Acta Anaesthesiol Scand 2014; ••: ••–•• Printed in Singapore. All rights reserved
© 2014 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd ACTA ANAESTHESIOLOGICA SCANDINAVICA
doi: 10.1111/aas.12319
Review Article
New oral anticoagulants: clinical indications, monitoring and treatment of acute bleeding complications C. Fenger-Eriksen1, A.-M. Münster2 and E. L. Grove3
1 Department of Anaesthesia and Intensive Care, Viborg Regional Hospital, Viborg, 2Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg and 3Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark
New oral anticoagulants like the direct thrombin inhibitor, dabigatran (Pradaxa®), and factor Xa-inhibitors, rivaroxaban (Xarelto®) and apixaban (Eliquis®) are available for prophylaxis and treatment of thromboembolic disease. They are emerging alternatives to warfarin and provide equal or better clinical outcome together with reduced need for routine monitoring. Methods for measuring drug concentrations are available, although a correlation between plasma drug concentrations and the risk of bleeding has not been firmly established. Standard laboratory measures like prothrombin time and activated partial thromboplastin time are not sensitive enough to detect thrombin or factor Xa inhibition provided by new oral anticoagulants. Thus, these standard tests may only be used as a crude estimation of the actual anticoagulation status. Further challenges
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or decades, vitamin K antagonists have been a cornerstone in the treatment of deep vein thrombosis, pulmonary and peripheral arterial embolism, and in the prevention of thromboembolic complications, including stroke, in patients with mechanical heart valves or atrial fibrillation. Vitamin K is essential for the formation of biologically functional forms of coagulation factors II, VII, IX and X and the anticoagulant factor proteins C and S. However, numerous food and drug interactions with vitamin K antagonists are known, and close and frequent monitoring is required using the international normalised ratio (INR), as therapeutic and safety range is narrow.1 New oral anticoagulants (NOACs), including direct thrombin inhibitors and factor Xa-inhibitors, are emerging alternatives for prophylaxis and treatment of venous thromboembolism (VTE), particularly in patients undergoing orthopaedic surgery and patients with atrial fibrillation.2–5 NOACs benefit from a more predictable effect, thus eliminating the need for routine monitoring. For stroke pre-
regarding patients receiving new oral anticoagulants who presents with major bleeding or need for emergency surgery pose a unique problem. No established agents are clinically available to reverse the anticoagulant effect, although preclinical data report prothrombin complex concentrate as more efficient than fresh frozen plasma or other prohaemostatic agents. This review summaries current knowledge on approved new oral anticoagulants and discusses clinical aspects of monitoring, with particular focus on the management of the bleeding patient. Accepted for publication 10 March 2014 © 2014 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
vention in atrial fibrillation, NOACs are non-inferior to vitamin K antagonist therapy with a more advantageous side-effect profile in terms of fewer major/ fatal bleedings.3–7 In prophylaxis of VTE following ortopaedic surgery, NOACs provide more effective protection against VTE than low molecular weight heparins without an increased risk of bleeding.2,8 Even if patients experience major bleeding events, outcome seems better as indicated by shorter stay in intensive care and a trend to lower mortality in patients treated with dabigatran compared with those who had major bleeding on warfarin.9 Moreover, patients with major bleeding on dabigatran had a lower creatinine clearance, were older and more likely to receive concomitant treatment with aspirin or non-steroid anti-inflammatory drugs (NSAIDS) than patients with major bleeding on warfarin.9 Treatment with NOACs thus seems as an attractive alternative to vitamin K antagonists but, recently, important concerns have been raised. Firstly, elderly patients with reduced renal clearance may develop supra-therapeutic levels of NOACs,
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C. Fenger-Eriksen et al. Table 1 Pharmacodynamic and kinetic properties of new oral anticoagulants.
Mechanism of action Bioavailability (%) T1/2 (h) Time to Cmax (h) Plasma protein binding Dosage* Atrial fibrillation VTE treatment/prophylaxis Secondary prophylaxis after ACS Elimination Renal clearance (%) Hepatic degradation (%)
Dabigatran
Rivaroxaban
Apixaban
Pradaxa®
Xarelto®
Eliquis®
Thrombin inhibitor 3–7 12–16 2 35%
FXa inhibitor 60–70 5–13 2–4 90%
FXa inhibitor ∼66 8–15 3–4 87%
110/150 × 2 220 mg × 1 Not approved
20 mg × 1 10–15 mg × 1/2 2.5 mg × 2
5 mg × 2 2.5 mg × 2 Not approved
85 15
30 70†
30 70
*In patients with normal renal function, approximately 25% excreted with faeces. †Two third of rivaroxaban is metabolised in the liver and excreted with urine and faeces (50/50%). ACS, acute coronary syndromes; VTE; venous thromboembolism.
entailing an increased risk of bleeding.10 Accordingly, several case reports have been published on fatal bleeding following treatment with NOACs in the elderly.11–14 Secondly, bleeding episodes or the need for acute surgery in otherwise healthy patients call for prompt monitoring and reversal of NOAC therapy. However, at present no specific antidotes are available, and only limited information is available on how to manage, monitor and guide the bleeding patient on NOACs. This review summarises current knowledge on approved NOACs and discusses clinical aspects of monitoring, with particular focus on the management of the bleeding patient on NOACs.
Clinical indications. Stroke prevention in atrial fibrillation and venous thromboprophylaxsis following hip/knee replacement surgery. Dosage. For thromboprophylaxis following surgery, the dosage is 110 mg 1–4 h after surgery, and then 220 mg once daily. For stroke prevention in atrial fibrillation, 150 mg twice daily is recommended with a dose reduction to 110 mg twice daily in the elderly.
NOACs Dabigatran; Pradaxa® (direct thrombin inhibitor) Dabigatran etexilate (Pradaxa®; Boehringer Ingelheim, Ingelheim, Germany) is a prodrug of the direct thrombin inhibitor dabigatran, which is a direct, reversible, potent and competitive inhibitor of thrombin (Table 1 and Fig. 1). A prodrug is required as dabigatran itself is highly hydrophilic and not orally bioavailable. By inhibiting thrombin directly, dabigatran prevents the conversion of fibrinogen into fibrin and thus prevents thrombus formation. Dabigatran, which inhibits both fibrin-bound and free thrombin, is only involved in few drug interactions (mainly P-glycoprotein inhibitors, including verapamil and azole antifungals), and does not interact with food. The major route of elimination is the kidney, which clears about 85% of the drug, while the remaining part is metabolised in the liver.
2
Fig. 1. Drug targets for new oral anticoagulants.
NOACs and bleeding complications
Rivaroxaban; Xarelto® and Apixaban; Eliquis® (direct factor Xa-inhibitors) Rivaroxaban (Xarelto®; Bayer, Leverkusen, Germany) and apixaban (Eliquis®; Bristol-Myers Squibb, New York, NY, USA) selectively and competitively bind to FXa thereby inhibiting thrombin formation by blocking the interaction of FXa with its substrate prothrombin (Fig. 1). The bioavailability for both drugs is high and increases with food intake for rivaroxaban. About 30% of a dose is excreted unchanged via the kidneys for both drugs, while the remaining part of rivaroxaban undergo enzymatic inactivation in the liver. For Apixaban, 25% is transformed in the liver into metabolites and excreted in faeces. Clinical indications. Stroke prevention in atrial fibrillation, VTE prophylaxis following hip/knee replacement and treatment of VTE. Rivaroxaban has been approved in Europe for secondary prophylaxis after acute coronary syndromes, but clinical use in this setting is limited. Dosage. The recommended dose for thromboprophylaxis following surgery is 10 mg once daily, 15 mg twice daily for treatment or prophylaxsis against VTE/pulmonary embolism, 2.5 mg twice daily after acute coronary syndromes, and 20 mg once daily for stroke prevention in atrial fibrillation. Dose reduction in patients with reduced renal function is recommended. For all drugs and indications, dosage reductions must be considered in the elderly, patients with low body weight or reduced renal function and in patients with a risk of drug interactions, e.g. due to concomitant treatment with dabigatran and verapamil. An important caveat is that renal function is not static and often decreases, sometimes reversibly, with nephrotoxic drugs, comorbidity and increasing age.
Monitoring anticoagulant status When to monitor Patients in the need of acute surgery, patients presenting as potentially overdosed or with acute bleeding and patients with reduced hepatic or renal clearance are candidates for clarification of the actual anticoagulation status by means of laboratory monitoring. On the other hand, patients undergoing elective surgery or other types of invasive procedures do not require routine laboratory monitoring as the NOAC therapy could just simply be paused
Table 2 Preoperative withdrawal of new oral anticoagulants treatment prior to elective surgery/invasive procedures. Drug
Creatinine clearance (ml/min)
Risk of bleeding Low (h)
High (h)
Dabigatran Pradaxa® Rivaroxaban Xarelto® Apixaban Eliquis®
> 50 30–50* > 50 30–50 > 50 30–50
36 48 24 36 24 36
72 72–96 48 72 48 72
*This recommendation applies to all patients more than 75 years old despite normal renal function.
and the intervention postponed until the anticoagulant effect of the drugs has been either reduced or eliminated, depending of the extent of the bleeding risk. Based on an evaluation on age, kidney and hepatic function, the half-live of the drug, and the time point for the last dose, an estimate of the anticoagulant effect of the drug at a given time can be made and weighted against the risk of bleeding during the invasive procedure (low or high-risk procedures). Based on these considerations, and data from phase III trials, patients may safely undergo elective invasive procedures or surgery between 24−72 after the last dose administration.4,5 National guidelines have been proposed in several countries. Consensus-based perioperative dosing regimens for Dabigatran, Rivaroxaban and Apixaban are presented in Table 2.
How to monitor Assessment of the plasma concentration or the anticoagulant effect of NOACs on routine coagulation assays is sometimes highly desirable.
Dabigatran; Pradaxa® (direct thrombin inhibitor) Plasma concentrations in ng/ml can be measured using different tests, including Hemoclot® (Biophen), DTI® (Hyphen Biomed) and ECA-T® (Diagnostica Stago). These tests measure plasma concentrations between 50 and 500 ng/ml, and can be used to detect patients with an increased risk of bleeding, based on C-through values above 200 ng/ml and C-max values above 450 ng/ml. The detection limit of the tests is approximately 25 ng/ ml, and the test accuracy is lower at the lowest drug concentrations. The peak and through dabigatran plasma concentrations at steady state are shown in
3
C. Fenger-Eriksen et al. Table 3 New oral anticoagulants peak and through plasmaconcentrations at steady-state. C-max (ng/ml) Dabigatran, Pradaxa® 220 mg od 150 mg bid Rivaroxaban, Xarelto® 10 mg od 20 mg od Apixaban, Eliquis® 2.5 mg bid 5 mg bid
C-through (ng/ml)
References
183 (62–447) 184 (64–443)
37 (10–96) 90 (31–225)
van Ryn et al.15
125 (112–184) 215 (22–535)
9 (1–38) 32 (6–239)
Mueck et al.16 Mueck et al.16
23 (69.221) 171 (91–321)
79 (34–162) 103 (41–230)
Frost et al.17 and Leil et al.18
Data expressed as median (5th–95th percentiles). Bid, twice daily; od, once daily.
Table 3.15–18 Both the protrombin time (PT) and activated partial thromboplastin time (aPTT) are prolonged during Dabigatran treatment. However, both tests are relatively insensitive and suffer from a high degree of variability especially at high drug concentrations. The sensitivity depends on the different reagents used. Regardless of the reagent used, PT is insensitive to dabigatran at all concentrations. Several APTT reagents have been tested, and even though a higher sensitivity can be gained with the aPTT tests, the general conclusion has been that there is a poor correlation between the prolongation of the aPTT and the drug concentration measured. There is a lack of knowledge on how to monitor safety in dabigatran-treated patients before administrating trombolytic therapy. One may argue that if any anticoagulant activity could be measured, i.e. normal aPTT, PT, ECT/dTT (plasma concentrations < 25 ng/ml) and the dabigatran had been administered within the last 3–4 h it would not be safe to administer trombolytic therapy. However, no clinical data support this suggestion, and an individual evaluation of the total risk for the patient must always be performed. It should be noticed that the PT and aPTT tests could only be used to evaluate the anticoagulant effect of dabigatran if the patients do not suffer from another bleeding disorder (deficiency in coagulation factors), that could interfere with an otherwise normal values of PT or aPTT.
Rivaroxaban; Xarelto® (direct factor Xa-inhibitors) Peak and through values of rivaroxaban at steadystate are presented in Table 3. Measurements of the anti-Xa activity by specific methods is feasible using the STA-Rotachrom (Diagnostica Stago), Coatest (Instrumentary Laboratory), Biophen DiXal
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(Hypen Biomed), and several tests also enable conversion of anti-Xa activity to a plasma concentration (ng/ml).19 PT and aPTT are prolonged in patients treated with rivaroxaban. The sensitivity of aPTT is low at both low and high concentrations and the variability between methods high.20 In contrast, a good correlation has been found between the prolongation of the PT time and the plasma concentration of Rivaroxaban. Sensitivity and variability are highest at high concentrations and lowest at low concentrations, and sensitivity varies with different PT reagents used.
Apixaban; Eliquis® (direct factor Xa-inhibitors) Peak and through values at steady-state are presented in Table 3. Measurements of the anti-Xa activity by specific methods should be possible using the same competition anti-Xa-activity methods as for rivaroxaban. However, clinical data are still lacking. The STA-Rotachrom (Diagnostica Stago, Asniers sur Seine Cedex, France) test has been used to measure the effect of apixaban on FXa.21 A concentration-dependent increase in anti-FXa activity was observed in the dose range tested. Using the Coatest ((Instrumentation Laboratory, Bedford, MA, USA) and lyophilised Apixaban (10,000 ng/ml) kindly provided by Pfizer (New York, NY, USA), we have found the same strong correlation between Apixaban plasma concentration and the anti-Xa activity (AM Münster, unpublished data). PT and aPTT are prolonged, but with low sensitivity and high variability at all drug concentrations, these tests do therefore not seem clinically useful.
Interpretation of laboratory results Plasma drug concentrations and measurements of the effects of NOACs may serve as a useful guide in
NOACs and bleeding complications
some clinical situations, yet one should acknowledge that no formal therapeutic drug levels or safety intervals have been established. This leaves us only with the possibility of evaluating whether the plasma values are much lower or higher than expected during treatment, compared with plasma values obtained during the clinical trials. Results from patients undergoing invasive procedures in the phase III trials, leaves us with an estimate that a safety threshold in patients with a normal clearance could be around 30 ng/ml.22 These measurements could add clinical information on NOACs and could be beneficial to the total risk stratification of patients.
Dabigatran; Pradaxa® (direct thrombin inhibitor) Because the aPTT is prolonged during treatment with dabigatran, an abnormal aPTT in combination with a prolonged PT can therefore be used as an indicator of the presence of increased anticoagulant activity. On the other hand, a normal aPTT reflects low concentrations23 and could be used together with a normal PT to estimate low bleeding risk. Unpublished data using the aPTT reagent Pathrombin PL indicates that an aPTT two times higher than the upper normal reference interval at C-through and four times higher than the upper normal reference interval at C-max, could be used to identify patients with an increased bleeding risk (Münster et al. submitted). Importantly, clinicians at local hospitals should be familiar with the sensitivity of the tests used at their hospital, before implementation in clinical decision-making.
Rivaroxaban; Xarelto® (direct factor Xa-inhibitors) Proposal. A prolonged PT with a value 1.5 times above the upper normal reference interval at C-max (combined with a prolonged aPTT) indicates that the bleeding risk is increased. The same applies to an anti-Xa activity corresponding to a concentration above 25 ng/ml. In contrast, with a normal PT and anti-Xa activity measured below 25 ng/ml, the likelihood of bleeding due to treatment of rivaroxban could be considered low. No knowledge about the safety threshold in combination with thrombolytic therapy is available, and an individual risk assessment should thus be performed.
Apixaban; Eliquis® (direct factor Xa-inhibitors) Proposal. Use the anti-Xa activity method (competition methods), and regard values < 25 ng/ml as an
indicator of low bleeding risk. Values above this would properly be correlated to increasing bleeding risk with increasing values. There is no available knowledge on the risk of bleeding associated with the combination of apixaban with thrombolytic therapy, and an individual assessment should be performed.
Management of the bleeding patient on NOAC For many years, prothrombin complex concentrate (PCC) has been a safe and rapid treatment option for acute reversal of vitamin K antagonist therapy, as protamin sulphate immediately neutralises the anticoagulation affect from heparin. Patients receiving NOACs constitute a new challenge as no antidotes are currently available for any of the NOACs. Immediate reversal of the anticoagulant effect may be needed in patients on NOACs that require acute surgery or patients who present with a major or critical bleeding (e.g. with intracranial location).
General management of the bleeding patient Management of major bleeding, whether associated with NOACs or not, includes prompt control of the bleeding by surgery, compression, damage control surgery or radiological procedures. Further supportive care includes fluid resuscitation without synthetic colloids, proper transfusion strategy and treatment of coagulopathy by guided administration of haemostatic agents like fibrinogen concentrate and/or PCC.24,25
Oral-activated charcoal Gastric lavage followed by charcoal administration (with a standard dose for adults of 30–50 g) may reduce uptake and further exposure to NOACs. However, to take advantage of this treatment regimen charcoal has to be given within a few hours after NOAC intake. Furthermore, a high volume filling of the stomach prior to possible surgery preceded by general anaesthesia may limit the use of oral activated charcoal administration.
Fresh frozen plasma (FFP) FFP may increase levels of coagulation factors during bleeding, but it is unlikely that plasma treatment can overcome thrombin or FXa inhibition, respectively. At present, no data regarding the use of FFP in patients with NOAC-associated bleeding exist. In dabigatran-/rivaroxaban-treated mice, FFP
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C. Fenger-Eriksen et al.
reduced the volume of intracerebral haemorrhage, but had no effect on mortality.26,27 Additionally, FFP is associated with increased risks of volume overload and, rarely, allergic reactions, and infection.
Specific haemostatic agents A specific antidote for dabigatran (aDabi-Fab) has been developed. The affinity of the antidote for dabigatran is much higher (approximately 350 times) than dabigatran’s affinity for thrombin. So far, the antidote has been tested in vitro and in animal studies with very promising results although the product is yet not available for clinical use.28 A recombinant antidote for factor Xa-inhibitors (r-Antidote) exists and has so far proved efficacious to improve laboratory and parameters reduce blood loss in rats treated with factor Xa-inhibitors.29 Recombinant activated factor VII (NovoSeven®), PCCs-activated like (Feiba®) or non-activated threefactor (i.e. Profilnine®, Bebulin®), or four-factor PCCs (i.e. Beriplex®, Octaplex®, Kanokad®) are all commercially available coagulation factor products that stimulates thrombin generation. In the absence of a specific antidote for NOACs, these haemostatic agents have been extensively investigated as potential drugs for reversal. In a recent study by Eerenberg et al., 50 mg/kg of PCC reversed the effect of rivaroxaban but not dabigatran in healthy volunteers.30 In a comparable study, PCC, aPCC and rFVIIa all improved thrombin generation parameters in healthy volunteers receiving oral rivaroxaban or dabigatran.31 Although these results are supported by animal studies, human data and studies with clinical endpoints like bleeding are highly warranted.32 In a case series of five patients treated with dabigatran, Diaz et al. reported successful cessation of bleeding in four of five patients treated with PCC.33 In animal bleeding models, recombinant activated factor VII and PCC improved laboratory measures of coagulation after treatment with rivaroxaban but failed to reduce blood loss.34,35 Importantly, is must be emphasised that both PCC and rFVIIa are potent activators of in vivo blood coagulation and the use of these agents has been associated with increased risks of thromboembolic complications.36 This risk must be acknowledged and taken into account, when considering the use of these haemostatic agents. In our opinion, the evidence is insufficient to recommend first-line treatment with rFVII, aPCC or PCC in patients with bleeding not considered life threatening. On the other hand, these haemostatic agents may be considered in situations with ongoing life-threatening
6
bleeding. While awaiting further clinical trials on the effectiveness and potential dosage of these drugs, the following treatment may be initiated: PCC (e.g. Beriplex®, Octaplex®) 25 U/kg; repeat 1×/2× if indicated or aPCC (Feiba®) 50 IU/kg; max 200 IU/ kg/day although human data, especially on reversal of dabigatran, are lacking.37–40
Haemodialysis Because protein binding is only approximately 35%, dabigatran can be dialysed,41 and this may be useful in case of overdosing, urgent surgery or major bleeding. However, acute dialysis in a potentially haemodynamic unstable bleeding patient may limit the clinical usefulness. One case report reported successful management of a severe dabigatraninduced post-operative bleeding with dialysis and high-dose rFVIIa.42 Due to the high degree of protein-bound rivaroxaban and apixaban, haemodialysis is not indicated.
Management of regional anaesthesia in patients on NOACs Regional anaesthesia is to be considered as a highrisk surgical procedure because of the seriousness of a potential bleeding complication. Thus, based on the last intake of NOAC and evaluation of renal function, regional anaesthesia should be postponed 48–72 h as listed in Table 2. Even though platelet count, aPTT and PT/INR are within the reference interval before 48–72 h, there is so far not evidence to support regional anaesthesia even though these recommendations are slightly more conservative than guidelines published by the European Society of Anaesthesiology in 2010.43 For procedures with clinically sufficient haemostasis, the NOAC therapy can be resumed 6–8 h after the intervention. However, avoidance of thromboembolic events by resuming NOAC therapy shortly after surgical procedures should be outweighed against an increased bleeding risk.
Summary Blood coagulation is an essential part of haemostasis, and several anticoagulant drugs are available to prevent and treat thromboembolic disease. In addition to classic anticoagulants such as vitamin K antagonists, several NOACs have recently been introduced. These drugs offer several advantages compared with vitamin K antagonists, and an increased use of these drugs is expected, e.g. in patients with atrial fibrillation. Importantly, some
NOACs and bleeding complications
important issues must be acknowledged by clinicians responsible for patients treated with these drugs. Firstly, elderly patients and patients with reduced renal function have an increased risk of bleeding, and measuring renal function is of paramount importance prior to initiation of therapy with NOACS. Similarly, there is evidence supporting that concomitant treatment with NSAIDS or antiplatelet drugs increase the risk of bleeding in patients treated with NOACS and, therefore, avoiding these combinations or reducing the dose of NOAC should be considered.9,44 Finally, no specific antidotes are presently available, and we currently only have limited information on how to monitor and manage patients with bleeding complications during treatment with NOACs. Methods for measurements of drug concentrations have been established, although a correlation between a given plasma drug concentration and the likelihood of bleeding has not been firmly established. Standard laboratory assays like PT and APTT may be used as a crude estimation of the actual anticoagulation status but are not sensitive enough to decide if for instance regional anaesthesia can be safely undertaken. More importantly, sensitivity and variability of APPT and PT measurements from patients on NOAC depend of the reagent used, and it is therefore important to obtain more knowledge of these reagents. To ensure sufficient and proper coagulation capacity of the clotting factors inhibited by NOACs, the most reliable method is to delay surgery/ intervention until at least four times the half-life has passed. In situations with ongoing bleeding in patients treated with NOACs, administration of a procoagulant drug may by reasonable to support haemostasis. Currently, PCC seems to provide a better clinical bleeding outcome compared with recombinant-activated factor VII and especially FFP. Further clinical studies are warranted to determine optimal monitoring and ways of reversing the effect of NOACs.
Acknowledgements Signe Harley Nygaard Moore, Aarhus University hospital is acknowledged for graphical support. Conflicts of interest: The authors have no conflicts to declare. Funding: The study was supported by internal funding only.
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28.
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dynamics of rivaroxaban – an oral, direct factor xa inhibitor – in healthy subjects. Int J Clin Pharmacol Ther 2007; 45: 335–44. Frost C, Wang J, Nepal S, Schuster A, Barrett YC, Mosqueda-Garcia R, Reeves RA, LaCreta F. Apixaban, an oral, direct factor Xa inhibitor: single dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects. Br J Clin Pharmacol 2013; 75: 476–87. Leil TA, Feng Y, Zhang L, Paccaly A, Mohan P, Pfister M. Quantification of apixaban’s therapeutic utility in prevention of venous thromboembolism: selection of phase III trial dose. Clin Pharmacol Ther 2010; 88: 375–82. Samama MM, Contant G, Spiro TE, Perzborn E, Guinet C, Gourmelin Y, Le Flem L, Rohde G, Martinoli JL, Rivaroxaban Anti-Factor Xa Chromogenic Assay Field Trial Laboratories. Evaluation of the anti-factor Xa chromogenic assay for the measurement of rivaroxaban plasma concentrations using calibrators and controls. Thromb Haemost 2012; 107: 379– 87. Hillarp A, Baghaei F, Fagerberg Blixter I, Gustafsson KM, Stigendal L, Sten-Linder M, Strandberg K, Lindahl TL. Effects of the oral, direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays. J Thromb Haemost 2011; 9: 133–9. Barrett YC, Wang Z, Frost C, Shenker A. Clinical laboratory measurement of direct factor Xa inhibitors: anti-Xa assay is preferable to prothrombin time assay. Thromb Haemost 2010; 104: 1263–71. Pernod G, Albaladejo P, Godier A, Samama CM, Susen S, Gruel Y, Blais N, Fontana P, Cohen A, Llau JV, Rosencher N, Schved JF, de Maistre E, Samama MM, Mismetti P, Sié P, Working Group on Perioperative Haemostasis. 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. Arch Cardiovasc Dis 2013; 106: 382–93. Weitz JI, Quinlan DJ, Eikelboom JW. Periprocedural management and approach to bleeding in patients taking dabigatran. Circulation 2012; 126: 2428–32. Rossaint R, Bouillon B, Cerny V, Coats TJ, Duranteau J, Fernández-Mondéjar E, Filipescu D, Hunt BJ, Komadina R, Maegele M, Nardi G, Neugebauer E, Ozier Y, Riddez L, Schultz A, Vincent JL, Spahn DR, the STOP the Bleeding Campaign. The STOP the Bleeding Campaign. Crit Care 2013; 17: 136. Kozek-Langenecker SA, Afshari A, Albaladejo P, Santullano CA, De Robertis E, Filipescu DC, Fries D, Görlinger K, Haas T, Imberger G, Jacob M, Lancé M, Llau J, Mallett S, Meier J, Rahe-Meyer N, Samama CM, Smith A, Solomon C, Van der Linden P, Wikkelsø AJ, Wouters P, Wyffels P. Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology. Eur J Anaesthesiol 2013; 30: 270–382. Zhou W, Zorn M, Nawroth P, Bütehorn U, Perzborn E, Heitmeier S, Veltkamp R. Hemostatic therapy in experimental intracerebral hemorrhage associated with rivaroxaban. Stroke 2013; 44: 771–8. Zhou W, Schwarting S, Illanes S, Liesz A, Middelhoff M, Zorn M, Bendszus M, Heiland S, van Ryn J, Veltkamp R. Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke 2011; 42: 3594–9. Schiele F, van Ryn J, Canada K, Newsome C, Sepulveda E, Park J, Nar H, Litzenburger T. A specific antidote for dabigatran: functional and structural characterization. Blood 2013; 121: 3554–62.
29. Lu G, DeGuzman FR, Hollenbach SJ, Karbarz MJ, Abe K, Lee G, Luan P, Hutchaleelaha A, Inagaki M, Conley PB, Phillips DR, Sinha U. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med 2013; 19: 446–51. 30. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011; 124: 1573–9. 31. Marlu R, Hodaj E, Paris A, Albaladejo P, Cracowski JL, Pernod G. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb Haemost 2012; 108: 217–24. 32. Miesbach W, Seifried E. New direct oral anticoagulants – current therapeutic options and treatment recommendations for bleeding complications. Thromb Haemost 2012; 108: 625– 32. 33. Díaz MQ, Borobia AM, Núñez MA, Virto AM, Fabra S, Casado MS, García-Erce JA, Samama CM. Use of prothrombin complex concentrates for urgent reversal of dabigatran in the Emergency Department. Haematologica 2013; 98: e143–4. 34. Le Saché F, Le Bonniec B, Gaussem P, Dizier B, Tagzirt M, Godier A, Emmerich J, Samama CM. Recombinant activated factor VII and prothrombin complex concentrates have different effects on bleeding and arterial thrombosis in the haemodiluted rabbit. Br J Anaesth 2012; 108: 586– 93. 35. Godier A, Miclot A, Le Bonniec B, Durand M, Fischer AM, Emmerich J, Marchand-Leroux C, Lecompte T, Samama CM. Evaluation of prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit model. Anesthesiology 2012; 116: 94–102. 36. Levi M, Levy JH, Andersen HF, Truloff D. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med 2010; 363: 1791–800. 37. Pragst I, Zeitler SH, Doerr B, Kaspereit FJ, Herzog E, Dickneite G, van Ryn J. Reversal of dabigatran anticoagulation by prothrombin complex concentrate (Beriplex P/N) in a rabbit model. J Thromb Haemost 2012; 10: 1841–8. 38. Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J, Sinnaeve P, Camm AJ, Kirchhof P, European Heart Rhythm Association. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace 2013; 15: 625–51. 39. Spahn DR, Bouillon B, Cerny V, Coats TJ, Duranteau J, Fernández-Mondéjar E, Filipescu D, Hunt BJ, Komadina R, Nardi G, Neugebauer E, Ozier Y, Riddez L, Schultz A, Vincent JL, Rossaint R. Management of bleeding and coagulopathy following major trauma: an updated European guideline. Crit Care 2013; 17: R76. 40. Fawole A, Daw HA, Crowther MA. Practical management of bleeding due to the anticoagulants dabigatran, rivaroxaban, and apixaban. Cleve Clin J Med 2013; 80: 443–51. 41. Stangier J, Rathgen K, Stähle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet 2010; 49: 259– 68. 42. Warkentin TE, Margetts P, Connolly SJ, Lamy A, Ricci C, Eikelboom JW. Recombinant factor VIIa (rFVIIa) and hemodialysis to manage massive dabigatran-associated postcardiac surgery bleeding. Blood 2012; 119: 2172–4.
NOACs and bleeding complications 43. Gogarten W, Vandermeulen E, Van Aken H, Kozek S, Llau JV, Samama CM, European Society of Anaesthesiology. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol 2010; 27: 999–1015. 44. Sinnaeve PR, Van de Werf F. Do ingredients make the difference?: finding the best cocktail of an anticoagulant with antiplatelets. Circulation 2013; 127: 566–8.
Address: Mr Christian Fenger-Eriksen Department of Anaesthesia and Intensive Care Viborg Regional Hospital Heibergs Alle 8800 Viborg Denmark e-mail: [email protected]
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© 2014 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd ACTA ANAESTHESIOLOGICA SCANDINAVICA
doi: 10.1111/aas.12319
Review Article
New oral anticoagulants: clinical indications, monitoring and treatment of acute bleeding complications C. Fenger-Eriksen1, A.-M. Münster2 and E. L. Grove3
1 Department of Anaesthesia and Intensive Care, Viborg Regional Hospital, Viborg, 2Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg and 3Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark
New oral anticoagulants like the direct thrombin inhibitor, dabigatran (Pradaxa®), and factor Xa-inhibitors, rivaroxaban (Xarelto®) and apixaban (Eliquis®) are available for prophylaxis and treatment of thromboembolic disease. They are emerging alternatives to warfarin and provide equal or better clinical outcome together with reduced need for routine monitoring. Methods for measuring drug concentrations are available, although a correlation between plasma drug concentrations and the risk of bleeding has not been firmly established. Standard laboratory measures like prothrombin time and activated partial thromboplastin time are not sensitive enough to detect thrombin or factor Xa inhibition provided by new oral anticoagulants. Thus, these standard tests may only be used as a crude estimation of the actual anticoagulation status. Further challenges
F
or decades, vitamin K antagonists have been a cornerstone in the treatment of deep vein thrombosis, pulmonary and peripheral arterial embolism, and in the prevention of thromboembolic complications, including stroke, in patients with mechanical heart valves or atrial fibrillation. Vitamin K is essential for the formation of biologically functional forms of coagulation factors II, VII, IX and X and the anticoagulant factor proteins C and S. However, numerous food and drug interactions with vitamin K antagonists are known, and close and frequent monitoring is required using the international normalised ratio (INR), as therapeutic and safety range is narrow.1 New oral anticoagulants (NOACs), including direct thrombin inhibitors and factor Xa-inhibitors, are emerging alternatives for prophylaxis and treatment of venous thromboembolism (VTE), particularly in patients undergoing orthopaedic surgery and patients with atrial fibrillation.2–5 NOACs benefit from a more predictable effect, thus eliminating the need for routine monitoring. For stroke pre-
regarding patients receiving new oral anticoagulants who presents with major bleeding or need for emergency surgery pose a unique problem. No established agents are clinically available to reverse the anticoagulant effect, although preclinical data report prothrombin complex concentrate as more efficient than fresh frozen plasma or other prohaemostatic agents. This review summaries current knowledge on approved new oral anticoagulants and discusses clinical aspects of monitoring, with particular focus on the management of the bleeding patient. Accepted for publication 10 March 2014 © 2014 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
vention in atrial fibrillation, NOACs are non-inferior to vitamin K antagonist therapy with a more advantageous side-effect profile in terms of fewer major/ fatal bleedings.3–7 In prophylaxis of VTE following ortopaedic surgery, NOACs provide more effective protection against VTE than low molecular weight heparins without an increased risk of bleeding.2,8 Even if patients experience major bleeding events, outcome seems better as indicated by shorter stay in intensive care and a trend to lower mortality in patients treated with dabigatran compared with those who had major bleeding on warfarin.9 Moreover, patients with major bleeding on dabigatran had a lower creatinine clearance, were older and more likely to receive concomitant treatment with aspirin or non-steroid anti-inflammatory drugs (NSAIDS) than patients with major bleeding on warfarin.9 Treatment with NOACs thus seems as an attractive alternative to vitamin K antagonists but, recently, important concerns have been raised. Firstly, elderly patients with reduced renal clearance may develop supra-therapeutic levels of NOACs,
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C. Fenger-Eriksen et al. Table 1 Pharmacodynamic and kinetic properties of new oral anticoagulants.
Mechanism of action Bioavailability (%) T1/2 (h) Time to Cmax (h) Plasma protein binding Dosage* Atrial fibrillation VTE treatment/prophylaxis Secondary prophylaxis after ACS Elimination Renal clearance (%) Hepatic degradation (%)
Dabigatran
Rivaroxaban
Apixaban
Pradaxa®
Xarelto®
Eliquis®
Thrombin inhibitor 3–7 12–16 2 35%
FXa inhibitor 60–70 5–13 2–4 90%
FXa inhibitor ∼66 8–15 3–4 87%
110/150 × 2 220 mg × 1 Not approved
20 mg × 1 10–15 mg × 1/2 2.5 mg × 2
5 mg × 2 2.5 mg × 2 Not approved
85 15
30 70†
30 70
*In patients with normal renal function, approximately 25% excreted with faeces. †Two third of rivaroxaban is metabolised in the liver and excreted with urine and faeces (50/50%). ACS, acute coronary syndromes; VTE; venous thromboembolism.
entailing an increased risk of bleeding.10 Accordingly, several case reports have been published on fatal bleeding following treatment with NOACs in the elderly.11–14 Secondly, bleeding episodes or the need for acute surgery in otherwise healthy patients call for prompt monitoring and reversal of NOAC therapy. However, at present no specific antidotes are available, and only limited information is available on how to manage, monitor and guide the bleeding patient on NOACs. This review summarises current knowledge on approved NOACs and discusses clinical aspects of monitoring, with particular focus on the management of the bleeding patient on NOACs.
Clinical indications. Stroke prevention in atrial fibrillation and venous thromboprophylaxsis following hip/knee replacement surgery. Dosage. For thromboprophylaxis following surgery, the dosage is 110 mg 1–4 h after surgery, and then 220 mg once daily. For stroke prevention in atrial fibrillation, 150 mg twice daily is recommended with a dose reduction to 110 mg twice daily in the elderly.
NOACs Dabigatran; Pradaxa® (direct thrombin inhibitor) Dabigatran etexilate (Pradaxa®; Boehringer Ingelheim, Ingelheim, Germany) is a prodrug of the direct thrombin inhibitor dabigatran, which is a direct, reversible, potent and competitive inhibitor of thrombin (Table 1 and Fig. 1). A prodrug is required as dabigatran itself is highly hydrophilic and not orally bioavailable. By inhibiting thrombin directly, dabigatran prevents the conversion of fibrinogen into fibrin and thus prevents thrombus formation. Dabigatran, which inhibits both fibrin-bound and free thrombin, is only involved in few drug interactions (mainly P-glycoprotein inhibitors, including verapamil and azole antifungals), and does not interact with food. The major route of elimination is the kidney, which clears about 85% of the drug, while the remaining part is metabolised in the liver.
2
Fig. 1. Drug targets for new oral anticoagulants.
NOACs and bleeding complications
Rivaroxaban; Xarelto® and Apixaban; Eliquis® (direct factor Xa-inhibitors) Rivaroxaban (Xarelto®; Bayer, Leverkusen, Germany) and apixaban (Eliquis®; Bristol-Myers Squibb, New York, NY, USA) selectively and competitively bind to FXa thereby inhibiting thrombin formation by blocking the interaction of FXa with its substrate prothrombin (Fig. 1). The bioavailability for both drugs is high and increases with food intake for rivaroxaban. About 30% of a dose is excreted unchanged via the kidneys for both drugs, while the remaining part of rivaroxaban undergo enzymatic inactivation in the liver. For Apixaban, 25% is transformed in the liver into metabolites and excreted in faeces. Clinical indications. Stroke prevention in atrial fibrillation, VTE prophylaxis following hip/knee replacement and treatment of VTE. Rivaroxaban has been approved in Europe for secondary prophylaxis after acute coronary syndromes, but clinical use in this setting is limited. Dosage. The recommended dose for thromboprophylaxis following surgery is 10 mg once daily, 15 mg twice daily for treatment or prophylaxsis against VTE/pulmonary embolism, 2.5 mg twice daily after acute coronary syndromes, and 20 mg once daily for stroke prevention in atrial fibrillation. Dose reduction in patients with reduced renal function is recommended. For all drugs and indications, dosage reductions must be considered in the elderly, patients with low body weight or reduced renal function and in patients with a risk of drug interactions, e.g. due to concomitant treatment with dabigatran and verapamil. An important caveat is that renal function is not static and often decreases, sometimes reversibly, with nephrotoxic drugs, comorbidity and increasing age.
Monitoring anticoagulant status When to monitor Patients in the need of acute surgery, patients presenting as potentially overdosed or with acute bleeding and patients with reduced hepatic or renal clearance are candidates for clarification of the actual anticoagulation status by means of laboratory monitoring. On the other hand, patients undergoing elective surgery or other types of invasive procedures do not require routine laboratory monitoring as the NOAC therapy could just simply be paused
Table 2 Preoperative withdrawal of new oral anticoagulants treatment prior to elective surgery/invasive procedures. Drug
Creatinine clearance (ml/min)
Risk of bleeding Low (h)
High (h)
Dabigatran Pradaxa® Rivaroxaban Xarelto® Apixaban Eliquis®
> 50 30–50* > 50 30–50 > 50 30–50
36 48 24 36 24 36
72 72–96 48 72 48 72
*This recommendation applies to all patients more than 75 years old despite normal renal function.
and the intervention postponed until the anticoagulant effect of the drugs has been either reduced or eliminated, depending of the extent of the bleeding risk. Based on an evaluation on age, kidney and hepatic function, the half-live of the drug, and the time point for the last dose, an estimate of the anticoagulant effect of the drug at a given time can be made and weighted against the risk of bleeding during the invasive procedure (low or high-risk procedures). Based on these considerations, and data from phase III trials, patients may safely undergo elective invasive procedures or surgery between 24−72 after the last dose administration.4,5 National guidelines have been proposed in several countries. Consensus-based perioperative dosing regimens for Dabigatran, Rivaroxaban and Apixaban are presented in Table 2.
How to monitor Assessment of the plasma concentration or the anticoagulant effect of NOACs on routine coagulation assays is sometimes highly desirable.
Dabigatran; Pradaxa® (direct thrombin inhibitor) Plasma concentrations in ng/ml can be measured using different tests, including Hemoclot® (Biophen), DTI® (Hyphen Biomed) and ECA-T® (Diagnostica Stago). These tests measure plasma concentrations between 50 and 500 ng/ml, and can be used to detect patients with an increased risk of bleeding, based on C-through values above 200 ng/ml and C-max values above 450 ng/ml. The detection limit of the tests is approximately 25 ng/ ml, and the test accuracy is lower at the lowest drug concentrations. The peak and through dabigatran plasma concentrations at steady state are shown in
3
C. Fenger-Eriksen et al. Table 3 New oral anticoagulants peak and through plasmaconcentrations at steady-state. C-max (ng/ml) Dabigatran, Pradaxa® 220 mg od 150 mg bid Rivaroxaban, Xarelto® 10 mg od 20 mg od Apixaban, Eliquis® 2.5 mg bid 5 mg bid
C-through (ng/ml)
References
183 (62–447) 184 (64–443)
37 (10–96) 90 (31–225)
van Ryn et al.15
125 (112–184) 215 (22–535)
9 (1–38) 32 (6–239)
Mueck et al.16 Mueck et al.16
23 (69.221) 171 (91–321)
79 (34–162) 103 (41–230)
Frost et al.17 and Leil et al.18
Data expressed as median (5th–95th percentiles). Bid, twice daily; od, once daily.
Table 3.15–18 Both the protrombin time (PT) and activated partial thromboplastin time (aPTT) are prolonged during Dabigatran treatment. However, both tests are relatively insensitive and suffer from a high degree of variability especially at high drug concentrations. The sensitivity depends on the different reagents used. Regardless of the reagent used, PT is insensitive to dabigatran at all concentrations. Several APTT reagents have been tested, and even though a higher sensitivity can be gained with the aPTT tests, the general conclusion has been that there is a poor correlation between the prolongation of the aPTT and the drug concentration measured. There is a lack of knowledge on how to monitor safety in dabigatran-treated patients before administrating trombolytic therapy. One may argue that if any anticoagulant activity could be measured, i.e. normal aPTT, PT, ECT/dTT (plasma concentrations < 25 ng/ml) and the dabigatran had been administered within the last 3–4 h it would not be safe to administer trombolytic therapy. However, no clinical data support this suggestion, and an individual evaluation of the total risk for the patient must always be performed. It should be noticed that the PT and aPTT tests could only be used to evaluate the anticoagulant effect of dabigatran if the patients do not suffer from another bleeding disorder (deficiency in coagulation factors), that could interfere with an otherwise normal values of PT or aPTT.
Rivaroxaban; Xarelto® (direct factor Xa-inhibitors) Peak and through values of rivaroxaban at steadystate are presented in Table 3. Measurements of the anti-Xa activity by specific methods is feasible using the STA-Rotachrom (Diagnostica Stago), Coatest (Instrumentary Laboratory), Biophen DiXal
4
(Hypen Biomed), and several tests also enable conversion of anti-Xa activity to a plasma concentration (ng/ml).19 PT and aPTT are prolonged in patients treated with rivaroxaban. The sensitivity of aPTT is low at both low and high concentrations and the variability between methods high.20 In contrast, a good correlation has been found between the prolongation of the PT time and the plasma concentration of Rivaroxaban. Sensitivity and variability are highest at high concentrations and lowest at low concentrations, and sensitivity varies with different PT reagents used.
Apixaban; Eliquis® (direct factor Xa-inhibitors) Peak and through values at steady-state are presented in Table 3. Measurements of the anti-Xa activity by specific methods should be possible using the same competition anti-Xa-activity methods as for rivaroxaban. However, clinical data are still lacking. The STA-Rotachrom (Diagnostica Stago, Asniers sur Seine Cedex, France) test has been used to measure the effect of apixaban on FXa.21 A concentration-dependent increase in anti-FXa activity was observed in the dose range tested. Using the Coatest ((Instrumentation Laboratory, Bedford, MA, USA) and lyophilised Apixaban (10,000 ng/ml) kindly provided by Pfizer (New York, NY, USA), we have found the same strong correlation between Apixaban plasma concentration and the anti-Xa activity (AM Münster, unpublished data). PT and aPTT are prolonged, but with low sensitivity and high variability at all drug concentrations, these tests do therefore not seem clinically useful.
Interpretation of laboratory results Plasma drug concentrations and measurements of the effects of NOACs may serve as a useful guide in
NOACs and bleeding complications
some clinical situations, yet one should acknowledge that no formal therapeutic drug levels or safety intervals have been established. This leaves us only with the possibility of evaluating whether the plasma values are much lower or higher than expected during treatment, compared with plasma values obtained during the clinical trials. Results from patients undergoing invasive procedures in the phase III trials, leaves us with an estimate that a safety threshold in patients with a normal clearance could be around 30 ng/ml.22 These measurements could add clinical information on NOACs and could be beneficial to the total risk stratification of patients.
Dabigatran; Pradaxa® (direct thrombin inhibitor) Because the aPTT is prolonged during treatment with dabigatran, an abnormal aPTT in combination with a prolonged PT can therefore be used as an indicator of the presence of increased anticoagulant activity. On the other hand, a normal aPTT reflects low concentrations23 and could be used together with a normal PT to estimate low bleeding risk. Unpublished data using the aPTT reagent Pathrombin PL indicates that an aPTT two times higher than the upper normal reference interval at C-through and four times higher than the upper normal reference interval at C-max, could be used to identify patients with an increased bleeding risk (Münster et al. submitted). Importantly, clinicians at local hospitals should be familiar with the sensitivity of the tests used at their hospital, before implementation in clinical decision-making.
Rivaroxaban; Xarelto® (direct factor Xa-inhibitors) Proposal. A prolonged PT with a value 1.5 times above the upper normal reference interval at C-max (combined with a prolonged aPTT) indicates that the bleeding risk is increased. The same applies to an anti-Xa activity corresponding to a concentration above 25 ng/ml. In contrast, with a normal PT and anti-Xa activity measured below 25 ng/ml, the likelihood of bleeding due to treatment of rivaroxban could be considered low. No knowledge about the safety threshold in combination with thrombolytic therapy is available, and an individual risk assessment should thus be performed.
Apixaban; Eliquis® (direct factor Xa-inhibitors) Proposal. Use the anti-Xa activity method (competition methods), and regard values < 25 ng/ml as an
indicator of low bleeding risk. Values above this would properly be correlated to increasing bleeding risk with increasing values. There is no available knowledge on the risk of bleeding associated with the combination of apixaban with thrombolytic therapy, and an individual assessment should be performed.
Management of the bleeding patient on NOAC For many years, prothrombin complex concentrate (PCC) has been a safe and rapid treatment option for acute reversal of vitamin K antagonist therapy, as protamin sulphate immediately neutralises the anticoagulation affect from heparin. Patients receiving NOACs constitute a new challenge as no antidotes are currently available for any of the NOACs. Immediate reversal of the anticoagulant effect may be needed in patients on NOACs that require acute surgery or patients who present with a major or critical bleeding (e.g. with intracranial location).
General management of the bleeding patient Management of major bleeding, whether associated with NOACs or not, includes prompt control of the bleeding by surgery, compression, damage control surgery or radiological procedures. Further supportive care includes fluid resuscitation without synthetic colloids, proper transfusion strategy and treatment of coagulopathy by guided administration of haemostatic agents like fibrinogen concentrate and/or PCC.24,25
Oral-activated charcoal Gastric lavage followed by charcoal administration (with a standard dose for adults of 30–50 g) may reduce uptake and further exposure to NOACs. However, to take advantage of this treatment regimen charcoal has to be given within a few hours after NOAC intake. Furthermore, a high volume filling of the stomach prior to possible surgery preceded by general anaesthesia may limit the use of oral activated charcoal administration.
Fresh frozen plasma (FFP) FFP may increase levels of coagulation factors during bleeding, but it is unlikely that plasma treatment can overcome thrombin or FXa inhibition, respectively. At present, no data regarding the use of FFP in patients with NOAC-associated bleeding exist. In dabigatran-/rivaroxaban-treated mice, FFP
5
C. Fenger-Eriksen et al.
reduced the volume of intracerebral haemorrhage, but had no effect on mortality.26,27 Additionally, FFP is associated with increased risks of volume overload and, rarely, allergic reactions, and infection.
Specific haemostatic agents A specific antidote for dabigatran (aDabi-Fab) has been developed. The affinity of the antidote for dabigatran is much higher (approximately 350 times) than dabigatran’s affinity for thrombin. So far, the antidote has been tested in vitro and in animal studies with very promising results although the product is yet not available for clinical use.28 A recombinant antidote for factor Xa-inhibitors (r-Antidote) exists and has so far proved efficacious to improve laboratory and parameters reduce blood loss in rats treated with factor Xa-inhibitors.29 Recombinant activated factor VII (NovoSeven®), PCCs-activated like (Feiba®) or non-activated threefactor (i.e. Profilnine®, Bebulin®), or four-factor PCCs (i.e. Beriplex®, Octaplex®, Kanokad®) are all commercially available coagulation factor products that stimulates thrombin generation. In the absence of a specific antidote for NOACs, these haemostatic agents have been extensively investigated as potential drugs for reversal. In a recent study by Eerenberg et al., 50 mg/kg of PCC reversed the effect of rivaroxaban but not dabigatran in healthy volunteers.30 In a comparable study, PCC, aPCC and rFVIIa all improved thrombin generation parameters in healthy volunteers receiving oral rivaroxaban or dabigatran.31 Although these results are supported by animal studies, human data and studies with clinical endpoints like bleeding are highly warranted.32 In a case series of five patients treated with dabigatran, Diaz et al. reported successful cessation of bleeding in four of five patients treated with PCC.33 In animal bleeding models, recombinant activated factor VII and PCC improved laboratory measures of coagulation after treatment with rivaroxaban but failed to reduce blood loss.34,35 Importantly, is must be emphasised that both PCC and rFVIIa are potent activators of in vivo blood coagulation and the use of these agents has been associated with increased risks of thromboembolic complications.36 This risk must be acknowledged and taken into account, when considering the use of these haemostatic agents. In our opinion, the evidence is insufficient to recommend first-line treatment with rFVII, aPCC or PCC in patients with bleeding not considered life threatening. On the other hand, these haemostatic agents may be considered in situations with ongoing life-threatening
6
bleeding. While awaiting further clinical trials on the effectiveness and potential dosage of these drugs, the following treatment may be initiated: PCC (e.g. Beriplex®, Octaplex®) 25 U/kg; repeat 1×/2× if indicated or aPCC (Feiba®) 50 IU/kg; max 200 IU/ kg/day although human data, especially on reversal of dabigatran, are lacking.37–40
Haemodialysis Because protein binding is only approximately 35%, dabigatran can be dialysed,41 and this may be useful in case of overdosing, urgent surgery or major bleeding. However, acute dialysis in a potentially haemodynamic unstable bleeding patient may limit the clinical usefulness. One case report reported successful management of a severe dabigatraninduced post-operative bleeding with dialysis and high-dose rFVIIa.42 Due to the high degree of protein-bound rivaroxaban and apixaban, haemodialysis is not indicated.
Management of regional anaesthesia in patients on NOACs Regional anaesthesia is to be considered as a highrisk surgical procedure because of the seriousness of a potential bleeding complication. Thus, based on the last intake of NOAC and evaluation of renal function, regional anaesthesia should be postponed 48–72 h as listed in Table 2. Even though platelet count, aPTT and PT/INR are within the reference interval before 48–72 h, there is so far not evidence to support regional anaesthesia even though these recommendations are slightly more conservative than guidelines published by the European Society of Anaesthesiology in 2010.43 For procedures with clinically sufficient haemostasis, the NOAC therapy can be resumed 6–8 h after the intervention. However, avoidance of thromboembolic events by resuming NOAC therapy shortly after surgical procedures should be outweighed against an increased bleeding risk.
Summary Blood coagulation is an essential part of haemostasis, and several anticoagulant drugs are available to prevent and treat thromboembolic disease. In addition to classic anticoagulants such as vitamin K antagonists, several NOACs have recently been introduced. These drugs offer several advantages compared with vitamin K antagonists, and an increased use of these drugs is expected, e.g. in patients with atrial fibrillation. Importantly, some
NOACs and bleeding complications
important issues must be acknowledged by clinicians responsible for patients treated with these drugs. Firstly, elderly patients and patients with reduced renal function have an increased risk of bleeding, and measuring renal function is of paramount importance prior to initiation of therapy with NOACS. Similarly, there is evidence supporting that concomitant treatment with NSAIDS or antiplatelet drugs increase the risk of bleeding in patients treated with NOACS and, therefore, avoiding these combinations or reducing the dose of NOAC should be considered.9,44 Finally, no specific antidotes are presently available, and we currently only have limited information on how to monitor and manage patients with bleeding complications during treatment with NOACs. Methods for measurements of drug concentrations have been established, although a correlation between a given plasma drug concentration and the likelihood of bleeding has not been firmly established. Standard laboratory assays like PT and APTT may be used as a crude estimation of the actual anticoagulation status but are not sensitive enough to decide if for instance regional anaesthesia can be safely undertaken. More importantly, sensitivity and variability of APPT and PT measurements from patients on NOAC depend of the reagent used, and it is therefore important to obtain more knowledge of these reagents. To ensure sufficient and proper coagulation capacity of the clotting factors inhibited by NOACs, the most reliable method is to delay surgery/ intervention until at least four times the half-life has passed. In situations with ongoing bleeding in patients treated with NOACs, administration of a procoagulant drug may by reasonable to support haemostasis. Currently, PCC seems to provide a better clinical bleeding outcome compared with recombinant-activated factor VII and especially FFP. Further clinical studies are warranted to determine optimal monitoring and ways of reversing the effect of NOACs.
Acknowledgements Signe Harley Nygaard Moore, Aarhus University hospital is acknowledged for graphical support. Conflicts of interest: The authors have no conflicts to declare. Funding: The study was supported by internal funding only.
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Address: Mr Christian Fenger-Eriksen Department of Anaesthesia and Intensive Care Viborg Regional Hospital Heibergs Alle 8800 Viborg Denmark e-mail: [email protected]
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