Summary
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 30 ng/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 ® 30–50 U/kg) or non-activated PCC (50 U/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.
Résumé
Les nouveaux anticoagulants oraux (NACO), anti-IIa ou anti-Xa directs, sont destinés à être largement utilisés dans le traitement de la maladie thromboembolique veineuse ou dans la fibrillation atriale en remplacement des anti-vitamines K. Comme tout traitement anticoagulant, notamment aux doses dites « curatives », ils sont associés à un risque hémorragique spontané ou provoqué. De plus, une proportion non négligeable de patients traités sera confrontée à la nécessité d’un geste invasif en urgence. Compte tenu de l’absence d’antidote spécifique, les mesures à prendre doivent être définies dans ces situations. Le peu de données disponibles ne permet pas d’émettre des recommandations, mais seulement des propositions qui seront amenées à évoluer en fonction de l’expérience accumulée. Les propositions présentées dans cet article s’appliquent au dabigatran (Pradaxa ® ) et au rivaroxaban (Xarelto ® ), les données relatives à l’apixaban et à l’edoxaban étant encore trop peu nombreuses. Pour la chirurgie urgente à risque hémorragique, il est proposé de doser le taux plasmatique du médicament. Des taux inférieurs ou égales à 30 ng/mL, à la fois pour dabigatran et rivaroxaban, devraient permettre la réalisation d’une chirurgie à risque hémorragique élevé. Au-delà, il est convenu, dans la mesure du possible, de reporter l’intervention en surveillant l’évolution de la concentration du médicament. La conduite à tenir est alors définie selon le NACO et sa concentration. Si le dosage du médicament n’est pas disponible immédiatement, des propositions « dégradées » sur la base de tests usuels, TP et TCA, sont présentées. Ces tests ne permettent cependant pas d’évaluer réellement ni la concentration de médicament, ni le risque hémorragique qui en dépend. En cas d’hémorragie grave dans un organe critique, il est proposé de réduire l’effet du traitement anticoagulant par l’utilisation d’un médicament procoagulant non spécifique en première ligne (concentrés de complexe prothrombinique activé [FEIBA ® 30–50 U/kg] ou non activé [CCP 50 U/kg]). En dehors de cette situation, pour tout autre type d’hémorragie grave, l’administration d’un médicament procoagulant, potentiellement thrombogène chez ces patients, sera discutée en fonction du taux de NACO et des possibilités d’hémostase mécanique.
Background
New oral anticoagulants (NOACs), directly targeting thrombin (factor IIa) or factor Xa, are currently used for the treatment of venous thromboembolic disease (rivaroxaban, Xarelto ® , Bayer Schering) or for the prevention of systematic embolism in non-valvular atrial fibrillation (rivaroxaban; dabigatran, Pradaxa ® , Boehringer Ingelheim). Given their ease of use, these anticoagulants are intended for widespread use in such long-term indications. Beyond the potential bleeding complications reported in phase III trials, a notable proportion of treated patients – considered to be 10 to 20% per year – are likely to be exposed to emergency surgery or invasive procedures. Elective surgeries have already been the subject of proposals by the Working Group on Perioperative Haemostasis (GIHP) . The same group has also considered the management of bleeding and emergency invasive procedures in patients benefiting from treatment with NOACs in a curative scheme (except for prevention in major orthopaedic surgery).
The method used to develop these proposals was based on analysis of the literature reporting on the pharmacokinetic properties of these anticoagulants and their use in a surgical context. The text of the proposals was then submitted for several rounds of critical analysis by the members of GIHP, until a consensus was reached.
At the time when these proposals were made, there were very few data allowing recommendations to be made. The proposals are often based on extrapolations from data in the literature and cannot therefore constitute an absolute guide for prescription, but rather define the management bases that need to be evaluated.
Rationale
Rules regarding the management of new oral anticoagulant-treated patients during emergency surgery are poorly defined
At the time of the marketing of dabigatran and rivaroxaban, the rules regarding the management of patients in an emergency were not established. Summaries of Product Characteristics give no indications, except for the usual precautions and the need to postpone the emergency surgery or invasive procedure.
There are few data regarding perioperative management in an emergency of patients treated with dabigatran or rivaroxaban. Healey et al. described the management of patients treated with dabigatran in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial who had an elective invasive procedure. During this trial, 4591 patients had at least one surgery or invasive procedure, more than half of which were at low haemorrhagic risk. Urgent surgery represented 7.8% of all surgeries. There was no significant difference in major bleeds between the groups treated with dabigatran or vitamin K antagonists (VKAs). However, there was no clear indication of anticoagulant management (time, use of procoagulant drugs, etc.).
Regarding rivaroxaban, to date there is no description of the patients, in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) study, who underwent urgent surgery .
The published recommendations consist of expert opinions and are general. It is usually proposed to discontinue the anticoagulant drug, to transfer the patient to a ‘specialized’ centre, and to delay most urgent surgery in those at haemorrhagic risk. These recommendations are therefore of little use for the ‘specialized’ centres to which these patients will be sent.
New oral anticoagulant treatment at a curative dose is associated with haemorrhagic risk
In the EINSTEIN DVT trial, regarding the curative treatment of deep vein thrombosis, the rate of major bleedings with rivaroxaban (0.8%) was not significantly different from that observed in the comparator group treated with VKAs (1.2%) . In the EINSTEIN PE trial, regarding the curative treatment of pulmonary embolism, the rate of major bleedings, although twice as low as that of the VKA group, was 1.1% . In the treatment of venous thromboembolic disease, the rate of severe bleeding events in patients receiving dabigatran 150 mg twice daily was 1.6%, again similar to the VKA group (1.9%) . In non-valvular atrial fibrillation, the rate of intracranial bleedings reported was widely decreased with NOACs, but the rate of overall serious bleedings (3.1–5.6%) remained similar to the VKA group .
Specific measures must therefore be defined in case of occurrence of such complications and the haemorrhagic risk should be considered for emergency surgery or invasive procedures.
New oral anticoagulants have no specific validated antidote
The management of serious bleedings or emergency surgery is delicate due to the current lack of a specific antidote. Antagonists of dabigatran or the xabans are in phases I and II of clinical development and will not be available for at least 2 years.
The risk-benefit of procoagulant drugs is uncertain
Procoagulant drugs available in France are non-activated four-factor prothrombin complex concentrates (PCCs) (Kanokad ® , LFB; Octaplex ® , Octapharma; Confidex ® , CSL Behring), an activated PCC (activated prothrombin complex concentrate factor VIII inhibitor bypassing activity [FEIBA ® ], Baxter) and the recombinant human factor VIIa (Novoseven ® , NovoNordisk). Their use in this indication is off label.
In the absence of a specific antidote, we can suggest trying to counteract the anticoagulant effect of NOACs empirically using these drugs. Analysis of their potential efficiency was based on animal experimental data, in vivo/ex vivo studies in healthy volunteers and occasional clinical cases. There are no experimental data regarding the neutralization of an NOAC overdose.
The effect of PCCs is difficult to analyse. When reported, the doses used were generally higher (50 U/kg) than those used to antagonize the effect of VKAs . In this context, data on safety of doses that inhibit the action of VKAs are available. The frequency of the thrombotic complications associated with (but not necessarily attributable to) the administration of four-factor PCCs to inhibit the action of VKAs is low (1.8%) . The occurrence of these thrombotic complications is readily associated with the administration of high doses (> 50 U/kg) or the treatment of patients with severe liver disease .
The effect of FEIBA is evoked at doses of 30–50 U/kg, i.e., two times lower than those used in haemophilia . Human clinical use in this indication has been reported in only one case . There are no data on the safety of use of FEIBA in this targeted population with thrombotic risk factors.
Overall, recombinant factor VIIa seems to be poorly effective in the inhibition of the anticoagulant effect of dabigatran and rivaroxaban .
These procoagulant drugs do not alter the elimination of anticoagulant. There are no data on the impact of the administration of these agents on haemostasis tests in patients treated with NOACs.
Thus, the efficacy, safety and operating conditions (doses, rhythm, biological monitoring of these drugs) in this indication are not exactly known, which explains why they are discussed as second-line treatments in the proposals below, except for in cases of bleeding that are immediately life threatening or disabling.
Haemostasis tests for measuring new oral anticoagulant plasma concentration in an emergency
These haemostasis tests, which measure the plasma concentrations of these anticoagulants expressed in ng/mL, are currently deployed in few laboratories serving home emergency departments, but can be implemented easily. They are suitable for measuring concentrations between 500 and 50 ng/mL, including the maximum concentration (C max : 2–4 h after oral administration of the drug) and the average residual concentration (C min : just before the next dose). The tests are less accurate for low concentrations and their detection limit is usually around 25 ng/mL.
For dabigatran, several tests (Hemoclot ® , Biophen; DTI ® , Hyphen Biomed; ECA-T ® , Diagnostica Stago) are available. These tests are used to screen patients at risk of bleeding at steady state, based on a residual concentration greater than 200 ng/mL.
Measuring the anti-Xa activity by specific methods (Biophen DiXal ® , Hyphen Biomed; STA Liquid anti-Xa ® , Diagnostica Stago), several tests also allow evaluation of the plasma concentration of rivaroxaban .
It is possible to extrapolate a clinical haemostatic safety threshold corresponding to a new oral anticoagulant plasma concentration allowing urgent surgery
There are no preclinical or clinical data with which to establish a haemostatic safety threshold. However, data can be extrapolated from protocols used in clinical trials and Summaries of Product Characteristics.
Dabigatran is administered in atrial fibrillation at a dose of 150 mg or 110 mg, twice daily. Rivaroxaban is administered in atrial fibrillation (20 mg once daily) and for the treatment of deep vein thrombosis and pulmonary embolism at a dose of 15 mg twice daily and then 20 mg once daily. For these two NOACs, plasma concentrations are relatively similar for both C max and C min ( Table 1 ).
| Reference | C max (ng/mL) | C min (ng/mL) | |
|---|---|---|---|
| Dabigatran | |||
| 220 mg once daily | 183 (5–95 percentiles: 64–447) | 37 (5–95 percentiles: 10–96; 24 hours) | |
| 150 mg twice daily | 254 ± 70.5 | 80.3 ± 18.7 (12 hours) | |
| Rivaroxaban | |||
| 10 mg once daily a | 125 (5–95 percentiles: 91–195) | 9 (5–95 percentiles: 1–38; 24 hours) | |
| 20 mg once daily | 215 (5–95 percentiles: 22–535) | 32 (5–95 percentiles: 6–239; 24 hours) |
a There are no data for rivaroxaban 15 mg twice daily; 10 mg data are indicative here.
Regarding dabigatran, data on elective surgery are available from patients in the RE-LY study . In this study, patients whose creatinine clearance was normal and who benefited from surgery at bleeding risk were operated on between 24 and 72 hours after the last dose or four half-lives. Given the half-life of dabigatran in this population (13–18 h), we can deduce that these patients were operated on while the plasma concentration was probably less or equal to 30 ng/mL.
Regarding rivaroxaban, the only data available are derived from the ROCKET-AF design study . In this study, rivaroxaban was stopped 2 days before any surgical elective procedure again, four half-lives (7–13 h). Given the mean C max of rivaroxaban in this population, these patients were operated upon while the plasma concentration of the drug was probably less or equal to 30 ng/mL.
It appears that we can regard the same concentration of 30 ng/mL as compatible with surgical management, without increasing the risk of bleeding, especially in an emergency.
In case of unavailability of drug concentration measurements, the usual haemostasis tests (prothrombin time, activated partial thromboplastin time) may be useful
Tests dedicated to measuring the plasma concentration of NOACs 24 h/day are not available in all centres in an emergency setting. In contrast, conventional coagulation tests (prothrombin time [PT] and activated partial thromboplastin time [aPTT]) are available at any time. These common tests are relatively insensitive to the effects of NOACs and suffer, depending on the reagent, from significant variability at high concentrations. However, provided that the patient does not have a bleeding disorder linked to an associated disease, normal PT and aPTT results indicate, with sufficient probability for most situations encountered, that the drug is present at a very low residual concentration, which is close to the safety threshold mentioned above. Therefore, these usual tests meet the objective of ensuring that emergency surgery can be performed without further delay and without a significant increase in bleeding risk. PT and aPTT can also be used to estimate the time required to reach the safety threshold, but this estimate is less precise than that based on concentrations.
PT is insensitive to dabigatran. The prolongation of PT depends on drug concentration and the sensitivity of response depends on the reagent used. PT cannot be used independently, but can be integrated into an approach combining PT and aPTT. aPTT is prolonged with dabigatran, but, for high concentrations, is poorly correlated with the concentration measured by a dedicated test. However, its negative predictive value is interesting because normal aPTT generally reflects a low concentration. Its use is therefore suggested by some experts . Douxfils et al. studied the impact of different concentrations of dabigatran on aPTT measured with different reagents. For concentrations of 10 ng/mL, all reagents used (Actin FS ® , Cephascreen ® , CKPrest ® , PTT-A ® , Synthasil ® ), even taking into account some variability, gave a ratio of patient/control less or equal to 1.2.
PT is described as sensitive to the effect of rivaroxaban . In treated patients, prolongation of PT is proportional to the concentration of rivaroxaban and varies according to the reagent used . However, this variability is very low at a concentration of 25 ng/mL and between 30 and 50 ng/mL the PT ratio is less or equal to 1.2 . In contrast, a concentration of rivaroxaban of 150 ng/mL is responsible for the prolongation of PT, with a ratio between 1.2 and 1.5, depending on the reagent used . Hillarp et al. showed that aPTT was sensitive, with a large variability in response to high concentrations. However, for a concentration of 25 ng/mL, the aPTT ratio again remained less or equal to 1.2, regardless of the reagent (Actin FSL ® , PTT-A ® , TriniCLOT ® , APTT-DG ® , APTT-SP ® ).
As far as possible, it is recommended that the laboratory performs the usual coagulation tests and forwards the specific measurement request, in order to acquire the necessary experience in the interpretation of the usual tests. One of the critical factors is the sensitivity of the analytical technique and its ability to detect low concentrations of each NOAC. A selection of reagents that are sensitive to the effect of NOACs could be useful in the management of emergencies.
Finally, it is important to remember that measurement of the international normalized ratio has no place in the management of critical situations in patients treated with NOACs; it is designed for patients treated with oral anticoagulants. The ratio for PT and aPTT is preferred.
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