Practical Suggestions for an Optimal Management of Vitamin K Antagonists: Italian Federation of Centers for the Diagnosis of Thrombotic Disorders and the Surveillance of the Antithrombotic Therapies (FCSA) Position Paper.

In the era of direct oral anticoagulants, vitamin K antagonists retain a clinically relevant role in thrombotic disorders. In Italy, approximately 20% of the patients on anticoagulant therapies receives a VKA, in most cases warfarin. The optimal management of this drug is challenging and cannot disregard its intricate and unpredictable pharmacokinetic properties and patient's thrombotic and bleeding risk. Several clinical issues encountered during warfarin treatment are still unanswered and are tentatively addressed by physicians. In this regard, the Italian Federation of Centers for the diagnosis of thrombotic disorders and the Surveillance of the Antithrombotic therapies (FCSA) provides some experience-based good clinical practice's suggestions on the following topics: (1) how to start the anticoagulant treatment with warfarin and warfarin induction regimen; (2) how to manage a subtherapeutic INR value; (3) how to manage a supratherapeutic INR value in asymptomatic patients; and (4) how to manage the association of warfarin with interfering drugs.

Clot Waveform Analysis: From Hypercoagulability to Hypocoagulability - A Review.

CONTEXT.­: Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are coagulative screening tests used for the diagnosis of several pathologic conditions, such as liver failure, coagulation factor deficiencies, anti-phospholipid antibodies (lupus anticoagulant), and factor VIII inhibitors. A new test was developed several years ago to detect the amount of thrombin generated during plasma clotting, using low tissue factor concentrations and fluorogenic substrates, and it has since been used successfully in conditions ranging from hypocoagulable to hypercoagulable states. However, the test is expensive and difficult to perform in nonspecialized laboratories, and efforts have thus been made to find an economic and easily implementable test suitable for routine use, even in nonspecialist laboratories. OBJECTIVE.­: To evaluate clot waveform analysis (CWA) of PT and aPTT, aiming to show the dynamics of clot formation; that is, the "hidden" features of both tests. CWA can be implemented by using an automated coagulometer with dedicated software. The aim of this review was to evaluate whether CWA is able to detect both hypercoagulative and hypocoagulative states. DATA SOURCES.­: Using MedLine, we searched and retrieved articles relating to CWA. We only considered articles published in English, but with no limits in terms of article type, publication year, or geography. CONCLUSIONS.­: CWA was shown to be a reliable test in patients with both hypercoagulable and hypocoagulable states. It represents a simple and inexpensive global test that can easily provide information on the behavior of the coagulation system. Both the first and second derivatives are computed by using dedicated software implemented with an on-board algorithm in a routine automated coagulometer.

Do we need more guidance on thrombophilia testing? Challenges and special considerations.

INTRODUCTION: Thrombophilia testing (TT) is a laboratory procedure designed to detect the risk factors involved in the pathogenesis of vascular occlusions. The role of TT is also controversial because it has a limited impact on the choice and duration of antithrombotic treatments. AREAS COVERED: We reviewed, by examining MEDLINE up to October 2023. Accepted and not accepted thrombophilia markers are discussed along with the appropriateness or not of prescribing TT in several conditions such as: provoked and unprovoked venous thromboembolism (VTE), women who are planning a pregnancy whose relatives had VTE or have a hereditary thrombophilia, before assumption of estro-progestins, after multiple pregnant loss, arterial thrombosis, retinal vein occlusion, and splanchnic vein thrombosis. EXPERT OPINION: TT is not essential in the management of VTE, but it may be useful for limiting adverse events in case of thrombophilia. We expose our criticism of items afforded by other guidelines by presenting our opinion based on both the scientific evidence and clinical practice. We also deal with common mistakes in prescribing and interpretations of TT hoping to purpose an educational approach on this topic. Finally, we emphasize the creation of the expert in hemostasis and thrombosis who should be present in every hospital.

Contraceptives and Thrombosis: An Intertwined Revolutionary Road.

The development of oral contraceptives (OCs) began in 1921 and continued in the following years until the first regulatory approval from the Food and Drug Administration was granted in 1960. However, it took several years to realize that OCs presented an important but not frequent risk of venous thrombosis. Several reports ignored this dangerous effect and only in 1967 the Medical Research Council clearly stated this as an important risk. Later, research led to the formulation of second-generation OCs containing progestins, which nevertheless presented an increased thrombotic risk. In early 1980s, OCs containing third-generation progestins were introduced into the market. Only in 1995, it became clear that these new compounds induced a higher thrombotic risk than that related to the second-generation progestins. It appeared clear that the modulating action of progestins was against the procoagulant activity of estrogens. Lastly, at the end of the 2000s, OCs containing natural estrogens and a fourth-generation progestin (dienogest) became available. The prothrombotic effect of those natural products was not different from that of preparations containing second-generation progestins. Moreover, research over the years has produced much data on risk factors associated with OCs use such as age, obesity, cigarette smoking, and thrombophilia. These findings allowed us to better assess the individual thrombotic risk (both arterial and thrombotic) of each woman before offering an OC. Furthermore, research has shown that in high-risk people the use of single progestin is not dangerous as far as thrombosis is concerned. In conclusion, the OCs road has been long and difficult but has led to a great and unthinkable scientific and social enrichment since the 1960s.

Hormones and thrombosis: the dark side of the moon.

BACKGROUND: The main drawback of oral contraceptives (OC) and hormone replacement therapy (HRT) is an increased risk of venous and, to a lesser extent, arterial thrombosis. MATERIALS AND METHODS: This narrative, case-based review describes the effect of available estrogens and progestogens on the hemostatic system and their potential impact on the risk of thrombosis. Clinical cases are used to illustrate different options for prescribing OC and HRT in the real-word. The aim is to offer discussion topics that could be helpful to guide the choice of different hormonal treatments over a woman's lifetime and in the presence of risk factors. RESULTS: We describe physio-pathological changes occurring during the administration of hormonal therapies. Furthermore, we analyze the risk of venous and arterial thrombosis associated with different products, routes of administration and additional risk factors. New hormonal preparations, such as estradiol combined with dienogest, as well as non-oral hormonal therapies, are suggested to decrease thrombotic risk significantly. DISCUSSION: The availability of many products and different routes of administration allow most women to safely use contraception, as well as HRT. We encourage careful counselling instead of inflexible or fearful behavior, as expanding options and choices will allow women to make the best decisions for their health.

Living on Oral Anticoagulants: Duke Anticoagulation Satisfaction Scale Results.

BACKGROUND: Direct oral anticoagulants (DOACs) are widely used in patients with atrial fibrillation and venous thromboembolism. The lack of the need for laboratory monitoring and a better safety than vitamin K antagonists (VKAs) has probably changed the quality of life of patients on these oral anticoagulants. This was a real-life prospective observational cohort study. The aim was to evaluate if a long-term treatment with DOACs could offer a better quality of life than VKAs. Moreover, age, gender, education level, time in therapeutic range for VKAs, taking medication once or twice a day for DOACs, the total daily number of medications and thrombotic and bleeding complications were considered as variables probably associated with the quality of life of these patients. METHODS: Between January and December 2021, the Duke Anticoagulation Satisfaction Scale (DASS) 25-items was administered as an interview to patients on either VKAs or DOACs therapy. During the follow-up period, all of the patients were closely monitored to evaluate possible bleeding and thrombotic events. RESULTS: The analysis included 300 outpatients treated with VKAs and 254 treated with DOACs. In general, the quality of life was better in patients taking DOACs (DASS total score: DOACs = 44.7, 42.9-46.5 vs. VKAs = 51, 49.2-52.8, p < 0.0001) as the daily-life limitations, hassles and burdens and the psychological impact were less important than in patients on VKAs therapy. CONCLUSIONS: VKAs negatively influence the daily-life of the patients in terms of both less satisfaction and time-consuming tasks. DOACs confer a better quality of life even if some concerns emerge from not knowing how their therapy is working.

A journey to vasculopathy in systemic sclerosis: focus on haemostasis and thrombosis.

Systemic sclerosis is a multisystem connective tissue disease, characterized by endothelial autoimmune activation, along with tissue and vascular fibrosis leading to vasculopathy and to a progressive loss of angiogenesis. This condition further deranges the endothelial barrier favouring the opening of the endothelial junctions allowing the vascular leak in the surrounding tissues: this process may induce cell detachment which allows the contact between platelets and collagen present in the exposed subendothelial layer. Platelets first adhere to collagen via glycoprotein VI and then, immediately aggregate because of the release of von Willebrand factor which is a strong activator of platelet aggregation. Activated platelets exert their procoagulant activity, exposing on their membrane phospholipids and phosphatidylserine, enabling the adsorption of clotting factors ready to form thrombin which in turn drives the amplification of the coagulative cascade. An essential role in the activation of blood coagulation is the tissue factor (TF), which triggers blood coagulation. The TF is found abundantly in the subendothelial collagen and is also expressed by fibroblasts providing a haemostatic covering layer ready to activate coagulation when the endothelial injury occurs. The aim of this review is to focus the attention on the underlying mechanisms related to haemostasis and thrombosis pathophysiology which may have a relevant role in SSc as well as on a possible role of anticoagulation in this disease.

Performance and Interpretation of Clot Waveform Analysis.

The prothrombin time (PT) and the activated partial thromboplastin time (aPTT) are two basic tests for routine purposes, which are widely used in the clinical screening of coagulopathies. PT and aPTT are useful tests for detecting both symptomatic (hemorrhagic) and asymptomatic defects, but they are unsuitable for studying hypercoagulable states. However, these tests are available for studying the dynamic process of clot formation by means of the detection of the clot waveform analysis (CWA), which has been introduced several years ago. CWA can provide useful information on both hypocoagulable and hypercoagulable states. Nowadays it is possible to detect the whole clot formation both in the PT and aPTT tubes starting from the initial step of fibrin polymerization by means of specific and dedicated algorithm implemented in a coagulometer. In particular, CWA provides information on the velocity (first derivative), acceleration (second derivative), and density (delta) of clot formation. CWA has been applied to several pathologic conditions such as coagulation factor deficiency (including congenital hemophilia from factor VIII, IX, or XI deficiency), acquired hemophilia, disseminated intravascular coagulation (DIC), sepsis, replacement therapy management, chronic spontaneous urticarial, and liver cirrhosis, in patients with high venous thromboembolic risk before LMWH prophylaxis, and in patients with different hemorrhagic patterns along with an electron microscopy evaluation of the clot density. We report here materials and methods used for detecting the additional clotting parameters available in both PT and aPTT.

Chronic spontaneous urticaria: a low-grade disseminated intravascular coagulation only partially reversed by Omalizumab.

Chronic spontaneous urticaria (CSU) is a disorder characterized by wheals and/or angioedema. The coagulation cascade and inflammation pathways are closely linked together. The aim of our study was first to investigate the dynamics of clot formation in plasma (Clot Waveform Analysis, CWA) in a group of 47 patients with CSU along with other coagulative parameters dedicated to the study of hypercoagulability, such as D-Dimer, F 1 + 2 peptide, Fibrinogen, Platelet count and Mean Platelet Volume (MPV). Secondly, 23 out of 47 patients were treated with Omalizumab at four administration intervals from T0 to T4. A statistically significant increase in Activated Partial Thromboplastin (aPTT) ratio, D-Dimer, F1 + 2, Platelet count and MPV was found when compared with 53 healthy controls (HC). In contrast, the 2nd Derivative of aPTT showed lower values than those of the HC. No differences were found between 1st derivative of aPTT and Fibrinogen. D-Dimer only showed a significant difference between T0 and T3. An activation of both coagulation and fibrinolysis along with a weaker clot acceleration may be in agreement with a low-grade DIC. The accelerated turnover of platelets expressed by both an increase in platelet count and MPV further supports this pathway in CSU. Omalizumab does not affect the relationship between the immune and the hemostatic systems.

The ART of Thromboprophylaxis in the Prevention of Gestational Venous Thromboembolism.

Assisted reproductive techniques (ART) allow infertile couples to conceive. Use of hormones to obtain a controlled ovarian stimulation and an adequate growth of the endometrium preparatory for embryo implantation are not riskless. Among others, thrombotic events can occur during the ovulation induction or pregnancy following ART. As the number of women approaching ART to conceive is steadily increasing, the issue of thrombotic risk in this setting is relevant. Data on the weight of each risk factor and on potential benefit of thromboprophylaxis are largely lacking. In this review, we discuss risk of venous thromboembolism during pregnancy following ART, with a focus on general (i.e.: age, body mass index, thrombophilia, bed rest, transfusions) and ART-specific (i.e., polycystic ovarian syndrome, ovarian hyperstimulation syndrome) risk factors. We also attempt to provide some suggestions to guide clinical practice, based on available data and studies performed outside ART.

Management of DOAC in Patients Undergoing Planned Surgery or Invasive Procedure: Italian Federation of Centers for the Diagnosis of Thrombotic Disorders and the Surveillance of the Antithrombotic Therapies (FCSA) Position Paper.

Patients on anticoagulant treatment are constantly increasing, with an estimated prevalence in Italy of 2% of the total population. About a quarter of the anticoagulated patients require temporary cessation of direct oral anticoagulants (DOACs) or vitamin K antagonists for a planned intervention within 2 years from anticoagulation inception. Several clinical issues about DOAC interruption remain unanswered: many questions are tentatively addressed daily by thousands of physicians worldwide through an experience-based balancing of thrombotic and bleeding risks. Among possible valuable answers, the Italian Federation of Centers for the diagnosis of thrombotic disorders and the Surveillance of the Antithrombotic therapies (FCSA) proposes some experience-based suggestions and expert opinions. In particular, FCSA provides practical guidance on the following issues: (1) multiparametric assessment of thrombotic and bleeding risks based on patients' individual and surgical risk factor, (2) testing of prothrombin time, activated partial thromboplastin time, and DOAC plasma levels before surgery or invasive procedure, (3) use of heparin, (4) restarting of full-dose DOAC after high risk bleeding surgery, (5) practical nonpharmacological suggestions to manage patients perioperatively. Finally, FCSA suggests creating a multidisciplinary "anticoagulation team" with the aim to define the optimal perioperative management of anticoagulation.

Clinical history and gastrointestinal bleeding in patients taking oral anticoagulants.

BACKGROUND: Common risk factors for gastrointestinal bleeding (GIB) are advanced age and the use of antiplatelet or anticoagulants drugs for the prevention of cardiovascular diseases. METHODS: In this prospective real-world observational study, oral anticoagulated patients were recruited and followed between June 2013 and December 2019. The primary end-point was to evaluate a possible relationship between bleeding events and patients' clinical history of gastrointestinal disease prior to the start of the therapy. The secondary end-points were time of GIB appearance and the percentage of idiopathic or provoked events, i.e., bleeding due to a gastrointestinal disease. In case of GIB event all the patients were studied by means of endoscopic procedures. Cox regression was used to calculate the relative hazard ratios (HRs) of GIB for each considered clinical variable. RESULTS: 734 patients on both VKAs or DOACs were studied. Overall, 46 hemorrhagic events were recorded: 6 were major bleeding (0.42/100 patient-years) while 43 were clinically relevant non major bleeding (2.8/100 patient-years). The Cox regression analysis did not show any relationships among GIB and the variables considered. CONCLUSION: The patients' clinical history is neither a predictor for GIB bleeding nor a guide to the choice of the oral anticoagulant to be administered. Routinely applying bleeding risk screening, such as occult blood in the stool, should be added to the periodic laboratory checks for early recognition of patients at higher risk of GIB.

Findings from a multicentre, observational study on reproductive outcomes in women with unexplained recurrent pregnancy loss: the OTTILIA registry.

STUDY QUESTION: What evaluation and care is offered to women after unexplained recurrent pregnancy loss (RPL) or intra-uterine foetal death (IUFD) and what are the reproductive outcomes? SUMMARY ANSWER: Women are assessed for thrombophilia and often treated with low-molecular weight heparin (LMWH) and/or low-dose aspirin (ASA). WHAT IS KNOWN ALREADY: Randomized controlled trials (RCTs) on possible efficacy of heparins and/or aspirin have been inconclusive due to limited power to detect a difference and patient heterogeneity. STUDY DESIGN, SIZE, DURATION: Prospective multicentre cohort study performed in 12 hospitals in three countries between 2012 and 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS: All consecutive pregnant women with recurrent PL (≥3 losses or 2 losses in the presence of at least one euploid foetal karyotype) or at least one IUFD. Eligible women may have undergone thrombophilia testing before conception, at the discretion of local providers. The possible assignment of women to treatments (such as LMWH) was not decided a priori but was determined based on the responsible provider's current practice. Aims of the study were: (i) to evaluate factors associated with pregnancy outcome; (ii) to compare clinical management strategies in women with and without a subsequent successful pregnancy; and (iii) to evaluate characteristics of women who may benefit from antithrombotic therapy. A propensity score matching method was used to balance the differences in baseline characteristics. MAIN RESULTS AND THE ROLE OF CHANCE: A matched sample of 265 pregnant women was analysed, with all undergoing thrombophilia screening; 103 out of 119 (86.6%) with and 98/146 (67.1%) without thrombophilia were prescribed with LMWH and/or ASA. Overall, live-births were recorded in 204 cases (77%), PL or IUFD in 61 (23%) pregnancies. Logistic regression showed a significant interaction between thrombophilia and treatment with LMWH (P = 0.03). Findings from sensitivity analysis showed odds ratio (OR) for pregnancy loss in women with inherited or acquired thrombophilia in absence of any treatment was 2.9 (95% CI, 1.4-6.1); the administration of LMWH (with or without ASA) was associated with higher odds of live-birth (OR, 10.6; 95% CI, 5.0-22.3). Furthermore, in women without thrombophilia, the odds of live-birth was significantly and independently associated with LMWH prophylaxis (alone or in association with ASA) (OR, 3.6; 95% CI, 1.7-7.9). LIMITATIONS, REASONS FOR CAUTION: While the propensity score matching allows us to balance the differences in baseline characteristics, it does not eliminate all confounding. WIDER IMPLICATIONS OF THE FINDINGS: Antithrombotic prophylaxis during pregnancy may be effective in women with otherwise unexplained PL or IUFD, and even more useful in those with thrombophilia. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by Italian Ministry of Health (Ricerca Corrente 2018-2020). Dr G.P. has received research grant support from Bristol Myers Squibb/Pfizer Alliance, Janssen, Boston Scientific Corporation, Bayer, and Portola and consultant fees from Amgen and Agile Therapeutics. Dr E.G. has received consultant fees from Italfarmaco and Sanofi. All other authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER: NCT02385461.

Clot characterization by multidisciplinary approach: biochemical and imaging parameters in a hypocoagulative setting. A pilot study.

BACKGROUND: Clot characterization is, to the present days, a multimodal approach: scanning the clot by electron microscopy (SEM) is helpful for the visualization of fibrin structure along with laboratory parameters such as the clot waveform analysis (CWA) and thrombin generation in different settings of clot abnormalities. This study aimed to assess whether the coagulative parameters were consistent with the clot images texture acquired by SEM, and therefore to propose a more generalist and integrative approach to clots classification. DESIGN AND METHODS: In this pilot study, the examined population consists of eight healthy subjects, seven patients affected by Acquired Hemophilia A (AHA) and seven patients treated with Vitamin K Antagonists (VKAs), similar for age and gender. We studied the velocity and acceleration (1st and 2nd derivative of the aPTT) of clot formation (CWA), the thrombin generation, and the clots' scanning by SEM. Images acquired with SEM were then analyzed with the MATLAB software with the "Texture Analysis" methods to perform classification. Among the various texture parameters, we reported Contrast and Energy. RESULTS: Significant differences among healthy subjects, patients with AHA and those treated with VKAs were detected for the coagulative parameters. We found no differences between VKAs and AHA patients. Contrast and energy highlighted a significant difference among the three groups in agreement with the laboratory's parameters. We found no significant differences between VKAs and AHA patients. CONCLUSIONS: The use of SEM, CWA and thrombin generation parameters may be a starting point for studies aimed to demonstrate the general characteristics of clot formation in different clinical conditions with a multiparametric approach.

Patients' adherence to oral anticoagulants therapy: Comparison between vitamin K antagonists and direct oral anticoagulants.

BACKGROUND: Patient's adherence to oral anticoagulant therapy is essential to prevent and treat thrombotic events. METHODS: To assess the patients' adherence Morisky Medication Adherence Scale 8-items was used. The target population included 785 consecutive outpatients, of whom 384 were on Vitamin K Antagonists and 401 on Direct Oral Anticoagulants. Moreover, we evaluate which variable among age, gender, having experienced a thrombotic episode, time in the therapeutic range for patients on Vitamin K Antagonists, being naive and once versus twice daily drug assumption for patients on Direct Oral Anticoagulants, could affect adherence to therapy. RESULTS: Morisky Medication Adherence Scale 8-items score was 8 in both groups. The intentional non-adherence obtained the lowest score while the unintentional non-adherence is the most frequent problem in patients treated with either Vitamin K Antagonists or Direct Oral Anticoagulants. Age > 75 years, male gender, having experienced a thrombotic episode, being naive and assuming Direct Oral Anticoagulants twice a day were significantly associated with a higher risk to forget assuming the oral anticoagulant, to have more difficulty in remembering to take it or to bring it in case of travel or leaving home. A low percentage of time in therapeutic range was associated with a not regularly assumption of the anticoagulants. CONCLUSION: Patients treated with Vitamin K Antagonists or Direct Oral Anticoagulants show a good adherence and persistence to their oral anticoagulant therapy. Several factors have been identified to affect patients' adherence and deserve a careful attention by the doctors at the Anticoagulation Clinic.

Trial of Rivaroxaban in AntiPhospholipid Syndrome (TRAPS): Two-year outcomes after the study closure.

BACKGROUND: Trial of Rivaroxaban in AntiPhospholipid Syndrome was a prospective randomized, open-label, noninferiority study conducted in 14 centers in Italy. Rivaroxaban was compared with warfarin for the prevention of thromboembolic events, major bleeding, and vascular death in high-risk, triple-positive patients with antiphospholipid syndrome. OBJECTIVE: The aim of this paper is to report the events during the 2-year follow-up after the study closure. METHODS: On January 28, 2018, the trial was prematurely stopped by adjudication and safety committee for an excess of events in the rivaroxaban group. Randomized patients were advised on trial results and those randomized to rivaroxaban were solicited to switch to warfarin. All 14 participating centers were asked and accepted to follow their patients for clinical events. This report describes the rate of events that occurred between January 28, 2018, and January 28, 2020. RESULTS: Of 120 randomized patients, 115 were available for follow-up. Outcome events were two in six (33.3%) patients who remained on direct oral anticoagulants (DOACs) and six in 109 (5.7%) patients on warfarin (hazard ratio [HR] 6.9; 95% confidence interval [CI] 1.4-34.5, P = .018). The two patients on DOACs (one taking dabigatran and one taking rivaroxaban) suffered from thromboembolic events, whereas of the six patients with composite outcomes on warfarin, three had thromboembolic events (HR for thrombosis 13.3; 95% CI 2.2-79.9, P = .005). CONCLUSION: These data further support the use of warfarin in high-risk patients with antiphospholipid syndrome.

The Repeatable Battery for the Assessment of Neuropsychological Status as a screening strategy for HIV-Associated Neurocognitive Disorders.

HIV-infected people are at risk for neurocognitive impairment (HIV-Associated Neurocognitive Disorders - HAND). To evaluate whether the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), a widely used neurocognitive screening tool, could be a valid instrument for HAND identification, we evaluated 166 HIV-infected subjects. Our results showed that 96 (57.8%) HIV-infected scored RBANS Total Index Score <85 (at least one SD below the normal), 12 (7.2%) of them scored RBANS Total Index Score <70 (at least 2 SD below the normal, indicating a possible HIV-Associated Dementia). The more compromised areas were Immediate and Delayed Memory, and Attention. In the group with RBANS Total Index Score <85, there were significantly lower scores of Mini Mental State Examination (P = 0.0008), Clock Drawing Test (P = 0.0015) and higher score of Geriatric Depression Scale (P = 0.02) compared to the RBANS Total Index Score ≥85 group. Using a stepwise logistic regression, considering RBANS Total Index Score as dependent variable, we found a positive interaction with tenofovir/emtricitabine assumption (P = 0.027), Clock Drawing Test (P = 0.0125) and educational level (P = 0.0054). Being the viro-immunological markers not capable of predicting cognitive decline in HIV-infected individuals, our data suggest that RBANS may be a valid tool for the early identification of HIV-related cognitive impairment.

Position paper on the safety/efficacy profile of Direct Oral Anticoagulants in patients with Chronic Kidney Disease: Consensus document of Società Italiana di Nefrologia (SIN), Federazione Centri per la diagnosi della trombosi e la Sorveglianza delle terapie Antitrombotiche (FCSA) and Società Italiana per lo Studio dell'Emostasi e della Trombosi (SISET).

Direct oral anticoagulants (DOAC) are mostly prescribed to prevent cardioembolic stroke in patients with non-valvular atrial fibrillation (AF). An increasing number of guidelines recommend DOAC in AF patients with preserved renal function for the prevention of thromboembolism and an increased use of DOAC in daily practice is recorded also in elderly patients. Aging is associated with a reduction of glomerular filtration rate and impaired renal function, regardless of the cause, increases the risk of bleeding. Multiple medication use (polypharmacy) for treating superimposed co-morbidities is common in both elderly and chronic kidney disease (CKD) patients and drug-drug interaction may cause accumulation of DOAC, thereby increasing the risk of bleeding. There is uncertainty on the safety profile of DOAC in patients with CKD, particularly in those with severely impaired renal function or end stage renal disease, due to the heterogeneity of studies and the relative paucity of data. This document reports the position of three Italian scientific societies engaged in the management of patients with atrial fibrillation who are treated with DOAC and present with CKD.