-
1.
Role of rivaroxaban in the management of atrial fibrillation: insights from clinical practice.
Vimalesvaran, K, Dockrill, SJ, Gorog, DA
Vascular health and risk management. 2018;:13-21
Abstract
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, and it leads to significant morbidity and mortality, predominantly from ischemic stroke. Vitamin K antagonists, mainly warfarin, have been used for decades to prevent ischemic stroke in AF, but their use is limited due to interactions with food and other drugs, as well as the requirement for regular monitoring of the international normalized ratio. Rivaroxaban, a direct factor Xa inhibitor and the most commonly used non-vitamin K oral anticoagulant, avoids many of these challenges and is being prescribed with increasing frequency for stroke prevention in non-valvular AF. Randomized controlled trial (RCT) data from the ROCKET-AF(Rivaroxaban once daily oral direct Factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation) trial have shown rivaroxaban to be non-inferior to warfarin in preventing ischemic stroke and systemic embolism and to have comparable overall bleeding rates. Applicability of the RCT data to real-world practice can sometimes be limited by complex clinical scenarios or multiple comorbidities not adequately represented in the trials. Available real-world evidence in non-valvular AF patients with comorbidities - including renal impairment, acute coronary syndrome, diabetes mellitus, malignancy, or old age - supports the use of rivaroxaban as safe and effective in preventing ischemic stroke in these subgroups, though with some important considerations required to reduce bleeding risk. Patient perspectives on rivaroxaban use are also considered. Real-world evidence indicates superior rates of drug adherence with rivaroxaban when compared with vitamin K antagonists and with alternative non-vitamin K oral anticoagulants - perhaps, in part, due to its once-daily dosing regimen. Furthermore, self-reported quality of life scores are highest among patients compliant with rivaroxaban therapy. The generally high levels of patient satisfaction with rivaroxaban therapy contribute to overall favorable clinical outcomes.
-
2.
Antithrombotic treatment in peripheral artery disease.
Olinic, DM, Tataru, DA, Homorodean, C, Spinu, M, Olinic, M
VASA. Zeitschrift fur Gefasskrankheiten. 2018;(2):99-108
Abstract
This review treats antithrombotic use for peripheral arterial disease (PAD). In asymptomatic patients, there are no scientific data to support single antiplatelet therapy (SAPT) for primary prophylaxis. In symptomatic PAD, SAPT with aspirin or clopidogrel is indicated. The efficacy of aspirin is controversial. Clopidogrel may be preferred over aspirin. Ticagrelor is not superior to clopidogrel in reducing major adverse cardiovascular events and major adverse limb events, but lowers the risk of ischaemic stroke. In symptomatic PAD, dual antiplatelet therapy (DAPT) with clopidogrel and aspirin does not provide benefit over SAPT with aspirin alone and is associated with increased risk of major bleeding. DAPT with ticagrelor 60 mg b. i. d. and aspirin provides a significant major adverse cardiovascular events reduction in symptomatic PAD patients and may be considered in PAD patients with prior myocardial infarction. The use of a new thrombin receptor antagonist, vorapaxar, on top of SAPT or DAPT with aspirin and/or clopidogrel, reduces the risk of acute limb ischaemia and peripheral artery revascularization in patients with symptomatic PAD, at the cost of an increased risk for bleeding. Rivaroxaban (2.5 mg b. i. d.) plus aspirin (100 mg daily) is the first antithrombotic association that proved significant benefit for PAD patients, in terms of strong endpoints - total mortality and cardiovascular mortality. Therefore, this association shows the strongest evidence for secondary prevention of symptomatic PAD patients. In PAD patients undergoing percutaneous peripheral interventions, at least four weeks of DAPT with aspirin and clopidogrel is recommended after infrainguinal stent implantation. Stenting below-the-knee arteries is often followed by a longer period of DAPT, but no specific evidence is available. Anticoagulation is mandatory to prevent arterial occlusion during radial or brachial invasive procedures. The strategy includes use of unfractioned heparin, bivalirudin or enoxaparin. Vitamin K antagonists may be considered after autologous vein infrainguinal bypass.
-
3.
Management of Intraprocedural Anticoagulation in Patients on Non-Vitamin K Antagonist Oral Anticoagulants Undergoing Catheter Ablation for Atrial Fibrillation: Understanding the Gaps in Evidence.
Martin, AC, Godier, A, Narayanan, K, Smadja, DM, Marijon, E
Circulation. 2018;(6):627-633
Abstract
Catheter ablation has gained a prominent role in the management of atrial fibrillation (AF), with recent data providing positive evidence on hard outcomes, including hospitalization and mortality. Ablation, however, exposes the patient to a rather unique situation, combining risks for both major bleeding and thromboembolic events. In this setting, the critical importance of rigorous anticoagulation during the procedure has been underlined, and the latest international guidelines now recommend performing AF catheter ablation with uninterrupted non-vitamin K antagonist oral anticoagulants (NOACs) and concomitant administration of unfractionated heparin adjusted to achieve and maintain a target activated clotting time of ≥300 seconds. Whereas observational studies and randomized controlled trials support the safety and efficacy of uninterrupted NOAC strategy for AF catheter ablation, recent experiences have questioned this point, showing a greater unfractionated heparin requirement in NOAC-treated patients compared with vitamin K antagonists-treated patients to achieve the target activated clotting time. Important gaps in evidence regarding optimal intraprocedural anticoagulation management need to be acknowledged. A thorough appreciation of the physiology of anticoagulation during AF catheter ablation and the relevant differences between vitamin K antagonists and NOACs is required, while also understanding the limitations of activated clotting time measurement with regard to accurate intraprocedural anticogulation monitoring. This review aims to provide a critical look at this relatively ignored aspect of AF catheter ablation, especially pitfalls in NOAC monitoring, and to identify gaps in knowledge that need to be addressed in the near future.
-
4.
State of play and future direction with NOACs: An expert consensus.
Cohen, AT, Lip, GY, De Caterina, R, Heidbuchel, H, Zamorano, JL, Agnelli, G, Verheugt, F, Camm, AJ
Vascular pharmacology. 2018;:9-21
-
-
Free full text
-
Abstract
Atrial fibrillation (AF) and venous thromboembolism (VTE) are cardiovascular conditions significant in contemporary practice. In both, the use of anticoagulation with vitamin K antagonists (VKAs) has been traditionally used to prevent adverse events. However, VKA therapy is associated with challenges relating to dose maintenance, the need to monitor anticoagulation, and bleeding risks. The non-vitamin K oral anticoagulants (NOACs) are becoming accepted as a clear alternative to VKA therapy for both AF and VTE management. The aim of this paper was to review contemporary evidence on the safety of NOACs in both conditions. A comprehensive literature review was conducted to explore key safety issues and expert consensus was achieved from eight professionals specialised in AF and VTE care. Consensus-based statements were formulated where available evidence was weak or contradictory. The expert statements in this paper form a key overview of the safety of NOACs compared with VKA therapy, and the comparative safety of different NOACs. It is apparent that a detailed patient work-up is required in order to identify and manage individual risk factors for bleeding and thrombosis prior to NOAC therapy. Additional measures, such as dose reductions, may also be used to maintain the safety of NOACs in practice.
-
5.
The American College of Chest Physician score to assess the risk of bleeding during anticoagulation in patients with venous thromboembolism.
Palareti, G, Antonucci, E, Mastroiacovo, D, Ageno, W, Pengo, V, Poli, D, Testa, S, Tosetto, A, Prandoni, P
Journal of thrombosis and haemostasis : JTH. 2018;(10):1994-2002
-
-
Free full text
-
Abstract
UNLABELLED Essentials The risk of bleeding influences the duration of anticoagulation (AC) after venous thromboembolism. We assessed the ACCP bleeding risk score in an inception-cohort of patients receiving AC. 53% were categorized at high-risk, but their bleeding rate was low during long-term AC. ACCP score had low predictive value for bleeding. SUMMARY Background The American College of Chest Physicians (ACCP) guideline proposes a score to decide on extended anticoagulation after an unprovoked venous thromboembolism (VTE). Methods We investigated the ACCP score to predict bleeding risk in an inception cohort of 2263 patients on long-term anticoagulation (1522 treated with vitamin K antagonists [VKAs] and the remaining with direct oral anticoagulants [DOACs]) belonging to the Italian START2 Register. Results More than half the patients were categorized as high risk; nevertheless, a higher proportion received anticoagulation for > 1 year compared with those in the low-risk category. For 3130 years (median 12 [interquartile range 6, 24] months), 48 bleeding outcomes occurred (1.53%/year) in the cohort (1.7%/year and 0.95%/year in high- and low-risk categories, respectively). The c-statistic of the ACCP score was 0.55 (0.48-0.63), 0.50 (0.42-0.58) and 0.56 (0.48-0.64) in low-, moderate- and high-risk categories, respectively. The bleeding incidence was higher during the first 90 days of treatment (3.0%/year) than afterwards (1.2%/year; relative risk (RR), 2.5 [1.3-4.7]), and similar among the three categories. The bleeding rate was not different during the initial 3 months of treatment in patients receiving VKAs or DOACs; it was, however, lower in the latter patients in the subsequent period (0.5%/year vs. 1.4%/year, respectively). Conclusion The bleeding rate during extended treatment was rather low in our patients. ACCP score had insufficiently predictive value for bleeding and cannot be used to guide decisions on extended treatment. New prediction tools for bleeding risk during anticoagulant treatments (including DOACs) are required.
-
6.
Management of cancer-associated venous thromboembolism - a case-based practical approach.
Voigtlaender, M, Langer, F
VASA. Zeitschrift fur Gefasskrankheiten. 2018;(2):77-89
Abstract
In patients with solid tumours or haematological malignancies, venous thromboembolism (VTE) is a leading cause of death and significantly contributes to morbidity and healthcare resource utilization. Current practice guidelines recommend long-term anticoagulation with low-molecular-weight heparin (LMWH) as the treatment of choice for cancer-associated VTE, based on clinical trial data showing an overall improved safety and efficacy profile of LMWH compared to vitamin K antagonists. However, several open questions remain, e. g. with regard to the intensity and duration of LMWH therapy; moreover, recent real-world evidence indicates that adherence to parenteral anticoagulation with LMWH over the course of treatment is poor in clinical practice. In this regard, the direct oral factor Xa or thrombin inhibitors (DOACs) have emerged as potential alternatives in the management of patients with cancer-associated VTE, albeit findings from randomized controlled studies with a direct head-to-head comparison of DOACs with LMWH, the current standard of care, are still lacking. Based on the case of a lymphoma patient experiencing symptomatic pulmonary embolism during immunochemotherapy, this article aims at both highlighting the current state-of-the-art approach to cancer-associated VTE and pointing out some of the unresolved, controversial issues clinicians have to face when taking care of haematology and oncology patients with already established or with high risk of developing VTE. These issues include the management of patients with incidental pulmonary embolism or thrombocytopenia, the use of DOACs, and the initiation of pharmacological thromboprophylaxis in non-surgical cancer patients.
-
7.
Rosuvastatin use improves measures of coagulation in patients with venous thrombosis.
Biedermann, JS, Kruip, MJHA, van der Meer, FJ, Rosendaal, FR, Leebeek, FWG, Cannegieter, SC, Lijfering, WM
European heart journal. 2018;(19):1740-1747
Abstract
AIMS: Observational studies indicate that statins reduce the risk of recurrent venous thrombosis (VT). However, trials have not been performed and the mechanism is unknown. We aimed to determine whether statin therapy improves the coagulation profile in patients with prior VT. METHODS AND RESULTS Randomized clinical trial (NCT01613794). Patients were randomized to rosuvastatin 20 mg/day for 4 weeks or no intervention. Blood was drawn at baseline and at end of study. The primary outcome was factor (F) VIIIC. In total, five coagulation factors were measured: FVIIIC, von Willebrand factor:Ag, FVIIC, FXI:C, and D-dimer. Among 247 randomized participants, mean age was 58 years, 62% were women and 49% had unprovoked VT. For all tested coagulation factors, mean levels were clearly decreased at end of study in rosuvastatin users, whereas they hardly differed in non-statin users. Results were most consistent for FVIIIC where mean FVIIIC levels were 7.2 IU/dL [95% CI (confidence interval) 2.9-11.5] lower in rosuvastatin users, while among non-users, no change in FVIIIC was observed (mean difference -0.1; 95% CI -3.0 to 2.9). The mean age and sex adjusted difference in FVIIIC change was -6.7 IU/dL (95% CI -12.0 to -1.4) in rosuvastatin users vs. non-users. Subgroup analyses revealed that the decrease in coagulation factors by rosuvastatin was more pronounced in participants with unprovoked VT and in those with cardiovascular risk factors. CONCLUSION Rosuvastatin 20 mg/day substantially improved the coagulation profile among patients with prior VT. These results suggest that statin therapy might be beneficial in patients at risk of recurrent VT.
-
8.
Abnormal coagulation and enhanced fibrinolysis due to lysinuric protein intolerance associates with bleeds and renal impairment.
Pitkänen, HH, Kärki, M, Niinikoski, H, Tanner, L, Näntö-Salonen, K, Pikta, M, Kopatz, WF, Zuurveld, M, Meijers, JCM, Brinkman, HJM, et al
Haemophilia : the official journal of the World Federation of Hemophilia. 2018;(5):e312-e321
Abstract
INTRODUCTION Lysinuric protein intolerance (LPI), a rare autosomal recessive transport disorder of cationic amino acids lysine, arginine and ornithine, affects intestines, lungs, liver and kidneys. LPI patients may display potentially life-threatening bleeding events, which are poorly understood. AIMS To characterize alterations in haemostatic and fibrinolytic variables associated with LPI. METHODS We enrolled 15 adult patients (8 female) and assessed the clinical ISTH/SSC-BAT bleeding score (BS). A variety of metabolic and coagulation assays, including fibrin generation test derivatives, clotting time (CT) and clot lysis time (CLT), thromboelastometry (ROTEM), and PFA-100 and Calibrated Automated Thrombogram (CAT), were used. RESULTS All patients had mild-to-moderate renal insufficiency, and moderate bleeding tendency (BS 4) without spontaneous bleeds. Mild anaemia and thrombocytopenia occurred. Traditional clotting times were normal, but in contrast, CT in fibrin generation test, and especially ROTEM FIBTEM was abnormal. The patients showed impaired primary haemostasis in PFA, irrespective of normal von Willebrand factor activity, but together with lowered fibrinogen and FXIII. Thrombin generation (TG) was reduced in vitro, according to CAT-derived endogenous thrombin potential, but in vivo TG was enhanced in the form of circulating prothrombin fragment 1 and 2 values. Very high D-dimer and plasmin-α2-antiplasmin (PAP) complex levels coincided with shortened CLT in vitro. CONCLUSIONS Defective primary haemostasis, coagulopathy, fibrin abnormality (FIBTEM, CT and CLT), low TG in vitro and clearly augmented fibrinolysis (PAP and D-dimer) in vivo were all detected in LPI. Altered fibrin generation and hyperfibrinolysis were associated with the metabolic and renal defect, suggesting a pathogenetic link in LPI.
-
9.
The chaperone-like sodium phenylbutyrate improves factor IX intracellular trafficking and activity impaired by the frequent p.R294Q mutation.
Pignani, S, Todaro, A, Ferrarese, M, Marchi, S, Lombardi, S, Balestra, D, Pinton, P, Bernardi, F, Pinotti, M, Branchini, A
Journal of thrombosis and haemostasis : JTH. 2018;(10):2035-2043
-
-
Free full text
-
Abstract
UNLABELLED Essentials Missense mutations often impair protein folding, and thus intracellular trafficking and secretion. Cellular models of severe type I hemophilia B were challenged with chaperone-like compounds. Sodium phenylbutyrate improved intracellular trafficking and secretion of the frequent p.R294Q. The increased coagulant activity levels (∼3%) of p.R294Q would ameliorate the bleeding phenotype. SUMMARY Background Missense mutations often impair protein folding and intracellular processing, which can be improved by small compounds with chaperone-like activity. However, little has been done in coagulopathies, where even modest increases of functional levels could have therapeutic implications. Objectives To rescue the expression of factor IX (FIX) variants affected by missense mutations associated with type I hemophilia B (HB) through chaperone-like compounds. Methods Expression studies of recombinant (r)FIX variants and evaluation of secreted levels (ELISA), intracellular trafficking (immunofluorescence) and activity (coagulant assays) before and after treatment of cells with chaperone-like compounds. Results As a model we chose the most frequent HB mutation (p.R294Q, ~100 patients), compared with other recurrent mutations associated with severe/moderate type I HB. Immunofluorescence studies revealed retention of rFIX variants in the endoplasmic reticulum and negligible localization in the Golgi, thus indicating impaired intracellular trafficking. Consistently, and in agreement with coagulation phenotypes in patients, all missense mutations resulted in impaired secretion (< 1% wild-type rFIX). Sodium phenylbutyrate (NaPBA) quantitatively improved trafficking to the Golgi and dose dependently promoted secretion (from 0.3 ± 0.1% to 1.5 ± 0.3%) only of the rFIX-294Q variant. Noticeably, this variant displayed a specific coagulant activity that was higher (~2.0 fold) than that of wild-type rFIX in all treatment conditions. Importantly, coagulant activity was concurrently increased to levels (3.0 ± 0.9%) that, if achieved in patients, would ameliorate the bleeding phenotype. Conclusions Altogether, our data detail molecular mechanisms underlying type I HB and candidate NaPBA as affordable 'personalized' therapeutics for patients affected by the highly frequent p.R294Q mutation, and with reduced access to substitutive therapy.
-
10.
Use of the SAMe-TT2R2 score to predict anticoagulation control in atrial fibrillation and venous thromboembolism patients receiving vitamin K antagonists: A review.
Zulkifly, H, Lip, GYH, Lane, DA
Heart rhythm. 2018;(4):615-623
Abstract
Identifying patients who are likely to achieve and maintain a therapeutic international normalized ratio when prescribed a vitamin K antagonist for stroke prevention in atrial fibrillation (AF) and venous thromboembolism (VTE) is challenging. The SAMe-TT2R2 score was developed on the basis of common clinical factors that can highlight patients who may be unable to achieve and maintain good anticoagulation control and for whom a "trial of warfarin" would be inadvisable. This review summarizes the main published prospective and retrospective studies that have validated the SAMe-TT2R2 score in patients with AF and VTE treated with a vitamin K antagonist and how the SAMe-TT2R2 score could aid clinical decision making; 19 studies were included. Taken together, validation studies suggest that the SAMe-TT2R2 score is able to predict good or poor anticoagulation control in patients with AF and VTE, although data on patients with VTE are limited (3 studies). The available evidence suggests that the SAMe-TT2R2 score may be a useful tool to aid clinical decision making for oral anticoagulants in patients with AF and VTE.