Isabelle Gouin-Thibault

Surgery and invasive procedures in patients on long-term treatment with direct oral anticoagulants: thrombin or factor-Xa inhibitors. Recommendations of the Working Group on Perioperative Haemostasis and the French Study Group on Thrombosis and Haemostasis.

Direct oral anticoagulants (DOAs)--inhibitors of thrombin or factor-Xa--are expected to replace vitamin K antagonists in most of their indications. Patients receiving long-term treatment with DOAs are likely to be exposed to elective or emergency surgery or invasive procedures. Owing to the present lack of experience in such conditions, we cannot make recommendations, but only propose perioperative management for optimal safety regarding the risk of bleeding and thrombosis. DOAs may increase surgical bleeding, they have no validated antagonists, they cannot be monitored by simple standardized laboratory assays and their pharmacokinetics vary significantly between patients. Although DOAs differ in many respects, the proposals in the perioperative setting need not be specific to each. For procedures with low haemorrhagic risk, a therapeutic window of 48 hours (last administration 24 hours before surgery, restart 24 hours after) is proposed. For procedures with medium or high haemorrhagic risk, we suggest stopping DOAs 5 days before surgery to ensure complete elimination in all patients. Treatment should be resumed only when the risk of bleeding has been controlled. In patients at high thrombotic risk (e.g. those in atrial fibrillation with a history of stroke), bridging with heparin (low molecular-weight heparin, or unfractionated heparin, if the former is contraindicated) is proposed. In an emergency, the procedure should be postponed for as long as possible (minimum 1-2 half-lives) and non-specific antihaemorrhagic agents, such as recombinant human activated factor VIIa or prothrombin complex concentrates should not be given for prophylactic reversal due to their uncertain benefit-risk.

Assessment of apixaban plasma levels by laboratory tests: suitability of three anti-Xa assays

While laboratory monitoring is not required in patients treated with apixaban, a direct factor-Xa inhibitor, assessment of its concentration is useful in some critical situations. However, few data are available on its effect on coagulation tests and on the suitability of anti-Xa assays for its quantification. It was the objective of this study to identify laboratory tests suitable for apixaban concentration assessment. Coagulation tests - PT and aPTT- and anti-Xa assays were performed in apixaban-spiked plasma samples. To evaluate the sensitivity of PT and aPTT to apixaban, we conducted a first monocenter part, with a wide range of concentrations (50-1,000 ng/ml), a large panel of reagents (20 reagents), and two coagulometers (STAR®, Stago and ACL TOP®, IL), and a second multicenter part involving 13 laboratories using either a common PT reagent (RecombiPlastin2G®) or the local PT and aPTT reagents. In the multicentre part, five blinded apixaban-spiked plasma samples (0/100/200/400/800 ng/ml - checked by HPLC-MS/MS) were used; apixaban concentrations were measured with three anti-Xa assays, apixaban calibrators and controls (Stago). PT and aPTT tests using a large panel of reagents displayed a low sensitivity to a wide range of apixaban concentrations. The concentrations to double PT ranged from 400 to >1,000 ng/ml with the 10 reagents. With the three anti-Xa assays, inter-laboratory precision and accuracy were below 11% and 12%, respectively. In conclusion, whereas PT and aPTT tests were not sensitive enough to detect apixaban, the three anti-Xa assays tested using lyophilised apixaban calibrators and controls allowed to reliably quantify a wide range of apixaban concentrations.

Safety Profile of Different Low-Molecular Weight Heparins Used at Therapeutic Dose

Low-molecular weight heparins (LMWHs) have been shown to be as safe and effective as unfractionated heparin (UFH) for the treatment of acute venous thrombosis and non-life-threatening pulmonary embolism. Different reports have shown that LMWHs may also be used to treat patients with unstable angina or non-Q-wave infarction. The safety of LMWHs used at therapeutic dose has been widely studied in pivotal clinical trials and analysed in several meta-analyses. However, despite the wide development and use of LMWHs, several issues regarding the safety and optimal use of LMWHs remain unanswered.The main adverse effect of LMWHs is bleeding and it is uncertain whether a weight-adjusted dosage regimen without laboratory monitoring can be used in patients with a high risk of bleeding, such as patients with renal failure, elderly patients, obese patients or pregnant women. These patients are usually excluded from clinical trials and only a few studies, not sufficiently powered to estimate efficacy and safety, have been carried out in these special populations. Most of the available data comes from pharmacokinetic or population pharmacodynamic studies or clinical reports. Results in patients with renal impairment who are not undergoing haemodialysis suggest that a reduction in calculated creatinine clearance levels is associated with an increased risk of accumulation of anti-Xa activity, the extent of which differs depending on the individual LMWH and the extent to which the compound is cleared by the kidney. The limited data available regarding the use of therapeutic doses of LMWHs in obese patients suggest that there is no need to cap the dose at a maximal allowable dose. Long-term (3-month) treatment with LMWHs appears to be as effective and safe as oral anticoagulant therapy for the treatment of venous thromboembolism. It appears that each LMWH is a distinct compound with unique pharmacokinetic and pharmacodynamic profiles. Until more data are available regarding these special populations, periodic monitoring of anti-Xa activity levels may be recommended to detect accumulation and/or an overdose and minimise the bleeding risk.The non-haemorrhagic adverse effects of the LMWHs include heparin-induced thrombocytopenia (HIT) and osteoporosis. The incidence of HIT appears to be lower with LMWHs than with UFH; there is currently not enough data to compare the frequency of HIT between the various LMWHs. LMWHs also appear to carry a lower risk of causing osteoporosis than UFH.In conclusion, studies that include special population patients are required to make conclusive recommendations concerning the safety and monitoring of the different LMWHs.

Chirurgies et actes invasifs chez les patients traités au long cours par un anticoagulant oral anti-IIa ou anti-Xa direct: Propositions du Groupe d’intérêt en hémostase périopératoire (GIHP) et du Groupe d’études sur l’hémostase et la thrombose (GEHT)

Direct oral anticoagulants (DOAs), inhibitors of factor IIa or Xa, are expected to replace vitamin K antagonists in most of their indications. It is likely that patients on long-term treatment with DOAs will be exposed to elective or emergency surgery or invasive procedures. Due to the present lack of experience in such conditions, we cannot make recommendations, but only propose perioperative management for optimal safety as regards the risk of bleeding and thrombosis. DOAs may increase surgical bleeding, they have no validated antagonists, they cannot be monitored by simple, standardised laboratory assays, and their pharmacokinetics vary significantly from patient to patient. Although DOAs differ in many respects, the proposals in the perioperative setting need not be specific to each. For procedures with low risk of haemorrhage, a therapeutic window of 48 h (last administration 24h before surgery, restart 24h after) is proposed. For procedures with medium or high haemorrhagic risk, we suggest stopping DOAs 5 days before surgery to ensure complete elimination of the drug in all patients. The treatment should be resumed only when the risk of bleeding has been controlled. In patients with a high risk of thrombosis (e.g. those in atrial fibrillation with an antecedent of stroke), bridging with heparin (low molecular weight, or unfractionated if the former is contraindicated) is proposed. In emergency, the procedure should be postponed for as long as possible (minimum 1-2 half-lives) and non-specific anti-haemorrhagic agents, such as recombinant human activated factor VIIa, or prothrombin concentrates, should not be given for prophylactic reversal, due to their uncertain benefit-risk.

Elderly Medical Patients Treated with Prophylactic Dosages of Enoxaparin Influence of Renal Function on Anti-Xa Activity Level

BackgroundThe safety and optimal use of prophylactic treatment with low-molecular-weight heparins in elderly patients with impaired renal function remain undefined.MethodsThe primary aim of this study was to analyse, in ‘real life’, the influence of renal function, as assessed by Creatinine clearance (CLcr), on the level of anti-Xa activity in medical hospitalised elderly patients receiving prophylactic dosages of enoxaparin. Consecutive hospitalised acutely ill medical patients aged ≥75 years receiving daily dosages of enoxaparin 4000IU for up to 10 days were prospectively enrolled in two centres. Peak anti-Xa activity was measured at the beginning and during the course of therapy.ResultsOne hundred and twenty-five patients (31 men, 94 women), mean age 87.5 ± 6.3 years, mean bodyweight 56.4±11.9kg and mean CLcr 39.8 ± 16.1 mL/min, were enrolled in the study. The mean maximum anti-Xa activity (day 1 to day 10) [anti-Xamaxl–l0] was 0.64 ± 0.23 IU/mL (range 0.24–1.50 IU/mL). Weak negative correlations were found between CLcr and anti-Xamax and between bodyweight and anti-Xamax. Mean anti-Xamax was slightly but significantly higher in patients with CLcr of 20–30 mL/min compared with patients with CLcr of 31–40,41–50 or 51–80 mL/min (0.72 versus 0.61, 0.61 and 0.60 IU/ mL, respectively), and in patients weighing <50kg compared with patients weighing 50–60kg or >60kg (0.74 vs 0.64 and 0.52 IU/mL, respectively). Serious bleeding occurred in five patients, but anti-Xamax values in these patients were not different to those in patients without bleeding (p = 0.77). Individual anti-Xamax at the beginning or during the course of treatment was measured in the subgroup of 58 patients in whom anti-Xa activity was measured at least once during the study. The mean anti-Xamax value was slightly but significantly higher during the course of the therapy than at the beginning of the study (0.63 ± 0.26 IU/mL vs 0.56±0.23 IU/mL, p = 0.012).ConclusionOnly CLcr <30 mL/min and bodyweight <50kg were associated with significantly higher anti-Xamax values. The clinical relevance of these increases remains questionable. No conclusions about the safety of enoxaparin in elderly medical patients can be drawn from these findings.

Haemorrhagic complications of vitamin k antagonists in the elderly: risk factors and management.

In patients >75 years of age, the two main indications for oral anticoagulant therapy with vitamin K antagonists (VKAs) are treatment of venous thromboembolic disease and prevention of systemic embolism in patients with nonvalvular atrial fibrillation. In both indications, a target International Normalized Ratio of 2.5 (range 2.0–3.0) is recommended. Bleeding is the adverse effect feared by physicians that most limits the use of VKAs in older frail patients. In this paper, we discuss (i) the risk of VKA-related bleeding with advancing age; (ii) the severity of bleeding complications and particularly the risk of intracranial haemorrhage in older patients; (iii) the risk factors for bleeding related to patient characteristics; and (iv) the risk factors or determinants for bleeding related to treatment variables (warfarin induction and maintenance administration, instability of anticoagulation, poor compliance and patient’s education level, and concomitant use of drugs). Avoiding over-anticoagulation and/or reducing periods of overdosing in the course of oral anticoagulant treatment with tailored monitoring may help to minimise the risk of bleeding in older patients.

Improving Anticoagulation Control in Hospitalized Elderly Patients on Warfarin

OBJECTIVES: To determine the effect of patient characteristics and of specific guidelines that were developed for managing warfarin therapy in older adults and included in an in‐house computer program on anticoagulation quality.

The effectiveness of platelet supplementation for the reversal of ticagrelor-induced inhibition of platelet aggregation: An in-vitro study.

BACKGROUND Management of ticagrelor-induced bleeding is challenging, as no antidote is currently available. Platelet transfusion, usually proposed to reverse antiplatelet drugs, has been suggested to be ineffective but few data are available. OBJECTIVE To assess the efficacy of platelet supplementation to restore platelet aggregation inhibited by ticagrelor. DESIGN In vitro study. SETTING Blood samples were obtained from the French Blood Bank Institute. PARTICIPANTS Healthy blood donors. INTERVENTIONS Whole blood from healthy donors was spiked with ticagrelor or aspirin (used as a positive control). MAIN OUTCOME MEASURES Platelet aggregation was investigated with impedance aggregometry on whole blood [expressed in ohms (V)] and light transmission aggregometry (expressed in %) on platelet-rich plasma using ADP or arachidonic acid as agonists for ticagrelor or aspirin, respectively. Platelet supplementation was defined as the addition of washed platelet suspension increasing at least 60% of whole blood platelet count. RESULTS Ticagrelor (3.25 mM) inhibited ADP-induced platelet aggregation compared with control either in whole blood (2 vs. 13 V, P < 0.05) or in platelet-rich plasma (15 vs. 75% P < 0.05). Aspirin (25 mM) inhibited arachidonic acid-induced aggregation (1 vs. 7.5 V, P < 0.05 in whole blood and 5 vs. 77.5%, P = 0.01 in platelet-rich plasma). Platelet supplementation completely restored arachidonic acid-induced platelet aggregation in whole blood (10 vs. 1 V, P = 0.008) and platelet-rich plasma (73 vs. 5%, P < 0.01) in aspirin-treated samples, whereas it failed to correct ADP-induced aggregation (2 vs. 2 V in whole blood and 13.5 vs. 15% in platelet-rich plasma, P > 0.05) in ticagrelor-treated samples. We also report a case of a ticagrelor-treated patient in whom platelet transfusion failed to restore ADP-induced platelet aggregation. CONCLUSION Platelet supplementation restored platelet aggregation in aspirin-spiked but not in ticagrelor-spiked samples. These results do not support the use of platelet transfusion to reverse the effects of ticagrelor.

Surgery and invasive procedures in patients on long-term treatment with oral direct thrombin or factor Xa inhibitors

Direct oral anticoagulants (DOAs), inhibitors of factor IIa or Xa, are expected to replace vitamin K antagonists in most of their indications. It is likely that patients on long-term treatment with DOAs will be exposed to elective or emergency surgery or invasive procedures. Due to the present lack of experience in such conditions, we cannot make recommendations, but only propose perioperative management for optimal safety as regards the risk of bleeding and thrombosis. DOAs may increase surgical bleeding, they have no validated antagonists, they cannot be monitored by simple, standardised laboratory assays, and their pharmacokinetics vary significantly from patient to patient. Although DOAs differ in many respects, the proposals in the perioperative setting need not be specific to each. For procedures with low risk of haemorrhage, a therapeutic window of 48 h (last administration 24h before surgery, restart 24h after) is proposed. For procedures with medium or high haemorrhagic risk, we suggest stopping DOAs 5 days before surgery to ensure complete elimination of the drug in all patients. The treatment should be resumed only when the risk of bleeding has been controlled. In patients with a high risk of thrombosis (e.g. those in atrial fibrillation with an antecedent of stroke), bridging with heparin (low molecular weight, or unfractionated if the former is contraindicated) is proposed. In emergency, the procedure should be postponed for as long as possible (minimum 1-2 half-lives) and non-specific anti-haemorrhagic agents, such as recombinant human activated factor VIIa, or prothrombin concentrates, should not be given for prophylactic reversal, due to their uncertain benefit-risk.

Warfarin Therapy: Influence of Pharmacogenetic and Environmental Factors on the Anticoagulant Response to Warfarin

Warfarin is difficult to use because of a marked inter- and intraindividual variability among patients in the required dosage. Recent advances in understanding the vitamin K cycle have been made. Besides well-known demographic or environmental factors (advanced age, vitamin K intake, concomitant drugs, comorbid conditions, and acute illnesses), genetic single nucleotide polymorphisms (SNPs) have been identified as strongly affecting the maintenance dosage and its variability. SNPs of vitamin K epoxide reductase complex subunit-1 (VKORC1) gene have been identified, affecting the enzyme shown as one of the target of vitamin K antagonist. SNPs of cytochrome P450 2C9 (CYP2C9) gene have been shown to decrease the catabolism of warfarin. The combined analysis of VKORC1, CYP2C9 SNPs, and age may account for more than 50% of the individual variability in the warfarin maintenance dosage. Predicting models of warfarin maintenance dosage taking into account these individual parameters are currently developed.