Balancing thromboembolic risk against vitamin K antagonist-related bleeding and accelerated calcification: is fondaparinux the Holy Grail for end-stage renal disease patients with atrial fibrillation?

Patients with end-stage renal disease (ESRD) may classically present with highly contrasting derangements of haemostasis, ranging from haemorrhagic diathesis to increased thrombotic risk [1]. Unfortunately, the current guidelines on anticoagulant (AC) therapy do not fully cover the spectrum of thromboembolic conditions potentially affecting ESRD patients [2–4]. These guidelines recommend standard AC treatments for conditions, such as acute deep vein thrombosis, pulmonary embolism, mechanical heart valves and antiphospholipid syndrome, but appear much less clear-cut when dealing with another very common thromboembolic condition, such as atrial fibrillation (AF). In this regard, the value of conventional oral AC (OAC) therapy with vitamin K antagonists (VKA), such as warfarin, for ESRD patients with AF has been seriously challenged, except for those with prior cardioembolic ischaemic stroke [5]. Other recent data suggest some benefit for VKA use in lessadvanced stages of CKD, even though at the price of an increased risk of haemorrhagic complications [6]. Following the demonstration of the better efficacy/manageability compared with conventional OAC, a number of new AC drugs have been introduced that act by direct inhibition of either thrombin (dabigatran etexilate) or factor Xa (rivaroxaban and apixaban) [7]. All of these new drugs have the advantage of oral administration, without needing long-term monitoring; however, they are primarily excreted by the kidney, with a substantial renal clearance [8]. Thus, it is not surprising that renal impairment is one of the putative risk factors for bleeding complications. Unfortunately, a major problem is that renal patients, especially those with ESRD, have been often excluded from randomized controlled trials (RCTs) with these novel AC drugs [8]. Two major issues, specific to the clinical context of ESRD, render conventional OAC therapy even more challenging [9]: (i) the increased bleeding risk notoriously associated with declining kidney function; (ii) the recently discovered side-effect of VKA (the most commonly used conventional OAC drugs), consisting in the acceleration of medial and intimal vascular calcification, a strong and independent risk factor for cardiovascular complications and mortality [10]. Thus, alternatives to VKA with a sound safety profile are urgently required, especially for patients with the most advanced stages of chronic kidney disease (CKD). In this issue of Nephrol Dial Transplant., Speeckaert et al. [11] suggest that Fondaparinux, a parenteral indirect FXa inhibitor that shows a prolonged half-life in ESRD patients, thus allowing thrice weekly administration, could represent a possible therapeutic option in the conundrum of the prophylaxis against thromboembolic risk in ESRD with AF. In their observational pilot study on six ESRD patients undergoing a total of 459 treatments, Fondaparinux administered