Anticoagulants, renal failure and atrial fibrillation

Abstract

The prevalence of atrial fibrillation (AF) in patients with chronic renal failure (CRF) and end-stage renal disease (ESRD) is very high and also in this population AF is associated with an increased risk of stroke. Warfarin is the treatment of choice for AF to prevent thromboembolic events, but it has been reported that its use in CRF and hemodialysis (HD) patients is associated with an increased risk of bleeding compared with patients with normal renal function. Moreover, historical studies suggest that warfarin increases the incidence of both ischemic and hemorrhagic strokes in HD patients. However, a clear benefit:risk ratio against warfarin in patients with CRF or ESRD and AF has not been demonstrated. New oral anticoagulants, thrombin or factor Xa inhibitors, are now available. Patients with severe CRF (i.e., glomerular filtration rate < 30 mL/min) and with ESRD, however, were excluded from the trials that have established their efficacy and safety. The advent of new oral anticoagulants raises the important question if patients with severe CRF and ESRD should be excluded or not from this new therapeutic opportunity.

Keywords::

• anticoagulants
• atrial fibrillation
• hemodialysis
• renal failure

Over the past decade the studies demonstrating a high prevalence of atrial fibrillation (AF) in patients with chronic renal failure (CRF) and end-stage renal disease (ESRD) have increased. In hemodialysis (HD) patients, the reported prevalence is between 13 and 27% [1,2]. It is quite likely that these values are underestimated, in particular as regards the forms of paroxysmal arrhythmia that are often undiagnosed or confused with other arrhythmias. There is an increasing trend in the prevalence of AF in the population of patients with severe kidney disease or on dialysis [3]. Even in this population, as well as in that with normal renal function, AF is associated with an increased risk of stroke [4], and the nephrologists experience the complex dilemma as to whether or not to administer oral anticoagulant therapy (OAT) to this category of patients. The greatest difficulties in undertaking the anticoagulant therapy in CRF patients derive from the observation that advanced renal disease sees the presence of two opposite situations: on the one hand, the presence of a high risk of stroke due to an acceleration of atherosclerotic processes [5], on the other, a series of multifactorial alterations in the coagulation system leading to a high risk of bleeding [6]. When AF occurs in a patient with severe kidney disease or in chronic HD therapy, we must decide whether to prescribe OAT at the risk of major bleeding events or not, thereby exposing the patient to a higher risk of thromboembolism. Warfarin has never been tested in people with ESRD and the clinical indications for its use was simply derived from the evidence obtained in the population of patients with AF and without kidney disease, in whom efficacy in the prevention of thromboembolic events was demonstrated.

As often happens when heart disease occurs in CRF or HD patients, cardiac guidelines are of little help. The most widely used thromboembolic risk score, CHADS₂, recently amended in CHA₂DS_2-VASc in an attempt to improve the stratification in intermediate-risk patients, has never been validated in a population of patients with kidney disease. This is despite the fact that the individual variables taken into consideration in the CHA₂DS_2-VASc (congestive heart failure/LV dysfunction, hypertension, age ≥ 75 years, diabetes mellitus, stroke/TIA/thromboembolism, vascular disease, age 65 – 74, sex category), have an extremely high frequency in patients with CRF and, in particular, in those with ESRD. In the population of HD patients, the percentage of hypertension is over 90%, one-third of them are diabetics, the majority has a vasculopathy and many are elderly [7]. It follows that the majority of chronic HD patients with AF reaches a score of CHA₂DS_2-VASc ≥ 2 and, therefore, according to the cardiology guidelines, should be anticoagulated given its high potential thromboembolic risk.

The clinicians, however, have difficulties in prescribing a vitamin K inhibitor therapy, like warfarin, not only for the abovementioned high risk of bleeding in his/her patients but also because the literature data suggest that the use of warfarin in this population increases mortality and the incidence of both ischemic and hemorrhagic strokes [8,9]. Moreover, a recent large study showed a benefit of warfarin in terms of protection from the risk of thromboembolism, at the cost of an increased bleeding risk in HD patients with AF [10]. However, it must be said that there are neither prospective studies nor randomized trials (difficult to realize in dialysis patients) demonstrating a clear benefit/risk against warfarin in patients with CRF or ESRD and AF. In recent years, only a few scientific publications have appeared that contain flowcharts, based primarily on clinical common sense considerations, which suggest what to do in a patient with the simultaneous presence of ESRD and AF [11]. However, we are far from having irrefutable evidence in our hands of sound clinical guidelines.

The review by Salam et al. systematically analyzes the state of the complex problem of the use of warfarin in patients with AF and severe kidney disease [12]. It also faces the problem of use in these subjects of the new oral anticoagulants, thrombin or factor Xa inhibitors. Even in this case, patients with severe CRF and with ESRD were excluded from the trials – that have established the efficacy and safety of new molecules – because for many of these new drugs, the elimination occurs primarily through the kidney. Despite this, we can draw some important considerations to focus on. First, there are available data on dabigatran and rivaroxaban use in subjects with a glomerular filtration rate between 50 and 30 mL/min that show that even in this patient population aspects of drug efficacy and safety are maintained [13,14] Second, pilot studies have been performed on a small number of patients with ESRD to assess the safety of administration of dabigatran [15]. Third, only about 20% of the new molecule, apixaban, is removed via the kidneys and the remainder in the feces. This might facilitate the design of a trial to evaluate efficacy and safety in patients with severe CRF or ESRD in which there is an indication for OAT.

In conclusion, there is still much to be done. In particular, it is necessary to carry out further studies to clarify the risk:benefit ratio of anticoagulation in CRF and HD patients. Many safety aspects should also be elucidated and not only as regards the bleeding risk. A recent and detailed analysis by the randomized evaluation of long-term anticoagulant therapy (RE-LY) has shown that myocardial infarctions were numerically more frequent with dabigatran as compared with warfarin [16]. These data associated with the knowledge of the high prevalence of ischemic heart disease in the ESRD patient population [7] raise some concerns as to the possible use of new anticoagulants in a patient already burdened by a significant cardiovascular system impairment. Hence, the advent of new oral anticoagulants raises an important question: Should patients with severe CRF and ESRD be excluded from this new therapeutic opportunity or can we also think of giving them the possibility of gaining a clinical advantage from these new molecules, if properly dosed?

Declaration of interest

The authors state no conflict of interest and have received no payment in preparation of this manuscript.