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Thromboembolism after COVID-19 vaccine in patients with preexisting thrombocytopenia.
Mauriello, A, Scimeca, M, Amelio, I, Massoud, R, Novelli, A, Di Lorenzo, F, Finocchiaro, S, Cimino, C, Telesca, R, Chiocchi, M, et al
Cell death & disease. 2021;(8):762
Abstract
While vaccination is the single most effective intervention to drastically reduce severe disease and death following SARS-CoV-2 infection, as shown in UK and Israel, some serious concerns have been raised for an unusual adverse drug reaction (ADR), including vaccine-induced immune thrombotic thrombocytopenia (VITT) with concurrent low platelets as well as capillary leak syndrome. In fact, the overall safety of the vaccine is highlighted by the low frequency of ADR considering that in UK, by the early June, 40 million first doses and 29 million second doses have been injected; nonetheless, 390 thrombotic events, including 71 fatal events have been reported. Interestingly, the cases reported low platelet counts with the presence of anti-platelet factor-4 (PF4) antibodies, indicating an abnormal clotting reaction. Here, out of three referred cases, we report a post-vaccine clinical case of fatal thrombosis with postmortem examination and whole exome sequencing (WES) analysis, whose pathogenesis appeared associated to a preexisting condition of thrombocytopenia due to myelodysplasia.
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2.
Guidelines for mono, double and triple antithrombotic therapy.
van Uden, RCAE, Houtenbos, I, Griffioen-Keijzer, A, Odekerken, DAM, van den Bemt, PMLA, Becker, ML
Postgraduate medical journal. 2021;(1153):730-737
Abstract
Guidelines for antithrombotic therapy are complex, especially if a patient has several indications that require antithrombotic therapy. In general, no patient should receive lifelong double or triple antithrombotic therapy. In this overview, we outline the most common indications for mono, double and triple antithrombotic therapy; the preferred antithrombotic therapy and the recommended duration of therapy. Both antiplatelet therapy and therapeutic anticoagulation therapy with vitamin K antagonists or direct oral anticoagulants were included. European guidelines were used or, if no European guidelines were available, the Dutch guidelines were used.
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Application of an adjusted patient blood management protocol in patients undergoing elective total hip arthroplasty: towards a zero-percent transfusion rate in renal patients-results from an observational cohort study.
Hourlier, H, Fennema, P
Journal of orthopaedic surgery and research. 2021;(1):697
Abstract
BACKGROUND Renal patients are at high risk of blood transfusion following major orthopaedic surgery. A variety of patient blood management (PBM) policies have been proposed to reduce the rate of transfusions. The aim of this observational study was to assess the performance of an adjusted PBM protocol in patients with chronic kidney disease (CKD) undergoing elective total hip arthroplasty (THA). METHODS A total of 1191 consecutive patients underwent elective unilateral THA and took part in an adjusted PBM protocol. The PBM protocol consisted of epoetin (EPO) alfa therapy prescribed by the surgeon, routine administration of tranexamic acid (TXA), an avascular approach to the hip and postoperative prophylaxis of thromboembolism. The performance of this PBM protocol was analysed in patients with a glomerular filtration rate (GFR) below or above 60 ml/min/1.73 m2 at baseline. Haemoglobin levels were controlled at admission, on postoperative day (POD) 1 and on POD 7 ± 1. A bleeding index (BI) was used as a proxy for blood loss. RESULTS In total, 153 patients (12.9%) presented with a modification of diet in renal disease value below 60 at baseline. Of these, 20 (13.1%) received EPO therapy and 120 (78.4%) received TXA. None of the patients received allogenic blood transfusions during the first perioperative week. The mean BI for the entire study population was 2.7 (95% CI 2.6, 2.8). CKD did not exert a significant impact on the BI (p = 0.287). However, it was found that both TXA and EPO therapy significantly lowered the BI (difference, - 0.3, p < 0.001). There were no thromboembolic complications in renal patients who received TXA and/or EPO therapy. CONCLUSIONS A zero-percent transfusion rate during the first perioperative week is attainable in patients with stage 3 or stage 4 CKD undergoing contemporary elective THA. With the use of a pragmatic blood-sparing protocol, patients with renal dysfunction did not have an increased risk of bleeding and did not have an increased incidence in the rate of perioperative blood transfusions.
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Rivaroxaban Versus Warfarin in Patients with Mechanical Heart Valves: Open-Label, Proof-of-Concept trial-The RIWA study.
Duraes, AR, de Souza Lima Bitar, Y, Schonhofen, IS, Travassos, KSO, Pereira, LV, Filho, JAL, Neto, MG, Junior, RA, Roever, L
American journal of cardiovascular drugs : drugs, devices, and other interventions. 2021;(3):363-371
Abstract
BACKGROUND AND PURPOSE To date, vitamin K antagonists are the only available oral anticoagulants in patients with mechanical heart valves. In this way, we developed a pilot trial with rivaroxaban. METHODS The RIWA study was a proof-of-concept, open-label, randomized clinical trial and was designed to assess the incidence of thromboembolic and bleeding events of the rivaroxaban-based strategy (15 mg twice daily) in comparison to dose-adjusted warfarin. Patients were randomly assigned in a 1:1 ratio and were followed prospectively for 90 days. RESULTS A total of 72 patients were enrolled in the present study. Of these, 44 patients were randomized: 23 patients were allocated to the rivaroxaban group and 21 to the warfarin group. After 90 days of follow-up, the primary outcome occurred in one patient (4.3%) in the rivaroxaban group and three patients (14.3%) in the warfarin group (risk ratio [RR] 0.27; 95% confidence interval [CI] 0.02-2.85; P = 0.25). Minor bleeding (without discontinuation of medical therapy) occurred in six patients (26.1%) in the rivaroxaban group versus six patients (28.6%) in the warfarin group (RR 0.88; 95% CI 0.23-3.32; P = 0.85). One patient in the warfarin group died from myocardial infarction. No cases of hemorrhagic stroke, valve thrombosis, peripheral embolic events, or new intracardiac thrombus were related in both groups. CONCLUSIONS In this pilot study, rivaroxaban 15 mg twice daily had thromboembolic and bleeding events similar to warfarin in patients with mechanical heart valves. These data confirm the authors' proof-of-concept and suggest that a larger trial with a similar design is not unreasonable. CLINICALTRIAL. GOV IDENTIFIER NCT03566303.
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5.
Effectiveness and Safety of Off-label Dosing of Non-vitamin K Antagonist Anticoagulant for Atrial Fibrillation in Asian Patients.
Lee, KN, Choi, JI, Boo, KY, Kim, DY, Kim, YG, Oh, SK, Baek, YS, Lee, DI, Roh, SY, Shim, J, et al
Scientific reports. 2020;(1):1801
Abstract
Non-vitamin K antagonist anticoagulants (NOACs) have been used to prevent thromboembolism in patients with atrial fibrillation (AF) and shown favorable clinical outcomes compared with warfarin. However, off-label use of NOACs is frequent in practice, and its clinical results are inconsistent. Furthermore, the quality of anticoagulation available with warfarin is often suboptimal and even inaccurate in real-world data. We have therefore compared the effectiveness and safety of off-label use of NOACs with those of warfarin whose anticoagulant intensity was accurately estimated. We retrospectively analyzed data from 2,659 and 3,733 AF patients at a tertiary referral center who were prescribed warfarin and NOACs, respectively, between 2013 and 2018. NOACs were used at off-label doses in 27% of the NOAC patients. After adjusting for significant covariates, underdosed NOAC (off-label use of the reduced dose) was associated with a 2.5-times increased risk of thromboembolism compared with warfarin, and overdosed NOAC (off-label use of the standard dose) showed no significant difference in either thromboembolism or major bleeding compared with warfarin. Well-controlled warfarin (TTR ≥ 60%) reduced both thromboembolism and bleeding events. In conclusion, the effectiveness of NOACs was decreased by off-label use of the reduced dose.
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6.
Rationale and design of PROACT Xa: A randomized, multicenter, open-label, clinical trial to evaluate the efficacy and safety of apixaban versus warfarin in patients with a mechanical On-X Aortic Heart Valve.
Jawitz, OK, Wang, TY, Lopes, RD, Chavez, A, Boyer, B, Kim, H, Anstrom, KJ, Becker, RC, Blackstone, E, Ruel, M, et al
American heart journal. 2020;:91-99
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Abstract
Vitamin K antagonists are the only approved oral anticoagulants for long-term prophylaxis against valve thrombosis and thromboembolism in patients with a mechanical heart valve. Despite the proven efficacy and safety of anticoagulation with the oral direct factor Xa inhibitor apixaban compared with warfarin in high-risk populations including subjects with atrial fibrillation or with venous thromboembolism, it remains unknown whether patients with a mechanical heart valve can be safely managed with apixaban. The On-X Aortic Heart Valve and On-X Ascending Aortic Prosthesis with the Vascutek Gelweave Valsalva Graft may have lower rates of valve thrombosis and thromboembolism than conventional bileaflet and tilting disc valves due its unique pyrolytic carbon composition and flared inlet design. DESIGN PROACT Xa is a randomized, multicenter, open-label, active-controlled trial comparing apixaban with warfarin in patients with an On-X Aortic Heart Valve or On-X Ascending Aortic Prosthesis with the Vascutek Gelweave Valsalva Graft. The study will randomize approximately 1,000 patients from approximately 60 sites in North America who underwent aortic valve replacement at least 3 months prior. Patients will be randomized 1:1 to receiving apixaban 5 mg twice daily or warfarin with a target international normalized ratio of 2.0-3.0. The last randomized participant will be followed for at least 2 years. The primary efficacy outcome is the composite of valve thrombosis and valve-related thromboembolism, and the primary safety outcome is major bleeding. Assuming the primary outcome occurs in warfarin-anticoagulated patients at a rate of 1.75%/patient-year, the study has more than 90% power to assess noninferiority of apixaban treatment with an absolute noninferiority margin of 1.75%/patient-year. A second co-primary analysis is to compare the hazard rate for the apixaban arm to twice the objective performance criterion for thromboembolism and valve thrombosis, that is, 3.4%/patient-year. SUMMARY PROACT Xa will determine whether patients with an On-X Aortic Heart Valve can be anticoagulated with apixaban as an alternative to warfarin.
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7.
Atrial Fibrillation and Malignancy: The Clinical Performance of Non-Vitamin K Oral Anticoagulants-A Systematic Review.
Russo, V, Bottino, R, Rago, A, Micco, PD, D' Onofrio, A, Liccardo, B, Golino, P, Nigro, G
Seminars in thrombosis and hemostasis. 2019;(2):205-214
Abstract
Atrial fibrillation (AF) is commonly diagnosed in the setting of active cancer. Because of an increased risk of either thromboembolic events or bleeding, the decision to initiate therapeutic anticoagulation in patients with active cancer can be challenging. Moreover, little is still known about the optimal anticoagulation therapy in the setting of AF and cancer, and no guidelines are as yet available. Considering that nonvitamin K antagonist oral anticoagulants (NOACs) are recommended as alternatives to vitamin K antagonists for stroke prevention in AF patients with CHA2DS2-VASc score ≥2, the authors performed a systematic review of the current literature to describe the efficacy and safety of NOACs in AF patients with malignancy.
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8.
Fixed-Dose Four-Factor Prothrombin Complex Concentrate for Vitamin K Antagonist Reversal: Does One Dose Fit All?
Schwebach, AA, Waybright, RA, Johnson, TJ
Pharmacotherapy. 2019;(5):599-608
Abstract
Four-factor prothrombin complex concentrate (4F-PCC) has emerged as the preferred option for emergent reversal of vitamin K antagonists (VKAs); however, the optimal dosing strategy is unknown. Although several studies have attempted to determine the optimal dose of 4F-PCC using a variety of dosing regimens, no dosing strategy has been found to be superior. Many of these studies have evaluated a low, fixed dose of 4F-PCC rather than individualized dosing as recommended in product labeling. The purpose of this review was to evaluate the efficacy and safety of various fixed-dose strategies of 4F-PCC for emergent VKA reversal and to assess limitations of the existing literature. A search of the PubMed database was performed from the earliest available date through 2018 for relevant articles describing fixed-dose 4F-PCC for VKA reversal. Reference lists of relevant articles were also manually reviewed. Most currently available studies are primarily observational and heterogeneous in design. A very low fixed dose of 500 IU is likely inadequate for successful VKA reversal, but increased fixed doses of 1000-1500 IU have found some degree of success and may be considered for VKA reversal. However, many of these studies consistently identified a trend toward international normalized ratio (INR) reversal failure in patients presenting with high baseline INR values or intracranial hemorrhage, suggesting that higher 4F-PCC doses are needed in these patients. Available studies are underpowered to determine whether a dose-dependent association with thrombotic risk exists. Additional large, randomized studies are needed to determine the optimal dosing strategy and ascertain the role for fixed-dose 4F-PCC.
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Anticoagulation in atrial fibrillation : Current evidence and guideline recommendations.
Erath, JW, Hohnloser, SH
Herz. 2018;(1):2-10
Abstract
Atrial fibrillation (AF) is the most frequently encountered sustained arrhythmia with a prevalence of 0.5-10%, depending predominantly on age. The arrhythmia is associated with significant morbidity and mortality, mainly due to thromboembolic events including stroke and systemic embolisms. These complications can be effectively prevented with anticoagulation therapy either with vitamin K antagonists (VKA) or with non-vitamin K antagonists (NOAC). VKA therapy is effective in preventing strokes but these medications are difficult to use, are associated with significant bleeding risk, and have pharmacokinetic/dynamic properties that make their use cumbersome. NOACs-either factor II or factor Xa inhibitors-have been developed over the past two decades and have been tested against VKA in large randomized controlled trials. This trial evidence was complemented more recently by increasing real-world data comprising several 100,000 patients. Finally, NOACs have been examined for their use in specific clinical situations, for example, in patients undergoing cardioversion, catheter ablation, or coronary interventions. In all of these clinical scenarios, NOACs have been similarly effective or-in many instances-even superior to treatment with VKA. Recent guidelines, therefore, recommend NOAC therapy for stroke prevention in AF as first-line therapy.
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10.
[The Multimorbid Patient: Use of New Oral Anticoagulants in Patients with Chronic Kidney Disease].
Mohebbi, N
Praxis. 2018;(13):683-687
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Abstract
The Multimorbid Patient: Use of New Oral Anticoagulants in Patients with Chronic Kidney Disease Abstract. Increasing life expectancy in Western countries is associated with a high prevalence of multiple chronic diseases which is defined by the term "multimorbidity". Many of these patients suffer from chronic kidney disease (CKD) and thrombogenic comorbidities such as atrial fibrillation with the need for oral anticoagulation. For decades vitamin K antagonists have been exclusively prescribed for oral anticoagulation. However, due to altered pharmacokinetics and bioavailability of these drugs in CKD, a significant risk of bleeding exists. The introduction of direct oral anticoagulants as a new and promising alternative to vitamin K antagonists was -especially for CKD patients - highly anticipated. However, data from randomized studies are missing for older patients with advanced CKD. Consequently, a careful evaluation of the risk-benefit ratio is recommended for this sensitive patient population.