoietin]. / Stratégie préopératoire d'épargne sanguine homologue et érythropoïétine en péri-chirurgie.

The amount of transfused blood is related to blood loss calculated for the specific type of surgical procedure, transfusion hematocrit trigger and patient's red blood cell mass on the day before surgery. To optimise the benefit/cost and benefit/risk ratios of blood transfusion, a correct prescription must be done in accordance with the patient's red blood cell mass and surgical blood loss. Indeed, there is a clear need to define the appropriate uses of blood management methods and to seek new methods of improving perioperative blood management. The number of moderately anaemic patients undergoing surgery is currently thought to be 20%. Where transfusion requirements are estimated at two to three blood units, as for instance in the most common types of orthopaedic surgery, preoperative haemoglobin is the key factor governing transfusion needs. In this case, the simplest approach is to prescribe Epoetin Alfa subcutaneous at a dose of 600 IU/kg/week starting three weeks before the surgery. In addition, it is important in all cases to give concomitant iron supplements. Concomitant use of other methods to decrease allogeneic blood requirements is of no value. Obviously, the higher the haematocrit the day prior to surgery, the higher the patient's RBC mass and the greater the patient's permitted blood loss, decreasing the transfusion trigger. In this way, allogeneic blood loss is reduced, but without the need for the patient to attend the blood transfusion center and to undergo laboratory screening and testing of donated blood, and without the risk of inducing preoperative anaemia compared with sequential autologous blood donation. But, to optimise the benefit/cost ratio, we try to define precisely the patient populations likely to benefit from preoperative erythropoietin. Using different examples, management is proposed with algorithms.

[Comparison of Orth-Evac and Solcotrans Plus devices for the autotransfusion of blood drained after total knee joint arthroplasty]. / Comparaison des dispositifs Orth-Evac et Solcotrans Plus pour l'autotransfusion du sang drainé après arthroplastie totale du genou.

Surgical wound blood which is ched through drains after total knee replacement surgery with a tourniquet may be returned to the patient using special collecting devices. This study aimed to compare two systems, Orth-Evac and Solcotrans Plus an to assess the safety of the reinfusion of non washed blood cells. It included 30 patients scheduled for total knee replacement surgery, free from tumoral or coagulation disease and allocated randomly in three groups of 10 each: the Orth-Evac group (OGr), the Solcotrans Plus group (SGr) and the Control group (CGr). The devices, not containing an anticoagulant, were connected to the deep suction drains in the operating room, after skin closure and before the tourniquet removal. The salvaged blood was reinfused in the subsequent six hours via a 40 microns filter. The volume of collected blood was measured and homologous blood was added as required, to maintain a hematocrit of 30%. A blood sample was obtained the day before surgery (D - 1), before reinfusion (D0), two hours later (D + 2h), one day later (D + 1), and from the collecting device before reinfusion. The statistical analysis used the Kruskal-Wallis test and Steel-Dwass procedure to confirm the difference between two groups. The three groups did not differ in age, weight, height and gender. The volume of salvaged and autotransfused blood was 925 +/- 156 mL in OGr and 605 +/- 178 mL in SGr respectively, transfusion of homologous blood was required in two patients of OGr, four of SGr and six of CGr. At D + 1, the hematocrit was comparable in all groups (OGr = 28%, SGr = 28.2% and CGr = 28.5%).(ABSTRACT TRUNCATED AT 250 WORDS)