Clinicians' adherence to guidelines for the preoperative management of direct oral anticoagulants in a tertiary hospital: a retrospective study.

INTRODUCTION: Despite clear, relatively easy-to-use guidance, many clinicians find the preoperative management of direct oral anticoagulants (DOACs) challenging. Inappropriate management can delay procedures and lead to haemorrhagic or thromboembolic complications. We aimed to describe preoperative management practices regarding DOACs in a tertiary hospital and clinicians' adherence to in-house recommendations. METHOD: We included all patients being treated with DOACs who underwent elective surgery in 2019 and 2020 (n = 337). In-house recommendations for perioperative management were largely comparable to the 2022 American College of Chest Physicians guidelines. RESULTS: Typical patients were older adults with multiple comorbidities and high thrombotic risk stratification scores, and 65.6% (n = 221) had not undergone recommended preoperative anticoagulation management protocols. Patients operated on using local anaesthesia (adjusted OR = 0.30, 95%CI 0.14-0.66; p < 0.01) were less likely to have been treated following institutional recommendations, but no association between their procedure's bleeding risk and adherence was found. Clinicians' failures to adhere to recommendations mostly involved late or non-indicated interruptions of anticoagulation treatment (n = 89, 26.4%) or inappropriate heparin bridging (n = 54, 16.0%). Forty-five (13.3%) procedures had to be postponed. Incorrect preoperative anticoagulation management was directly responsible for 12/45 postponements (26.7% of postponements). CONCLUSION: This study highlights clinicians' low adherence rates to institutional recommendations for patients treated with DOACs scheduled for elective surgery in a tertiary hospital centre. To the best of our knowledge, this is the first clinical study addressing the issue of clinicians' adherence to guidelines for the preoperative management of DOACs. Going beyond the issue of whether clinicians are knowledgeable about guidelines or have them available, this study questions how generalisable guidelines are in a tertiary hospital managing many highly polymorbid patients. Further studies should identify the causes of poor adherence.

Thrombin generation and fibrin clot structure after vitamin D supplementation.

OBJECTIVE: Vitamin D deficiency is associated with increased risks of arterial and venous cardiovascular events. Hypothetically, supplementation with vitamin D may lead to a less prothrombotic phenotype, as measured by global coagulation assays and fibrin clot structure. METHODS: In this prospective cohort study, we enrolled adult outpatients attending the Primary Care Division of the Geneva University Hospitals with a severe vitamin D deficiency (25-hydroxyvitamin-D3 (25-OHD) <25 nmol/L), excluding obese patients or with a recent acute medical event. We evaluated changes in coagulation times, thrombin generation assay, clot formation and clot lysis time, 25-OHD and parathormone before and 1-3 months after cholecalciferol oral supplementation with one-time 300,000 IU then 800 IU daily. Paired t-tests with a two-sided alpha of 0.05 compared absolute mean differences. RESULTS: The 48 participants had a mean age of 43.8 ± 13.8 years. After supplementation, 25-OHD levels increased from 17.9 ± 4.6 nmol/L to 62.5 ± 20.7 nmol/L 6.4 ± 3.0 weeks after inclusion. Endogenous thrombin potential and thrombin generation peak values both decreased significantly (-95.4 nM × min (95%CI -127.9 to -62.8), P < 0.001; -15.1 nM (-23.3 to -6.8), P < 0.001). The maximum absorbance by turbidimetry decreased significantly (P = 0.001) after supplementation. There was no change in clot lysis time, coagulation times or plasminogen activator inhibitor-1 and homocysteine levels. CONCLUSIONS: In severe vitamin D deficiency, a high-dose cholecalciferol supplementation was associated with a reduction in thrombin generation and an average decreased number of fibrin protofibrils per fibers and fibrin fiber size measured by turbidimetry. This suggests that severe vitamin D deficiency may be associated with a potentially reversible prothrombotic profile.

Evaluation of recombinant factor VIIa, tranexamic acid and desmopressin to reduce prasugrel-related bleeding: A randomised, placebo-controlled study in a rabbit model.

BACKGROUND: Prasugrel is a thienopyridine that inhibits platelet aggregation more rapidly and effectively than clopidogrel, with an increased bleeding risk. OBJECTIVE: The current study aimed to evaluate the efficacy of three nonspecific haemostatic drugs - recombinant activated factor VII (rFVIIa), tranexamic acid and desmopressin (DDAVP) - to limit blood loss after administration of prasugrel in a rabbit model of bleeding while also evaluating any prothrombotic effects. DESIGN: Randomised, placebo-controlled study. SETTING: Faculty of Medicine, University of Geneva, Switzerland, in 2013. ANIMALS: Anaesthetised and artificially ventilated rabbits (n=56). INTERVENTIONS: Animals were randomly allocated to one of five groups: control (placebo-placebo), prasugrel-placebo, rFVIIa (prasugrel-rFVIIa 150 µg kg), tranexamic acid (prasugrel-tranexamic acid 20 mg kg) or DDAVP (prasugrel-DDAVP 1 µg kg). Two hours after an oral prasugrel loading dose (4 mg kg), a stenosis and an injury were inflicted on the carotid artery to induce cyclic flow reductions (CFRs) due to thrombosis. Haemostatic drugs were administered during the ensuing observation period. MAIN OUTCOME MEASURES: Standardised hepatosplenic sections were performed to evaluate the primary endpoint of blood loss, monitored for 15 min. Ear-immersion bleeding time and incidence of CFRs were secondary endpoints. RESULTS: Prasugrel decreased ADP-induced platelet aggregation (light transmission method) from 66 ±â€Š4% (mean ±â€ŠSD) to 41 ±â€Š7% (P < 0.001) and doubled blood loss: 10.7 g (10.1 to12.7) [median (interquartile range)] vs. 20.0 g (17.0 to 24.4), P = 0.003 in the control and prasugrel-placebo groups, respectively. rFVIIa, tranexamic acid and DDAVP reduced neither hepatosplenic blood loss [19.7 g (14.0 to 27.6), 25.2 g (22.6 to 28.7) and 22.9 g (16.8 to 28.8), respectively] nor bleeding time compared with placebo. Regarding safety, rVIIa induced three or more CFRs in 5/12 rabbits, vs. 0/12 in the prasugrel-placebo group (P = 0.037), whereas tranexamic acid and DDAVP did not increase them. CONCLUSION: The three studied haemostatic drugs rFVIIa, tranexamic acid and DDAVP failed to reduce prasugrel-related bleeding in this model. rFVIIa-treated rabbits were more prone to arterial thrombotic events. TRIAL REGISTRATION: NA.

Management of direct oral anticoagulants in patients undergoing elective surgeries and invasive procedures: Updated guidelines from the French Working Group on Perioperative Hemostasis (GIHP) - September 2015.

Since 2011, data on patients exposed to direct oral anticoagulants (DOAs) while undergoing invasive procedures have accumulated. At the same time, an increased hemorrhagic risk during perioperative bridging anticoagulation without thrombotic risk reduction has been demonstrated. This has led the GIHP to update their guidelines published in 2011. For scheduled procedures at low bleeding risk, it is suggested that patients interrupt DOAs the night before irrespective of type of drug and to resume therapy six hours or more after the end of the invasive procedure. For invasive procedures at high bleeding risk, it is suggested to interrupt rivaroxaban, apixaban and edoxaban three days before. Dabigatran should be interrupted according to the renal function, four days and five days if creatinine clearance is higher than 50mL/min and between 30 and 50mL/min, respectively. For invasive procedures at very high bleeding risk such as intracranial neurosurgery or neuraxial anesthesia, longer interruption times are suggested. Finally, bridging with parenteral anticoagulation and measurement of DOA concentrations can no longer routinely be used.

Direct oral anticoagulants: a guide for daily practice.

In recent years, small oral compounds that specifically block activated coagulation factor X (FXa) or thrombin (FIIa) have become alternatives to the anticoagulants that had been used for several decades. As of today, these direct oral anticoagulants (DOACs) include dabigatran etexilate (thrombin inhibitor) and apixaban, edoxaban and rivaroxaban (inhibitors of FXa). While there is no doubt that DOACs represent a major step forward in the management of patients with venous thromboembolic disease and atrial fibrillation, new challenges have arisen. They need to be addressed with the necessary pragmatism on the basis of evidence. Indeed, a better understanding of the management of these last-generation antithrombotics will favour safer use and increase confidence of the practitioner for the prescription of these drugs. The aim of this article is to present practical suggestions for the prescription and use of these drugs in everyday clinical practice, based on clinical experience and recently updated recommendations of the European Heart Rhythm Association and the American College of Chest Physicians among other scientific organisations. We address issues such as pharmacokinetics, dosing, side effects, limitations of use, drug interactions, switching from and to other anticoagulants, renal function, concomitant administration of antiplatelet agents and perioperative use. We also address the issue of monitoring and reversal, taking advantage of the most recent development in this latter area. Rather than being one additional set of recommendations, our narrative review aims at assisting the practicing physician in his or her daily handling of these novel anticoagulant compounds, based on frequently asked questions to the authors, a group of experienced specialists in the field who have, however, no commitment to issue guidelines.

Impact of non-inhibited platelet supplementation on platelet reactivity in patients treated with prasugrel or ticagrelor for an acute coronary syndrome: An ex vivo study.

Managing bleeding in patients receiving P2Y12 inhibitors is challenging. Few data are available regarding the efficacy of platelet transfusion in patients treated with prasugrel or ticagrelor. The aim of this study was to evaluate the minimal amount of platelet supplementation (in terms of ratio of non-inhibited platelets to inhibited platelets) necessary to restore platelet reactivity in platelet-rich plasma (PRP) of patients treated with aspirin and a prasugrel or ticagrelor loading dose for an acute coronary syndrome. PRP samples from patients were mixed ex vivo with increasing proportions of pooled PRP from healthy volunteers. Platelet reactivity was challenged with adenosine diphosphate (ADP), arachidonic acid, collagen or thrombin receptor activating peptide using light transmission aggregometry. The primary endpoint was the proportion of patient samples recovering an ADP-induced maximal aggregation (ADP-Aggmax) value above 40%. In patients treated with prasugrel (n = 32), ADP-Aggmax increased progressively with supplements of pooled PRP, with an average increase of 7.9% (95% CI [7.1; 8.8], p < 0.001) per each 20% increase in the ratio of non-inhibited platelets to inhibited platelets. A ratio of 60% was associated with 90% of patients reaching the primary endpoint. In patients treated with ticagrelor (n = 15), ADP-Aggmax did not significantly increase with any level of supplements. In conclusions, ex vivo addition of non-inhibited platelets significantly improved ADP-Aggmax in patients treated with prasugrel with a dose-dependent effect. There was no evidence of such a reversal in patients treated with ticagrelor. These results suggest that platelet transfusion may be more effective in blunting bleeding in patients treated with prasugrel, than those treated with ticagrelor.

Direct oral anticoagulants in the treatment and long-term prevention of venous thrombo-embolism.

Direct oral anticoagulants (DOACs) specifically target factor IIa or Xa and represent a major step forward in the treatment of acute- and long-term prevention of venous thrombo-embolism (VTE). They are at least as effective and as safe as conventional therapy (heparins and vitamin-K inhibitors) and have practical advantages, such as fixed dosing and no need for laboratory monitoring. These antithrombotic agents introduce a new paradigm for the day-to-day management of VTE. Direct oral anticoagulants should streamline the management of most patients with VTE and will facilitate care in the outpatient setting. Nevertheless, it remains uncertain how to select specific DOACs for particular profiles of patients, and the optimal management of bleeding complications is evolving.

Management of major bleeding complications and emergency surgery in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors: proposals of the working group on perioperative haemostasis (GIHP) - March 2013.

Direct new oral anticoagulants (NOACs) - inhibitors of thrombin or factor Xa - are intended to be used largely in the treatment of venous thromboembolic disease or the prevention of systematic embolism in atrial fibrillation, instead of vitamin K antagonists. Like any anticoagulant treatment, they are associated with spontaneous or provoked haemorrhagic risk. Furthermore, a significant proportion of treated patients are likely to be exposed to emergency surgery or invasive procedures. Given the absence of a specific antidote, the action to be taken in these situations must be defined. The lack of data means that it is only possible to issue proposals rather than recommendations, which will evolve according to accumulated experience. The proposals presented here apply to dabigatran (Pradaxa(®)) and rivaroxaban (Xarelto(®)); data for apixaban and edoxaban are still scarce. For urgent surgery with haemorrhagic risk, the drug plasma concentration should be less or equal to 30ng/mL for dabigatran and rivaroxaban should enable surgery associated with a high bleeding risk. Beyond that, if possible, the intervention should be postponed by monitoring the drug concentration. The course to follow is then defined according to the NOAC and its concentration. If the anticoagulant dosage is not immediately available, worse propositions, based on the usual tests (prothrombin time and activated partial thromboplastin time), are presented. However, these tests do not really assess drug concentration or the risk of bleeding that depends on it. In case of serious bleeding in a critical organ, the effect of anticoagulant therapy should be reduced using a non-specific procoagulant drug as a first-line approach: activated prothrombin complex concentrate (aPCC) (FEIBA(®) 30-50U/kg) or non-activated PCC (50U/kg). In addition, for any other type of severe haemorrhage, the administration of a procoagulant drug, which is potentially thrombogenic in these patients, is discussed according to the NOAC concentration and the possibilities of mechanical haemostasis.