Thromboprophylaxis in the obese surgical patient

Editor, We read with interest the European recommendations for thromboprophylaxis1,2 and specifically the chapter about thromboprophylaxis in obese surgical patients.3 We would like to make the following two remarks about the proposed injection regimens.1,2 The first comment concerns the twice-daily regimen with 3000 to 4000 anti-Xa IU or 4000 to 6000 anti-Xa IU of low molecular weight heparins depending on the patient's thrombotic risk. These grade 2B suggestions (and not recommendations) are based on nonrandomised trial data. Clearly, from a pharmacological point of view, the administration of 6000 anti-Xa IU of low molecular weight heparin generates a higher anti-Xa peak activity than that observed with a dosage of 4000 anti-Xa IU.4 However the analysis of studies performed during bariatric surgery on patients with a high BMI (≥50 kg m−2) showed that twice-daily injection of these high dosages could lead to values of the anti-Xa activity above prophylactic thresholds. Hence, in the study of Simone et al.,5 57% of patients (four out of seven patients) receiving 2 x 6000 anti-Xa IU of enoxaparin had anti-Xa activity values exceeding the threshold of 0.44 IU ml−1. The study of Borkgren et al.6 focusing on this same regimen for patients with a BMI more than 50 kg m−2 (n = 99) also demonstrated an overdosage in 16.5% of cases. It is therefore important to raise clinicians’ awareness of the potential risk of postoperative bleeding in patients treated with 2 x 6000 anti-Xa IU of low molecular weight heparins, in the context of surgery which differs from the medicine field without tissue damage. The second comment concerns the absence of a discussion about single or twice-daily injection strategies. Venclauskas et al.3 proposed twice-daily dosing identical to that used in the USA, whereas the European strategy has up until now preferred thromboprophylaxis with a single daily injection. However, two recent randomised trials published relating to bariatric surgery7,8 compared the effects of a higher single dose with twice-daily injections. The EFFORT trial,7 published in 2015 and mentioned in the chapter about thromboprophylaxis in obese surgical patients,3 compared two groups of 98 and 100 patients receiving two times injections of 4000 anti-Xa IU of enoxaparin or 5 mg of fondaparinux, respectively (instead of the 2.5 mg usually used in thromboprophylaxis). The results showed that the anti-Xa activity measured on the first day after surgery reached the prophylactic target more often in the fondaparinux group (74.2%) than in the enoxaparin group (32.4%). However, the mean duration of treatment was 2.5 days, which is very different from European standards. Our team published a controlled randomised trial in 2016 including three groups of 50 gastric bypass patients who received 4000, 6000 IU or twice-daily 4000 anti-Xa IU of enoxaparin as postoperative prophylaxis for a minimum period of 10 days.8 The patients who received 6000 anti-Xa IU of enoxaparin in a single daily injection had an anti-Xa activity within the defined target range (0.3 to 0.5 IU ml−1) more frequently than those receiving 4000 IU or 2 x 4000 anti-Xa IU of enoxaparin. Moreover, the single injection of a higher dose was associated with the return to baseline of platelet and granulocyte procoagulant microparticles concentrations on day 30 after surgery, whereas these microparticles remained elevated in the twice-daily 4000 anti-Xa IU group. A possible explanation would be that the first injection may have been insufficient to achieve massive factor Xa neutralisation, the remaining factor Xa thereby promoting thrombin generation, vascular platelet and cell activation in a feed-forward mechanism. Hence, the efficacy of the second injection would have been lowered by an excess of remaining factor Xa and generated thrombin, whereas a single 6000 UI injection could blunt the initial activity of all factor Xa. Granulocytes and derived microparticles already elevated owing to the inflammatory condition of obese patients may in turn activate platelets thereby contributing to the amplification loop. Therefore, in this randomised study, microparticles and anti-Xa factor concentrations were in favour of a single and high enoxaparin dose to assume long-term protection after bypass surgery. This higher dose, once-daily injection strategy might also be suggested in nonbariatric surgery in obese patients with a BMI more than 40 kg m−2. Indeed, the retrospective observational work of Wang et al.9 suggested that this category of patients could benefit from a higher dosage. Randomised trials are strongly required in this field. To conclude, our comments illustrate the difficulties in promoting strategies adapted to the management of obese patients, as the relevant data are limited and cannot be used to establish strong recommendations. Nevertheless, we consider it desirable, on the one hand, to warn about the potential risk of postoperative bleeding with the highest twice-daily doses, which can reach curative targets and, on the other hand, open the door to other strategies with a higher-dose once-daily injection, which have been the subject of randomised trials. Acknowledgements relating to this article Assistance with the letter: none. Financial support and sponsorship: none. Conflicts of interest: the cited study by Steib et al.8 was sponsored two-thirds by institutional grants (Program of interregional Research) and one-third by industrial grants (Sanofi-Aventis). Financial supporters had no role in the design and conduct of that study, in the collection, analysis of the data and in the preparation of the manuscript.