Topical Review Anticoagulant-Associated Intracranial Hemorrhage in the Era of Reversal Agents Thorsten Steiner, MD, MME; Jeffrey I. Weitz, MD; Roland Veltkamp, MD
I
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n patients taking oral anticoagulants (OACs), the annual rate of intracranial hemorrhage is 0.3% to 0.6%. Of these bleeds, 46% to 86% are intracerebral; 13% to 45% are subdural, and 1% to 8% are subarachnoidal.1,2 With 30- to 90-day mortality rates of 40% to 65%, intracerebral hemorrhage (ICH) has the worst prognosis. When we published a review on OAC-associated ICH in 2006, vitamin K antagonists (VKAs), such as warfarin, were the only available OAC.3 Since then, the options have expanded to include 4 direct OACs (DOACs; Table I in the online-only Data Supplement): dabigatran, which inhibits thrombin, and rivaroxaban, apixaban, and edoxaban, which inhibit factor Xa. For long-term use, the DOACs are licensed for stroke prevention in nonvalvular atrial fibrillation and for treatment of venous thromboembolism. Their approval was based on randomized controlled trials that compared them with warfarin for stroke prevention in >71 000 patients with nonvalvular AF4 and with VKAs in >27 000 patients with venous thromboembolism.5–8 These trials revealed that the DOACs were at least as effective as VKAs but were associated with less bleeding, particularly less ICH.9 With similar efficacy, better safety, and greater convenience compared with VKAs, most current guidelines recommend DOACs over VKAs for stroke prevention in atrial fibrillation and for treatment of venous thromboembolism. It is not surprising, therefore, that prescriptions for DOACs have overtaken those for VKAs in some countries.10 Despite the rapid uptake of the DOACs, however, at least 40% of patients continue to receive VKAs.10 Focusing on ICH in patients receiving OAC, this article (1) reviews the currently available evidence on reversal of DOACs and VKAs, (2) provides recommendations about reversal, and (3) identifies the remaining questions on ICH management.
also seem to be lower with DOACs than with warfarin.1,2 This article focuses on management of ICH and subdural hematomas. Management of subarachnoid hemorrhage is different and will not be discussed.
Causes of ICH and Hematoma Expansion Intracerebral bleeding is triggered by diseases of large or small cerebral vessels, which account for 15% and 85% of such bleeds, respectively. Large vessel disease includes arterial aneurysms, arteriovenous malformations, dural fistulas, and venous malformations. The major process underlying small vessel disease is deposition of extracellular material in the vessel wall. These deposits include lipid in the case of lipohyalinosis, which usually affects the penetrating arteries as a complication of longstanding hypertension,11 and ß-amyloid in cerebral amyloid angiopathy, which affects brain arterioles and capillaries and can lead to microaneurysm formation. In general, intracerebral bleeding in patients with hypertensive angiopathy occurs in deep cerebral locations, whereas bleeding with cerebral amyloid angiopathy is more often lobar. Current thinking is that intracerebral bleeding in patients taking OAC reflects spontaneous bleeding that is exacerbated by anticoagulation. Therefore, OAC sustains intracerebral hematoma formation but does not cause it. In most cases, intracerebral bleeding is fatal if there is hematoma expansion. Such expansion occurs as the result of the vessel-tissue pressure gradient and shear forces.12 The vessel-tissue pressure gradient is highest in the early stages of intracerebral bleeding immediately after vessel rupture. With hematoma expansion, the gradient decreases as the blood that leaks out of the vessel surrounds it and counteracts the tissue pressure from the leak. Expansion may be progressive if shear forces lead to rupture of adjacent diseased vessels or microaneurysms, thereby augmenting blood loss.13 In patients not on OAC, hematoma expansion occurs in 30% to 40% of patients within 3 to 6 hours after symptom onset. Rates of hematoma expansion are higher in patients taking VKAs; prospective studies report rates of hematoma expansion of 54%, whereas retrospective studies report rates
Burden of Anticoagulant-Associated ICH The annual rate of ICH ranges from 0.3% to 0.6% in patients taking VKAs and from 0.1% to 0.2% in those taking DOACs.1,2 DOACs are associated with an overall 50% reduction in the rate of ICH.4 Rates of subdural and subarachnoid hemorrhage
Received September 27, 2016; final revision received February 5, 2017; accepted February 9, 2017. From the Department of Neurology, Klinikum Frankfurt Höchst, Germany (T.S.); Department of Neurology, Heidelberg University Hospital, Germany (T.S., R.V.); Thrombosis and Atherosclerosis Research Institute and the Departments of Medicine and Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada (J.I.W.); and Department of Stroke, Medicine, Imperial College, London, United Kingdom (R.V.). The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA. 116.013343/-/DC1. Correspondence to Thorsten Steiner, MD, MME, Department of Neurology, Klinikum Frankfurt Höchst, Gotenstr. 6–8, 65929 Frankfurt, Germany. E-mail [email protected] (Stroke. 2017;48:1432-1437. DOI: 10.1161/STROKEAHA.116.013343.) © 2017 American Heart Association, Inc. Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.116.013343
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Steiner et al Reversal of Anticoagulant-Related ICH 1433 of 36%.14,15 Although in most cases hematoma expansion occurs within the first few hours of symptom onset, expansion can be delayed, and delayed hematoma expansion occurs more frequently in patients taking VKAs than in those not receiving anticoagulants.15 There are limited data on the frequency of hematoma expansion with DOACs. In a prospective study that enrolled 61 DOAC-treated patients presenting with ICH within 24 hours of symptom onset, 38% had hematoma expansion.16 Consequently, hematoma expansion seems to be a common complication of intracerebral hemorrhage regardless of whether patients are taking VKAs or DOACs. Therefore, once the diagnosis of intracerebral bleeding is established, anticoagulant reversal should be undertaken as soon as possible.13
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Coagulation Testing in ICH Patients to Identify Suitability for Reversal Selection of the appropriate coagulation test to determine the extent of anticoagulant activity and to assess the degree of reversal depends on which OAC the patient is taking. VKAs are monitored using the international normalized ratio (INR). The INR is widely available with rapid turnaround, and with point-of-care devices, the INR can be determined at the bedside. The INR is based on the prothrombin time (PT), a test that determines how long it takes for a clot to form after tissue factor is added to plasma. Tissue factor reagents vary in their responsiveness to reductions in the vitamin K–dependent clotting factors. To standardize them, manufacturers assign an international sensitivity index to each batch of reagent by comparing its responsiveness with that of an international reference standard. Sensitive reagents have international sensitivity index values between 0.94 and 1.4. The INR is derived by dividing the patient’s PT by the laboratory reference PT and raising this ratio to the power of the international sensitivity index. Routine coagulation tests are less useful for measuring the anticoagulant effects of the DOACs. Dabigatran has the greatest effect on the activated partial thromboplastin time (aPTT), whereas rivaroxaban, apixaban, and edoxaban have a greater effect on the PT than the aPTT. However, the effect of the DOACs on these tests is reagent dependent, and even with the most sensitive reagents, rivaroxaban and edoxaban affect the PT more than apixaban.17 Although one small study suggested that the INR measured using a point-of-care device is useful for assessing the extent of rivaroxaban anticoagulation in acute stroke patients, these results require confirmation.18 The thrombin time is the most sensitive test for dabigatran. The test is performed by adding thrombin to plasma and determining the time to clot formation. However, the assay is not standardized with respect to the amount or source of thrombin, and some laboratories include calcium, whereas others do not. Regardless of the procedure, the thrombin time is so sensitive to the effect of thrombin inhibitors that the test is prolonged even with low concentrations of dabigatran. Therefore, a normal test result in a patient with ICH excludes the presence of clinically relevant dabigatran concentrations and obviates the need for reversal.
The diluted thrombin time was introduced to render the test less sensitive to dabigatran. The assay is performed by diluting the plasma 8-fold with control plasma before adding thrombin and measuring the time to clot formation. Using a calibration curve constructed with calibrants containing known concentrations of dabigatran, the dabigatran level in the patient plasma can be determined. Reversal should be considered if the dabigatran concentration exceeds 30 ng/mL, the lower limit of quantification of the assay. Dabigatran concentrations can also be quantified using the ecarin clot time (ECT) or ecarin chromogenic assay. Ecarin is a snake venom that converts prothrombin to meizothrombin, a prothrombin intermediate clots fibrinogen and cleaves a chromogenic substrate and is sensitive to inhibition by dabigatran. Therefore, dabigatran prolongs the ECT and attenuates meizothrombin-induced cleavage of the chromogenic substrate in a concentration-dependent manner. By comparing the clotting time or color change with that in a calibration curve constructed with samples containing known amounts of dabigatran, the dabigatran concentration can be quantified. The lower limit of quantification is ≈20 ng/mL and reversal should be considered if the level is >30 ng/mL. Calibrated anti–factor Xa assays are available to quantify plasma levels of rivaroxaban, apixaban, or edoxaban. The tests are performed by adding factor Xa to plasma containing a chromogenic factor Xa–directed substrate. Factor Xa cleaves the substrate and generates color that is quantified using a plate reader. By inhibiting factor Xa, rivaroxaban, apixaban, and edoxaban reduce this color change in a concentration-dependent manner. Comparison with standard curves constructed with samples containing known concentrations of these drugs permits quantification of the drug level in patient samples. Reversal should be considered if drug levels exceed 30 ng/mL. Although the PT, INR, aPTT, and thrombin time are widely available, the diluted thrombin time, ECT, ecarin chromogenic assay, and anti–factor Xa assay are not. Furthermore, even when these tests are available, access may not be possible around the clock, and the turnaround time may be slow. These limitations underscore the need for readily and rapidly available tests to measure DOAC levels. The Working Group on Perioperative Haemostasis suggests that no reversal is required if the plasma concentration of dabigatran is ≤30 ng/ mL (or if the aPTT ratio is ≤1.2) or if the concentration of rivaroxaban is ≤30 ng/mL (or the PT ratio using a sensitive reagent is ≤1.2; Table II in the online-only Data Supplement).19
Reversal of OACs Reversal of VKAs The cornerstones of reversal of VKAs in patients with ICH are vitamin K and prothrombin complex concentrate (PCC) (Table). Fresh frozen plasma (FFP) should not be used for this indication unless PCC is unavailable. Likewise, rFVIIa should be avoided because it only replaces factor VIIa and not the other vitamin K–dependent clotting factors. Vitamin K Vitamin K should be given intravenously because it produces more rapid reversal than oral vitamin K, and oral administration
1434 Stroke May 2017 Table.
Reversal Agents for Oral Anticoagulants
Trade Name (Active Component), Manufacturer
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Target Substance(s)
Mechanism of Action
AndexXa (Andexanet alfa), Portola Pharmaceuticals
Factor Xa inhibitors, heparin, LMWH, and fondaparinux
Recombinant variant of human factor Xa that competes with native factor Xa for binding of rivaroxaban, apixaban, and edoxaban, and the heparin–, low-molecular-weight heparin–, and fondaparinux–antithrombin complex
(Ciraparantag, Aripazine), Perosphere Inc
Universal antidote
Charge-dependent, hydrogen bonding to apixaban, edoxaban, rivaroxaban, dabigatran, heparin, low-molecular-weight heparin, and fondaparinux
Praxbind (Idarucizumab), Boehringer Ingelheim
Dabigatran
3-factor or 4-factor-PCC: several commercial providers
Vitamin-K antagonists
Noncompetitive, specific, and direct binding of dabigatran Replacement of factors II, IX, X, and VII (4-factor PCC); protein C, S, and Z in some products
Suggested Dose
Price
Approval Status
Not yet available
Not yet approved
300 mg bolus
Not yet available
Not yet approved
5 g intravenous bolus
≈€3500 (5 g)*
Approved
25–50 U/kg IV
≈€100 for 4-factor PCC (500 U)
Approved suggested*
400 mg intravenous bolus followed by an intravenous infusion of 480 mg over 2 h for reversal of apixaban or rivaroxaban if >7 h previously and 800 mg followed by an infusion of 960 mg over 2 h for those taking rivaroxaban or rivaroxaban if ≤7 h previously or edoxaban
LMWH indicates low molecular weight heparin; and PCC, prothrombin complex concentrate. *Lower costs apply in some countries.
is problematic if the patient is obtunded. Intravenous vitamin K should be administered >20 to 30 minutes to reduce the risk of anaphylactoid reactions. Subcutaneous and intramuscular vitamin K should be avoided because absorption from these sites may be erratic. Even when vitamin K is given intravenously, it takes at least 12 hours to reduce the INR to normal levels. Therefore, PCC must be given in conjunction with vitamin K to provide rapid replacement of the missing clotting factors. Prothrombin Complex Concentrate Available in 3- and 4-factor format, 4-factor PCC is preferred because it contains a full complement of factor VII and factor IX, factor X, and prothrombin (Table). In contrast, 3-factor PCC contains little or no factor VII.20 PCC is superior to FFP for VKA reversal in ICH patients based on the results of the INR normalization in patients with ICH related to VKA trial.21 This study compared 4-factor PCC with FFP for normalization of the INR within 3 hours of admission in 50 ICH patients presenting within 12 hours of symptom onset.22 Compared with FFP, 4-factor PCC more effectively normalized the INR and significantly reduced the risk of hematoma expansion at 3 and 24 hours. By 48 hours, there were 5 deaths because of hematoma expansion in the FFP group and none in the group given PCC. These findings are supported by the results of other trials.23,24 rVIIa Although rFVIIa lowers the INR in patients on VKAs who present with ICH, it does not restore thrombin generation nor does it affect the duration of bleeding.25 In addition, rFVIIa has been associated with thrombotic events.26 Therefore, rFVIIa should not be used for VKA reversal.
Reversal of DOACs Specific Reversal Agents Idarucizumab Idarucizumab (Praxbind) is a Fab fragment of a humanized antibody against dabigatran that was licensed in 2015 and is now available worldwide (Table). It binds dabigatran with 350-fold higher affinity than thrombin to form a 1:1 stoichiometric complex that is cleared via the kidneys.27 In healthy volunteers with normal or moderately impaired renal function, idarucizumab rapidly and completely reversed the anticoagulant effects of dabigatran.28 Readministration of dabigatran 24 hours after idarucizumab administration produced full anticoagulation, and idarucizumab has been given more than once to volunteers without loss of activity.28 The REVERSE-AD study (Reversal Effects of Idarucizumab on Active Dabigatran; clinicaltrials.gov NCT02104947) was recently completed.29 This prospective cohort study enrolled 504 dabigatran-treated patients requiring reversal because of life-threatening or uncontrolled bleeding including ICH (group A) or requiring emergency surgery or urgent procedures that could not be delayed for at least 8 hours (group B). All patients were given 5 g of intravenous idarucizumab given as 2 boluses each of 2.5 g no more than 15 minutes apart. The primary efficacy end point was the percentage reversal of the anticoagulant effects of dabigatran within 4 hours of idarucizumab administration as determined using the diluted thrombin time and ECT. Results in the first 90 patients were reported in 201530 and those on the subsequent 494 patients were recently presented (298 in group A and 196 in group B).31 At 4 hours after idarucizumab administration, the median maximum reversal was 100% for the diluted thrombin time, ECT, and aPTT. In group
Steiner et al Reversal of Anticoagulant-Related ICH 1435 B, 93% of patients had normal periprocedural hemostasis. Information on the use of idarucizumab in ICH is still only available from the report on the first 90 patients. Of the 51 patients in group A, 18 presented with ICH. Idarucizumab normalized coagulation tests to the same extent in these patients as it did in those with major bleeding in other sites. No data on hematoma expansion in the ICH cohort have been reported, and such information will be difficult to obtain because early follow-up imaging was only performed in 9 of the 18 patients. The mortality rate in the 18 patients with ICH was 22.5%, whereas the mortality rate in the remaining 33 patients with major bleeding in other sites was 15%. By comparison, mortality rates with ICH in patients in the RE-LY study were 41%, 35%, and 36% with dabigatran 110 mg, dabigatran 150 mg, and warfarin, respectively.1,32 The lower mortality rate in the RE-VERSE AD study should be interpreted with caution, however, because there was no control group in the study. Downloaded from http://stroke.ahajournals.org/ by guest on October 21, 2017
Andexanet alfa Andexanet alfa (AndexXa) is a recombinant variant of human factor Xa that has its active site serine residue replaced with an arginine residue to eliminate catalytic activity and its membranebinding γ-carboxyglutamic acid domain removed to prevent incorporation in prothrombinase (Table). Andexanet acts by binding rivaroxaban, apixaban, and edoxaban with affinities similar to that of native factor Xa, thereby serving as a decoy that sequesters the drugs until they can be cleared. Andexanet alfa also reverses the anticoagulant effects of heparin, low-molecular-weight heparin and fondaparinux by competing with factor Xa and thrombin for binding to the heparin–antithrombin complex.33 The ANNEXA-4 trial (Ability of Andexanet Alfa to Reverse the Anticoagulant Activity-4; clinicaltrials.gov NCT02329327) is evaluating the efficacy and safety of andexanet reversal in patients taking rivaroxaban, apixaban, edoxaban, or enoxaparin presenting with major bleeding. Patients taking apixaban and those whose last dose of rivaroxaban was taken >7 hours previously receive an intravenous bolus of 400 mg followed by an infusion of 480 mg over 120 minutes. Patients receiving enoxaparin or those who took their last dose of rivaroxaban 20% but ≤30% compared with baseline) in 10 of the 12 ICH patients. Andexanet alfa is under consideration for approval by several regulatory agencies, but even if approved, it is unlikely to be available until 2018. Ciraparantag Ciraparantag (PER977) is a synthetic, water-soluble, cationic small molecule that was initially designed to bind to unfractionated heparin and low-molecular-weight heparin via noncovalent hydrogen bonding and charge–charge interactions (Table). Later, dynamic light-scattering studies revealed that the drug also binds dabigatran, rivaroxaban, apixaban, and edoxaban.35 In healthy volunteers given a single dose of oral edoxaban (60 mg) or subcutaneous enoxaparin (1.5 mg/kg), an intravenous bolus of ciraparantag shortened the prolonged whole blood clotting time in a concentration-dependent manner.35 The effect persisted for 24 hours, and there was no increase in the levels of D-dimer or thrombin–antithrombin complexes suggestive of a procoagulant state. The whole blood clotting time was used to monitor the effect of ciraparantag in these studies because ciraparantag binds citrate, the reagent into which blood is collected for coagulation testing. This phenomenon precludes the use of routine tests such as anti–factor Xa activity. Measurements of whole blood clotting time are not available in most hospitals, but a point-of-care microfluidic device is under development for its bedside determination. Phase III studies with ciraparantag have not been initiated, so development of this agent lags behind that of idarucizumab and andexanet alfa. Nonspecific Reversal Agents Prothrombin Complex Concentrate In volunteers given rivaroxaban or apixaban, 3- or 4-factor PCC at least partially reversed the PT and enhanced thrombin generation and in volunteers given edoxaban, 4-factor PCC attenuated bleeding from punch biopsy sites in a concentration-dependent manner. With 50 U/kg, PCC restored bleeding duration to background levels and enhanced thrombin generation.36 Although these findings are promising, solid evidence supporting the use of PCC in patients with ICH is lacking. Nonetheless, until specific reversal agents for rivaroxaban, apixaban, and edoxaban are available, PCC is the treatment of choice for patients taking these drugs who present with ICH. Activated PCC In a prospective study that included 127 patients with ICH, 50 U/kg of activated PCC (factor eight inhibitor bypassing activity) was administered.37 Of these, 6 patients were taking a DOAC. There was no hematoma expansion and no thrombotic complications in these 6 patients. Activated PCC has also been used in dabigatran-treated patients presenting with bleeding complications including one patient with ICH38 where the aPTT was partially normalized. Idarucizumab remains the treatment of choice for dabigatran reversal in patients with ICH, and activated PCC should only be used for reversal of rivaroxaban, apixaban, or edoxaban if PCC fails because there is no evidence that activated PCC is better than PCC for this indication, and the risk of thrombotic complications is likely to be greater with activated PCC than with PCC.20
1436 Stroke May 2017
Figure. Treatment algorithm for intracerebral hemorrhage related to oral anticoagulants (OACs). INR indicates international normalized ratio; PCC, prothrombin complex concentrate; and VKA, Vitamin K antagonist. *Other options can be chosen on an individual basis. Andexanet alpha is not yet available (see text).
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rFVIIa Although rFVIIa attenuated hematoma expansion in mouse models of dabigatran and rivaroxaban-associated ICH,39 data in humans are lacking. With no efficacy data and with the potential for thrombotic complications, rFVIIa should not be used for management of ICH in patients taking DOACs unless other measures have failed.
Practical Consideration for OAC Reversal OAC reversal in patients presenting with ICH should be undertaken as soon as possible. In those taking VKAs, the INR can rapidly be determined in the laboratory or with point-of-care devices, and reversal with intravenous vitamin K (5–10 mg) and PCC (30–50 U/kg) should be initiated if the iNR is >1.2 (Figure). Determination of drug levels is more complicated in patients taking DOACs. Because of their relatively short half-lives (Table I in the online-only Data Supplement), reversal may not be necessary if there is reliable evidence that the last dose was taken at least 48 hours previously. Renal and liver function and possible drug–drug interactions need to be assessed because this affects the clearance of DOACs. If there is uncertainty, however, laboratory testing may be helpful if it can be obtained rapidly. If quantitative tests are available, reversal should be undertaken in those with levels >30 ng/mL. Such reversal consists of intravenous idarucizumab (5 g) for reversal of dabigatran and PCC (50 U/kg) for reversal of rivaroxaban, apixaban, or edoxaban until specific reversal agents such as andexanet alfa and ciraparantag are available.
Unanswered Questions It remains unclear whether reversal improves clinical outcome in patients with OAC-associated ICH. Although PCC was of limited benefit in warfarin-treated patients who presented with ICH in one retrospective study, 2 others suggested that PCC alone or in combination with FFP improved outcome. In one study, the benefit of PCC was greatest when it was administered soon after presentation.14 Although the INCH trial was not powered for clinical outcomes, there was more rapid normalization of the INR and less early hematoma
expansion with PCC than with FFP.22 The impact of specific reversal agents or PCC on clinical outcomes in patients taking DOACs is uncertain. In animal models of ICH, PCC was more effective than FFP at preventing hematoma expansion39,40 and idarucizumab reduced mortality in those given dabigatran. In a pilot registry, PCC did not seem to prevent hematoma expansion, but these findings require confirmation in a setting with less potential for selection bias.16 Ideally, randomized controlled trials are needed to answer this question. However, placebo-controlled trials are likely to be considered unethical by most experts, and enrolment of sufficiently large numbers of patients to address clinical end points may not be feasible. In the interim, more information is needed about the safety and efficacy of idarucizumab, andexanet, and ciraparantag in ICH patients. Furthermore, the optimal approach to secondary stroke prevention after OAC-associated ICH needs to be determined prospectively. Finally, to streamline reversal, hospitals and regulatory agencies need to work together to ensure that quantitative tests for the DOACs are widely available with a rapid turnaround time. Development of point-of-care tests would help to rapidly identify DOAC-treated patients requiring reversal.
Disclosures Drs Steiner, Weitz, and Veltkamp disclose to have received consultancy and speaker fess from Bayer, BMS Pfizer, Boehringer Ingelheim, and Daiichy Sankyo; Dr Steiner discloses shares with NovoNordisk. Dr Veltkamp discloses to have received speaker fees from CSL Behring and significant research support from Bayer, BMS Pfizer, Boehringer Ingelheim, and Daiichy Sankyo.
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3. Steiner T, Rosand J, Diringer M. Intracerebral hemorrhage associated with oral anticoagulant therapy: current practices and unresolved questions. Stroke. 2006;37:256–262. doi: 10.1161/01.STR.0000196989.09900.f8. 4. Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a metaanalysis of randomised trials. Lancet. 2014;383:955–962. doi: 10.1016/ S0140-6736(13)62343-0. 5. Buller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366:1287–1297. doi: 10.1056/NEJMoa1113572. 6. Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, et al; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361:2342– 2352. doi: 10.1056/NEJMoa0906598. 7. Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, et al; PLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013;368:699–708. doi: 10.1056/ NEJMoa1207541. 8. Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, et al; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369:1406–1415. doi: 10.1056/NEJMoa1306638. 9. Caldeira D, Rodrigues FB, Barra M, Santos AT, de Abreu D, Gonçalves N, et al. Non-vitamin K antagonist oral anticoagulants and major bleeding-related fatality in patients with atrial fibrillation and venous thromboembolism: a systematic review and meta-analysis. Heart. 2015;101:1204–1211. doi: 10.1136/heartjnl-2015-307489. 10. Kakkar AK. Garfield-Register: Up-date, 2015. https://www.youtube. com/watch?v=0uHZCI9K-Ak; Accessed January 28, 2017. 11. Fisher CM. Hypertensive cerebral hemorrhage. Demonstration of the source of bleeding. J Neuropathol Exp Neurol. 2003;62:104–107. 12. Schlunk F, Greenberg SM. The pathophysiology of intracerebral hemorrhage formation and expansion. Transl Stroke Res. 2015;6:257–263. doi: 10.1007/s12975-015-0410-1. 13. Greenberg CH, Frosch MP, Goldstein JN, Rosand J, Greenberg SM. Modeling intracerebral hemorrhage growth and response to anticoagulation. PLoS One. 2012;7:e48458. doi: 10.1371/journal.pone.0048458. 14. Kuramatsu JB, Gerner ST, Schellinger PD, Glahn J, Endres M, Sobesky J, et al. Anticoagulant reversal, blood pressure levels, and anticoagulant resumption in patients with anticoagulation-related intracerebral hemorrhage. JAMA. 2015;313:824–836. doi: 10.1001/jama.2015.0846. 15. Flibotte JJ, Hagan N, O’Donnell J, Greenberg SM, Rosand J. Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage. Neurology. 2004;63:1059–1064. 16. Purrucker JC, Haas K, Rizos T, Khan S, Wolf M, Hennerici MG, et al. Early clinical and radiological course, management, and outcome of intracerebral hemorrhage related to new oral anticoagulants. JAMA Neurol. 2015;73:1–10. 17. Gosselin R, Grant RP, Adcock DM. Comparison of the effect of the anti-Xa direct oral anticoagulants apixaban, edoxaban, and rivaroxaban on coagulation assays. Int J Lab Hematol. 2016;38:505–513. doi: 10.1111/ijlh.12528. 18. Ebner M, Peter A, Spencer C, Härtig F, Birschmann I, Kuhn J, et al. Point-of-care testing of coagulation in patients treated with non-vitamin K antagonist oral anticoagulants. Stroke. 2015;46:2741–2747. doi: 10.1161/STROKEAHA.115.010148. 19. Pernod G, Albaladejo P, Godier A, Samama CM, Susen S, Gruel Y, et al; 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;106:382–393. doi: 10.1016/j.acvd.2013.04.009. 20. Frontera JA, Lewin JJ 3rd, Rabinstein AA, Aisiku IP, Alexandrov AW, Cook AM, et al. Guideline for reversal of antithrombotics in intracranial hemorrhage: a statement for healthcare professionals from the neurocritical care society and society of critical care medicine. Neurocrit Care. 2016;24:6–46. doi: 10.1007/s12028-015-0222-x. 21. Meretoja A, Parry-Jones A. Reply. Ann Neurol. 2016;79:332–333. doi: 10.1002/ana.24561. 22. Steiner T, Poli S, Griebe M, Hüsing J, Hajda J, Freiberger A, et al. Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial haemorrhage related to vitamin K antagonists (INCH): a randomised trial. Lancet Neurol. 2016;15:566–573. doi: 10.1016/S1474-4422(16)00110-1. 23. Sarode R, Milling TJ Jr, Refaai MA, Mangione A, Schneider A, Durn BL, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate
in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation. 2013;128:1234–1243. doi: 10.1161/CIRCULATIONAHA.113.002283. 24. Goldstein JN, Refaai MA, Milling TJ Jr, Lewis B, Goldberg-Alberts R, Hug BA, et al. Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomised trial. Lancet. 2015;385:2077–2087. doi: 10.1016/S0140-6736(14)61685-8. 25. Skolnick BE, Mathews DR, Khutoryansky NM, Pusateri AE, Carr ME. Exploratory study on the reversal of warfarin with rFVIIa in healthy subjects. Blood. 2010;116:693–701. doi: 10.1182/blood-2009-11-253492. 26. Diringer MN, Skolnick BE, Mayer SA, Steiner T, Davis SM, Brun NC, et al. Thromboembolic events with recombinant activated factor VII in spontaneous intracerebral hemorrhage: results from the Factor Seven for Acute Hemorrhagic Stroke (FAST) trial. Stroke. 2010;41:48–53. doi: 10.1161/STROKEAHA.109.561712. 27. Schiele F, van Ryn J, Canada K, Newsome C, Sepulveda E, Park J, et al. A specific antidote for dabigatran: functional and structural characterization. Blood. 2013;121:3554–3562. doi: 10.1182/blood-2012-11-468207. 28. Glund S, Stangier J, van Ryn J, Schmohl M, Moschetti V, Haazen W, et al. Restarting dabigatran etexilate 24 h after reversal with idarucizumab and redosing idarucizumab in healthy volunteers. J Am Coll Cardiol. 2016;67:1654–1656. doi: 10.1016/j.jacc.2016.01.043. 29. Pollack CV Jr, Reilly PA, Bernstein R, Dubiel R, Eikelboom J, Glund S, et al. Design and rationale for RE-VERSE AD: a phase 3 study of idarucizumab, a specific reversal agent for dabigatran. Thromb Haemost. 2015;114:198–205. doi: 10.1160/TH15-03-0192. 30. Bernstein R, Bushi W, Dubiel R, Eikelboom J, Huisman MV, Hylek E, et al. Effect of idarucizumab on intracranial bleeding - first results from RE-VERSE-AD: reversal effects of Idarucizumab in patients on active dabigatran. International Stroke Conference, American Stroke Association, Los Angeles, February 17, 2016. 31. Pollack CV, Jr., Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA, et al. American Heart Association. Abstract: updated results of the RE-VERSE AD study: idarucizumab for dabigatran reversal in patients with serious bleeding or requiring urgent surgery or interventions, 2016. https://professional.heart.org/professional/EducationMeetings/ MeetingsLiveCME/ScientificSessions/UCM_489715_Science-News— SS16-Clinical-Science-Special-Reports.jsp. Accessed January 28, 2017. 32. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–1151. doi: 10.1056/NEJMoa0905561. 33. Lu G, DeGuzman FR, Hollenbach SJ, Karbarz MJ, Abe K, Lee G, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med. 2013;19:446–451. doi: 10.1038/nm.3102. 34. Connolly SJ, Milling TJ Jr, Eikelboom JW, Gibson CM, Curnutte JT, Gold A, et al; ANNEXA-4 Investigators. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med. 2016;375:1131–1141. doi: 10.1056/NEJMoa1607887. 35. Ansell JE, Bakhru SH, Laulicht BE, Steiner SS, Grosso M, Brown K, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med. 2014;371:2141–2142. doi: 10.1056/NEJMc1411800. 36. Zahir H, Brown KS, Vandell AG, Desai M, Maa JF, Dishy V, et al. Edoxaban effects on bleeding following punch biopsy and reversal by a 4-factor prothrombin complex concentrate. Circulation. 2015;131:82– 90. doi: 10.1161/CIRCULATIONAHA.114.013445. 37. Dibu JR, Weimer JM, Ahrens C, Manno E, Frontera JA. The role of FEIBA in reversing novel oral anticoagulants in intracerebral hemorrhage. Neurocrit Care. 2016;24:413–419. doi: 10.1007/s12028-015-0213-y. 38. Faust AC, Peterson EJ. Management of dabigatran-associated intracerebral and intraventricular hemorrhage: a case report. J Emerg Med. 2014;46:525–529. doi: 10.1016/j.jemermed.2013.11.097. 39. Zhou W, Zorn M, Nawroth P, Bütehorn U, Perzborn E, Heitmeier S, et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with rivaroxaban. Stroke. 2013;44:771–778. doi: 10.1161/ STROKEAHA.112.675231. 40. Zhou W, Schwarting S, Illanes S, Liesz A, Middelhoff M, Zorn M, et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke. 2011;42:3594– 3599. doi: 10.1161/STROKEAHA.111.624650. Key Words: intracerebral hemorrhage ◼ oral anticoagulant ◼ reversal agent ◼ vitamin K antagonist
Anticoagulant-Associated Intracranial Hemorrhage in the Era of Reversal Agents Thorsten Steiner, Jeffrey I. Weitz and Roland Veltkamp
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Stroke. 2017;48:1432-1437; originally published online April 11, 2017; doi: 10.1161/STROKEAHA.116.013343 Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2017 American Heart Association, Inc. All rights reserved. Print ISSN: 0039-2499. Online ISSN: 1524-4628
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://stroke.ahajournals.org/content/48/5/1432
Data Supplement (unedited) at: http://stroke.ahajournals.org/content/suppl/2017/04/11/STROKEAHA.116.013343.DC1
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SUPPLEMENTAL MATERIAL
Supplemental table I: Practically relevant characteristics of oral anticogulants
Peak values (hrs) Half-life (hrs)
Excretion
Dabigatran
Apixaban
Rivaroxaban
Edoxaban
2–3
1–4
2–4
1–2
12–17
9 - 14
5 - 13
10 – 14
80% renal
30% renal
70% liver, 30% renal
50 % renal
P-gp P-gp competition, competition, CYP3A4 CYP3A4 CYP3A4 inhibitors inhibitors inhibitors P-gp: P-glycoprotein; CYP3A4: cytochrome P450 3A4 Drug-drug interaction
P-gp competition, no data
Vitamin-K-antagonists
Acenocoumarol: 9 hours Warfarin : 2 days Phenprocoumon: 7 days Hepatic, (warfarin in parts renal) Numerous
1
Supplemental table II: Effects of DOACs on coagulation tests and expert recommendation for the indication for reversal agents modified according to 1 Dabigatran
Rivaroxaban
Apixaban
Edoxaban
VKA
(é) to é
(é)
(é)
(é)
(é)
Prothrombin time (PT)
(é)
é to éé
(é)
é to éé
ééé
INR
(é)
é to éé
(é)
é to éé
ééé
Activated partial thromboplastin time (aPTT)
Global routine tests
Guide for indication for a reversal agents
Not specific but sensitive tests
Sensitive and specific tests
Insufficiently sensitive/specific
INR > 1.2
Thrombin time (TT)
ééé
Not applicable
Not applicable
Ecarin clotting time (ECT)
ééé
Not applicable
Not applicable
Heparin anti-Xa activity
Not applicable
Guide for indication for a reversal agents
TT < 3 x upper b limit of normal
Guide for indication a reversal agents
for
ééé
ééé
Anti Xa < 0.3 U LMWH
ééé
Not applicable
c
Diluted thrombin time
anti- factorXa activity calibrated for rivaroxaban
anti-factor Xa activity calibrated for apixaban
anti-factor Xa activity calibrated for edoxaban
INR
TT < 3 x upper b limit of normal
Functional concentration < 30 d ng/ml
Functional concentration < 30 d ng/ml
Functional concentration < 30 d ng/ml
> 1.2
aThese
are guidelines only and management must be individualized to each patient. recommendation by the authors. cCorresponds to 30 ng/ml; NOAC-calibrated assays should be used whenever possible. dIf measured>4 h after drug administration; extrapolated from published recommendations for surgery25 and supersedes older recommendations. INR, international normalized ratio; LMWH, low-molecular weight heparin; N/A: Not applicable bExpert
2
References 1.
Drouet L, Bal Dit Sollier C, Steiner T, Purrucker J. Measuring non-vitamin K antagonist oral anticoagulant levels: When is it appropriate and which methods should be used? Int J Stroke. 2016;11:748-758
3
I
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n patients taking oral anticoagulants (OACs), the annual rate of intracranial hemorrhage is 0.3% to 0.6%. Of these bleeds, 46% to 86% are intracerebral; 13% to 45% are subdural, and 1% to 8% are subarachnoidal.1,2 With 30- to 90-day mortality rates of 40% to 65%, intracerebral hemorrhage (ICH) has the worst prognosis. When we published a review on OAC-associated ICH in 2006, vitamin K antagonists (VKAs), such as warfarin, were the only available OAC.3 Since then, the options have expanded to include 4 direct OACs (DOACs; Table I in the online-only Data Supplement): dabigatran, which inhibits thrombin, and rivaroxaban, apixaban, and edoxaban, which inhibit factor Xa. For long-term use, the DOACs are licensed for stroke prevention in nonvalvular atrial fibrillation and for treatment of venous thromboembolism. Their approval was based on randomized controlled trials that compared them with warfarin for stroke prevention in >71 000 patients with nonvalvular AF4 and with VKAs in >27 000 patients with venous thromboembolism.5–8 These trials revealed that the DOACs were at least as effective as VKAs but were associated with less bleeding, particularly less ICH.9 With similar efficacy, better safety, and greater convenience compared with VKAs, most current guidelines recommend DOACs over VKAs for stroke prevention in atrial fibrillation and for treatment of venous thromboembolism. It is not surprising, therefore, that prescriptions for DOACs have overtaken those for VKAs in some countries.10 Despite the rapid uptake of the DOACs, however, at least 40% of patients continue to receive VKAs.10 Focusing on ICH in patients receiving OAC, this article (1) reviews the currently available evidence on reversal of DOACs and VKAs, (2) provides recommendations about reversal, and (3) identifies the remaining questions on ICH management.
also seem to be lower with DOACs than with warfarin.1,2 This article focuses on management of ICH and subdural hematomas. Management of subarachnoid hemorrhage is different and will not be discussed.
Causes of ICH and Hematoma Expansion Intracerebral bleeding is triggered by diseases of large or small cerebral vessels, which account for 15% and 85% of such bleeds, respectively. Large vessel disease includes arterial aneurysms, arteriovenous malformations, dural fistulas, and venous malformations. The major process underlying small vessel disease is deposition of extracellular material in the vessel wall. These deposits include lipid in the case of lipohyalinosis, which usually affects the penetrating arteries as a complication of longstanding hypertension,11 and ß-amyloid in cerebral amyloid angiopathy, which affects brain arterioles and capillaries and can lead to microaneurysm formation. In general, intracerebral bleeding in patients with hypertensive angiopathy occurs in deep cerebral locations, whereas bleeding with cerebral amyloid angiopathy is more often lobar. Current thinking is that intracerebral bleeding in patients taking OAC reflects spontaneous bleeding that is exacerbated by anticoagulation. Therefore, OAC sustains intracerebral hematoma formation but does not cause it. In most cases, intracerebral bleeding is fatal if there is hematoma expansion. Such expansion occurs as the result of the vessel-tissue pressure gradient and shear forces.12 The vessel-tissue pressure gradient is highest in the early stages of intracerebral bleeding immediately after vessel rupture. With hematoma expansion, the gradient decreases as the blood that leaks out of the vessel surrounds it and counteracts the tissue pressure from the leak. Expansion may be progressive if shear forces lead to rupture of adjacent diseased vessels or microaneurysms, thereby augmenting blood loss.13 In patients not on OAC, hematoma expansion occurs in 30% to 40% of patients within 3 to 6 hours after symptom onset. Rates of hematoma expansion are higher in patients taking VKAs; prospective studies report rates of hematoma expansion of 54%, whereas retrospective studies report rates
Burden of Anticoagulant-Associated ICH The annual rate of ICH ranges from 0.3% to 0.6% in patients taking VKAs and from 0.1% to 0.2% in those taking DOACs.1,2 DOACs are associated with an overall 50% reduction in the rate of ICH.4 Rates of subdural and subarachnoid hemorrhage
Received September 27, 2016; final revision received February 5, 2017; accepted February 9, 2017. From the Department of Neurology, Klinikum Frankfurt Höchst, Germany (T.S.); Department of Neurology, Heidelberg University Hospital, Germany (T.S., R.V.); Thrombosis and Atherosclerosis Research Institute and the Departments of Medicine and Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada (J.I.W.); and Department of Stroke, Medicine, Imperial College, London, United Kingdom (R.V.). The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA. 116.013343/-/DC1. Correspondence to Thorsten Steiner, MD, MME, Department of Neurology, Klinikum Frankfurt Höchst, Gotenstr. 6–8, 65929 Frankfurt, Germany. E-mail [email protected] (Stroke. 2017;48:1432-1437. DOI: 10.1161/STROKEAHA.116.013343.) © 2017 American Heart Association, Inc. Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.116.013343
1432
Steiner et al Reversal of Anticoagulant-Related ICH 1433 of 36%.14,15 Although in most cases hematoma expansion occurs within the first few hours of symptom onset, expansion can be delayed, and delayed hematoma expansion occurs more frequently in patients taking VKAs than in those not receiving anticoagulants.15 There are limited data on the frequency of hematoma expansion with DOACs. In a prospective study that enrolled 61 DOAC-treated patients presenting with ICH within 24 hours of symptom onset, 38% had hematoma expansion.16 Consequently, hematoma expansion seems to be a common complication of intracerebral hemorrhage regardless of whether patients are taking VKAs or DOACs. Therefore, once the diagnosis of intracerebral bleeding is established, anticoagulant reversal should be undertaken as soon as possible.13
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Coagulation Testing in ICH Patients to Identify Suitability for Reversal Selection of the appropriate coagulation test to determine the extent of anticoagulant activity and to assess the degree of reversal depends on which OAC the patient is taking. VKAs are monitored using the international normalized ratio (INR). The INR is widely available with rapid turnaround, and with point-of-care devices, the INR can be determined at the bedside. The INR is based on the prothrombin time (PT), a test that determines how long it takes for a clot to form after tissue factor is added to plasma. Tissue factor reagents vary in their responsiveness to reductions in the vitamin K–dependent clotting factors. To standardize them, manufacturers assign an international sensitivity index to each batch of reagent by comparing its responsiveness with that of an international reference standard. Sensitive reagents have international sensitivity index values between 0.94 and 1.4. The INR is derived by dividing the patient’s PT by the laboratory reference PT and raising this ratio to the power of the international sensitivity index. Routine coagulation tests are less useful for measuring the anticoagulant effects of the DOACs. Dabigatran has the greatest effect on the activated partial thromboplastin time (aPTT), whereas rivaroxaban, apixaban, and edoxaban have a greater effect on the PT than the aPTT. However, the effect of the DOACs on these tests is reagent dependent, and even with the most sensitive reagents, rivaroxaban and edoxaban affect the PT more than apixaban.17 Although one small study suggested that the INR measured using a point-of-care device is useful for assessing the extent of rivaroxaban anticoagulation in acute stroke patients, these results require confirmation.18 The thrombin time is the most sensitive test for dabigatran. The test is performed by adding thrombin to plasma and determining the time to clot formation. However, the assay is not standardized with respect to the amount or source of thrombin, and some laboratories include calcium, whereas others do not. Regardless of the procedure, the thrombin time is so sensitive to the effect of thrombin inhibitors that the test is prolonged even with low concentrations of dabigatran. Therefore, a normal test result in a patient with ICH excludes the presence of clinically relevant dabigatran concentrations and obviates the need for reversal.
The diluted thrombin time was introduced to render the test less sensitive to dabigatran. The assay is performed by diluting the plasma 8-fold with control plasma before adding thrombin and measuring the time to clot formation. Using a calibration curve constructed with calibrants containing known concentrations of dabigatran, the dabigatran level in the patient plasma can be determined. Reversal should be considered if the dabigatran concentration exceeds 30 ng/mL, the lower limit of quantification of the assay. Dabigatran concentrations can also be quantified using the ecarin clot time (ECT) or ecarin chromogenic assay. Ecarin is a snake venom that converts prothrombin to meizothrombin, a prothrombin intermediate clots fibrinogen and cleaves a chromogenic substrate and is sensitive to inhibition by dabigatran. Therefore, dabigatran prolongs the ECT and attenuates meizothrombin-induced cleavage of the chromogenic substrate in a concentration-dependent manner. By comparing the clotting time or color change with that in a calibration curve constructed with samples containing known amounts of dabigatran, the dabigatran concentration can be quantified. The lower limit of quantification is ≈20 ng/mL and reversal should be considered if the level is >30 ng/mL. Calibrated anti–factor Xa assays are available to quantify plasma levels of rivaroxaban, apixaban, or edoxaban. The tests are performed by adding factor Xa to plasma containing a chromogenic factor Xa–directed substrate. Factor Xa cleaves the substrate and generates color that is quantified using a plate reader. By inhibiting factor Xa, rivaroxaban, apixaban, and edoxaban reduce this color change in a concentration-dependent manner. Comparison with standard curves constructed with samples containing known concentrations of these drugs permits quantification of the drug level in patient samples. Reversal should be considered if drug levels exceed 30 ng/mL. Although the PT, INR, aPTT, and thrombin time are widely available, the diluted thrombin time, ECT, ecarin chromogenic assay, and anti–factor Xa assay are not. Furthermore, even when these tests are available, access may not be possible around the clock, and the turnaround time may be slow. These limitations underscore the need for readily and rapidly available tests to measure DOAC levels. The Working Group on Perioperative Haemostasis suggests that no reversal is required if the plasma concentration of dabigatran is ≤30 ng/ mL (or if the aPTT ratio is ≤1.2) or if the concentration of rivaroxaban is ≤30 ng/mL (or the PT ratio using a sensitive reagent is ≤1.2; Table II in the online-only Data Supplement).19
Reversal of OACs Reversal of VKAs The cornerstones of reversal of VKAs in patients with ICH are vitamin K and prothrombin complex concentrate (PCC) (Table). Fresh frozen plasma (FFP) should not be used for this indication unless PCC is unavailable. Likewise, rFVIIa should be avoided because it only replaces factor VIIa and not the other vitamin K–dependent clotting factors. Vitamin K Vitamin K should be given intravenously because it produces more rapid reversal than oral vitamin K, and oral administration
1434 Stroke May 2017 Table.
Reversal Agents for Oral Anticoagulants
Trade Name (Active Component), Manufacturer
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Target Substance(s)
Mechanism of Action
AndexXa (Andexanet alfa), Portola Pharmaceuticals
Factor Xa inhibitors, heparin, LMWH, and fondaparinux
Recombinant variant of human factor Xa that competes with native factor Xa for binding of rivaroxaban, apixaban, and edoxaban, and the heparin–, low-molecular-weight heparin–, and fondaparinux–antithrombin complex
(Ciraparantag, Aripazine), Perosphere Inc
Universal antidote
Charge-dependent, hydrogen bonding to apixaban, edoxaban, rivaroxaban, dabigatran, heparin, low-molecular-weight heparin, and fondaparinux
Praxbind (Idarucizumab), Boehringer Ingelheim
Dabigatran
3-factor or 4-factor-PCC: several commercial providers
Vitamin-K antagonists
Noncompetitive, specific, and direct binding of dabigatran Replacement of factors II, IX, X, and VII (4-factor PCC); protein C, S, and Z in some products
Suggested Dose
Price
Approval Status
Not yet available
Not yet approved
300 mg bolus
Not yet available
Not yet approved
5 g intravenous bolus
≈€3500 (5 g)*
Approved
25–50 U/kg IV
≈€100 for 4-factor PCC (500 U)
Approved suggested*
400 mg intravenous bolus followed by an intravenous infusion of 480 mg over 2 h for reversal of apixaban or rivaroxaban if >7 h previously and 800 mg followed by an infusion of 960 mg over 2 h for those taking rivaroxaban or rivaroxaban if ≤7 h previously or edoxaban
LMWH indicates low molecular weight heparin; and PCC, prothrombin complex concentrate. *Lower costs apply in some countries.
is problematic if the patient is obtunded. Intravenous vitamin K should be administered >20 to 30 minutes to reduce the risk of anaphylactoid reactions. Subcutaneous and intramuscular vitamin K should be avoided because absorption from these sites may be erratic. Even when vitamin K is given intravenously, it takes at least 12 hours to reduce the INR to normal levels. Therefore, PCC must be given in conjunction with vitamin K to provide rapid replacement of the missing clotting factors. Prothrombin Complex Concentrate Available in 3- and 4-factor format, 4-factor PCC is preferred because it contains a full complement of factor VII and factor IX, factor X, and prothrombin (Table). In contrast, 3-factor PCC contains little or no factor VII.20 PCC is superior to FFP for VKA reversal in ICH patients based on the results of the INR normalization in patients with ICH related to VKA trial.21 This study compared 4-factor PCC with FFP for normalization of the INR within 3 hours of admission in 50 ICH patients presenting within 12 hours of symptom onset.22 Compared with FFP, 4-factor PCC more effectively normalized the INR and significantly reduced the risk of hematoma expansion at 3 and 24 hours. By 48 hours, there were 5 deaths because of hematoma expansion in the FFP group and none in the group given PCC. These findings are supported by the results of other trials.23,24 rVIIa Although rFVIIa lowers the INR in patients on VKAs who present with ICH, it does not restore thrombin generation nor does it affect the duration of bleeding.25 In addition, rFVIIa has been associated with thrombotic events.26 Therefore, rFVIIa should not be used for VKA reversal.
Reversal of DOACs Specific Reversal Agents Idarucizumab Idarucizumab (Praxbind) is a Fab fragment of a humanized antibody against dabigatran that was licensed in 2015 and is now available worldwide (Table). It binds dabigatran with 350-fold higher affinity than thrombin to form a 1:1 stoichiometric complex that is cleared via the kidneys.27 In healthy volunteers with normal or moderately impaired renal function, idarucizumab rapidly and completely reversed the anticoagulant effects of dabigatran.28 Readministration of dabigatran 24 hours after idarucizumab administration produced full anticoagulation, and idarucizumab has been given more than once to volunteers without loss of activity.28 The REVERSE-AD study (Reversal Effects of Idarucizumab on Active Dabigatran; clinicaltrials.gov NCT02104947) was recently completed.29 This prospective cohort study enrolled 504 dabigatran-treated patients requiring reversal because of life-threatening or uncontrolled bleeding including ICH (group A) or requiring emergency surgery or urgent procedures that could not be delayed for at least 8 hours (group B). All patients were given 5 g of intravenous idarucizumab given as 2 boluses each of 2.5 g no more than 15 minutes apart. The primary efficacy end point was the percentage reversal of the anticoagulant effects of dabigatran within 4 hours of idarucizumab administration as determined using the diluted thrombin time and ECT. Results in the first 90 patients were reported in 201530 and those on the subsequent 494 patients were recently presented (298 in group A and 196 in group B).31 At 4 hours after idarucizumab administration, the median maximum reversal was 100% for the diluted thrombin time, ECT, and aPTT. In group
Steiner et al Reversal of Anticoagulant-Related ICH 1435 B, 93% of patients had normal periprocedural hemostasis. Information on the use of idarucizumab in ICH is still only available from the report on the first 90 patients. Of the 51 patients in group A, 18 presented with ICH. Idarucizumab normalized coagulation tests to the same extent in these patients as it did in those with major bleeding in other sites. No data on hematoma expansion in the ICH cohort have been reported, and such information will be difficult to obtain because early follow-up imaging was only performed in 9 of the 18 patients. The mortality rate in the 18 patients with ICH was 22.5%, whereas the mortality rate in the remaining 33 patients with major bleeding in other sites was 15%. By comparison, mortality rates with ICH in patients in the RE-LY study were 41%, 35%, and 36% with dabigatran 110 mg, dabigatran 150 mg, and warfarin, respectively.1,32 The lower mortality rate in the RE-VERSE AD study should be interpreted with caution, however, because there was no control group in the study. Downloaded from http://stroke.ahajournals.org/ by guest on October 21, 2017
Andexanet alfa Andexanet alfa (AndexXa) is a recombinant variant of human factor Xa that has its active site serine residue replaced with an arginine residue to eliminate catalytic activity and its membranebinding γ-carboxyglutamic acid domain removed to prevent incorporation in prothrombinase (Table). Andexanet acts by binding rivaroxaban, apixaban, and edoxaban with affinities similar to that of native factor Xa, thereby serving as a decoy that sequesters the drugs until they can be cleared. Andexanet alfa also reverses the anticoagulant effects of heparin, low-molecular-weight heparin and fondaparinux by competing with factor Xa and thrombin for binding to the heparin–antithrombin complex.33 The ANNEXA-4 trial (Ability of Andexanet Alfa to Reverse the Anticoagulant Activity-4; clinicaltrials.gov NCT02329327) is evaluating the efficacy and safety of andexanet reversal in patients taking rivaroxaban, apixaban, edoxaban, or enoxaparin presenting with major bleeding. Patients taking apixaban and those whose last dose of rivaroxaban was taken >7 hours previously receive an intravenous bolus of 400 mg followed by an infusion of 480 mg over 120 minutes. Patients receiving enoxaparin or those who took their last dose of rivaroxaban 20% but ≤30% compared with baseline) in 10 of the 12 ICH patients. Andexanet alfa is under consideration for approval by several regulatory agencies, but even if approved, it is unlikely to be available until 2018. Ciraparantag Ciraparantag (PER977) is a synthetic, water-soluble, cationic small molecule that was initially designed to bind to unfractionated heparin and low-molecular-weight heparin via noncovalent hydrogen bonding and charge–charge interactions (Table). Later, dynamic light-scattering studies revealed that the drug also binds dabigatran, rivaroxaban, apixaban, and edoxaban.35 In healthy volunteers given a single dose of oral edoxaban (60 mg) or subcutaneous enoxaparin (1.5 mg/kg), an intravenous bolus of ciraparantag shortened the prolonged whole blood clotting time in a concentration-dependent manner.35 The effect persisted for 24 hours, and there was no increase in the levels of D-dimer or thrombin–antithrombin complexes suggestive of a procoagulant state. The whole blood clotting time was used to monitor the effect of ciraparantag in these studies because ciraparantag binds citrate, the reagent into which blood is collected for coagulation testing. This phenomenon precludes the use of routine tests such as anti–factor Xa activity. Measurements of whole blood clotting time are not available in most hospitals, but a point-of-care microfluidic device is under development for its bedside determination. Phase III studies with ciraparantag have not been initiated, so development of this agent lags behind that of idarucizumab and andexanet alfa. Nonspecific Reversal Agents Prothrombin Complex Concentrate In volunteers given rivaroxaban or apixaban, 3- or 4-factor PCC at least partially reversed the PT and enhanced thrombin generation and in volunteers given edoxaban, 4-factor PCC attenuated bleeding from punch biopsy sites in a concentration-dependent manner. With 50 U/kg, PCC restored bleeding duration to background levels and enhanced thrombin generation.36 Although these findings are promising, solid evidence supporting the use of PCC in patients with ICH is lacking. Nonetheless, until specific reversal agents for rivaroxaban, apixaban, and edoxaban are available, PCC is the treatment of choice for patients taking these drugs who present with ICH. Activated PCC In a prospective study that included 127 patients with ICH, 50 U/kg of activated PCC (factor eight inhibitor bypassing activity) was administered.37 Of these, 6 patients were taking a DOAC. There was no hematoma expansion and no thrombotic complications in these 6 patients. Activated PCC has also been used in dabigatran-treated patients presenting with bleeding complications including one patient with ICH38 where the aPTT was partially normalized. Idarucizumab remains the treatment of choice for dabigatran reversal in patients with ICH, and activated PCC should only be used for reversal of rivaroxaban, apixaban, or edoxaban if PCC fails because there is no evidence that activated PCC is better than PCC for this indication, and the risk of thrombotic complications is likely to be greater with activated PCC than with PCC.20
1436 Stroke May 2017
Figure. Treatment algorithm for intracerebral hemorrhage related to oral anticoagulants (OACs). INR indicates international normalized ratio; PCC, prothrombin complex concentrate; and VKA, Vitamin K antagonist. *Other options can be chosen on an individual basis. Andexanet alpha is not yet available (see text).
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rFVIIa Although rFVIIa attenuated hematoma expansion in mouse models of dabigatran and rivaroxaban-associated ICH,39 data in humans are lacking. With no efficacy data and with the potential for thrombotic complications, rFVIIa should not be used for management of ICH in patients taking DOACs unless other measures have failed.
Practical Consideration for OAC Reversal OAC reversal in patients presenting with ICH should be undertaken as soon as possible. In those taking VKAs, the INR can rapidly be determined in the laboratory or with point-of-care devices, and reversal with intravenous vitamin K (5–10 mg) and PCC (30–50 U/kg) should be initiated if the iNR is >1.2 (Figure). Determination of drug levels is more complicated in patients taking DOACs. Because of their relatively short half-lives (Table I in the online-only Data Supplement), reversal may not be necessary if there is reliable evidence that the last dose was taken at least 48 hours previously. Renal and liver function and possible drug–drug interactions need to be assessed because this affects the clearance of DOACs. If there is uncertainty, however, laboratory testing may be helpful if it can be obtained rapidly. If quantitative tests are available, reversal should be undertaken in those with levels >30 ng/mL. Such reversal consists of intravenous idarucizumab (5 g) for reversal of dabigatran and PCC (50 U/kg) for reversal of rivaroxaban, apixaban, or edoxaban until specific reversal agents such as andexanet alfa and ciraparantag are available.
Unanswered Questions It remains unclear whether reversal improves clinical outcome in patients with OAC-associated ICH. Although PCC was of limited benefit in warfarin-treated patients who presented with ICH in one retrospective study, 2 others suggested that PCC alone or in combination with FFP improved outcome. In one study, the benefit of PCC was greatest when it was administered soon after presentation.14 Although the INCH trial was not powered for clinical outcomes, there was more rapid normalization of the INR and less early hematoma
expansion with PCC than with FFP.22 The impact of specific reversal agents or PCC on clinical outcomes in patients taking DOACs is uncertain. In animal models of ICH, PCC was more effective than FFP at preventing hematoma expansion39,40 and idarucizumab reduced mortality in those given dabigatran. In a pilot registry, PCC did not seem to prevent hematoma expansion, but these findings require confirmation in a setting with less potential for selection bias.16 Ideally, randomized controlled trials are needed to answer this question. However, placebo-controlled trials are likely to be considered unethical by most experts, and enrolment of sufficiently large numbers of patients to address clinical end points may not be feasible. In the interim, more information is needed about the safety and efficacy of idarucizumab, andexanet, and ciraparantag in ICH patients. Furthermore, the optimal approach to secondary stroke prevention after OAC-associated ICH needs to be determined prospectively. Finally, to streamline reversal, hospitals and regulatory agencies need to work together to ensure that quantitative tests for the DOACs are widely available with a rapid turnaround time. Development of point-of-care tests would help to rapidly identify DOAC-treated patients requiring reversal.
Disclosures Drs Steiner, Weitz, and Veltkamp disclose to have received consultancy and speaker fess from Bayer, BMS Pfizer, Boehringer Ingelheim, and Daiichy Sankyo; Dr Steiner discloses shares with NovoNordisk. Dr Veltkamp discloses to have received speaker fees from CSL Behring and significant research support from Bayer, BMS Pfizer, Boehringer Ingelheim, and Daiichy Sankyo.
References 1. Hart RG, Diener HC, Yang S, Connolly SJ, Wallentin L, Reilly PA, et al. Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: the RE-LY trial. Stroke. 2012;43:1511– 1517. doi: 10.1161/STROKEAHA.112.650614. 2. Hankey GJ, Stevens SR, Piccini JP, Lokhnygina Y, Mahaffey KW, Halperin JL, et al; ROCKET AF Steering Committee and Investigators. Intracranial hemorrhage among patients with atrial fibrillation anticoagulated with warfarin or rivaroxaban: the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation. Stroke. 2014;45:1304–1312. doi: 10.1161/STROKEAHA.113.004506.
Steiner et al Reversal of Anticoagulant-Related ICH 1437
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3. Steiner T, Rosand J, Diringer M. Intracerebral hemorrhage associated with oral anticoagulant therapy: current practices and unresolved questions. Stroke. 2006;37:256–262. doi: 10.1161/01.STR.0000196989.09900.f8. 4. Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a metaanalysis of randomised trials. Lancet. 2014;383:955–962. doi: 10.1016/ S0140-6736(13)62343-0. 5. Buller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366:1287–1297. doi: 10.1056/NEJMoa1113572. 6. Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, et al; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361:2342– 2352. doi: 10.1056/NEJMoa0906598. 7. Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, et al; PLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013;368:699–708. doi: 10.1056/ NEJMoa1207541. 8. Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, et al; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369:1406–1415. doi: 10.1056/NEJMoa1306638. 9. Caldeira D, Rodrigues FB, Barra M, Santos AT, de Abreu D, Gonçalves N, et al. Non-vitamin K antagonist oral anticoagulants and major bleeding-related fatality in patients with atrial fibrillation and venous thromboembolism: a systematic review and meta-analysis. Heart. 2015;101:1204–1211. doi: 10.1136/heartjnl-2015-307489. 10. Kakkar AK. Garfield-Register: Up-date, 2015. https://www.youtube. com/watch?v=0uHZCI9K-Ak; Accessed January 28, 2017. 11. Fisher CM. Hypertensive cerebral hemorrhage. Demonstration of the source of bleeding. J Neuropathol Exp Neurol. 2003;62:104–107. 12. Schlunk F, Greenberg SM. The pathophysiology of intracerebral hemorrhage formation and expansion. Transl Stroke Res. 2015;6:257–263. doi: 10.1007/s12975-015-0410-1. 13. Greenberg CH, Frosch MP, Goldstein JN, Rosand J, Greenberg SM. Modeling intracerebral hemorrhage growth and response to anticoagulation. PLoS One. 2012;7:e48458. doi: 10.1371/journal.pone.0048458. 14. Kuramatsu JB, Gerner ST, Schellinger PD, Glahn J, Endres M, Sobesky J, et al. Anticoagulant reversal, blood pressure levels, and anticoagulant resumption in patients with anticoagulation-related intracerebral hemorrhage. JAMA. 2015;313:824–836. doi: 10.1001/jama.2015.0846. 15. Flibotte JJ, Hagan N, O’Donnell J, Greenberg SM, Rosand J. Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage. Neurology. 2004;63:1059–1064. 16. Purrucker JC, Haas K, Rizos T, Khan S, Wolf M, Hennerici MG, et al. Early clinical and radiological course, management, and outcome of intracerebral hemorrhage related to new oral anticoagulants. JAMA Neurol. 2015;73:1–10. 17. Gosselin R, Grant RP, Adcock DM. Comparison of the effect of the anti-Xa direct oral anticoagulants apixaban, edoxaban, and rivaroxaban on coagulation assays. Int J Lab Hematol. 2016;38:505–513. doi: 10.1111/ijlh.12528. 18. Ebner M, Peter A, Spencer C, Härtig F, Birschmann I, Kuhn J, et al. Point-of-care testing of coagulation in patients treated with non-vitamin K antagonist oral anticoagulants. Stroke. 2015;46:2741–2747. doi: 10.1161/STROKEAHA.115.010148. 19. Pernod G, Albaladejo P, Godier A, Samama CM, Susen S, Gruel Y, et al; 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;106:382–393. doi: 10.1016/j.acvd.2013.04.009. 20. Frontera JA, Lewin JJ 3rd, Rabinstein AA, Aisiku IP, Alexandrov AW, Cook AM, et al. Guideline for reversal of antithrombotics in intracranial hemorrhage: a statement for healthcare professionals from the neurocritical care society and society of critical care medicine. Neurocrit Care. 2016;24:6–46. doi: 10.1007/s12028-015-0222-x. 21. Meretoja A, Parry-Jones A. Reply. Ann Neurol. 2016;79:332–333. doi: 10.1002/ana.24561. 22. Steiner T, Poli S, Griebe M, Hüsing J, Hajda J, Freiberger A, et al. Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial haemorrhage related to vitamin K antagonists (INCH): a randomised trial. Lancet Neurol. 2016;15:566–573. doi: 10.1016/S1474-4422(16)00110-1. 23. Sarode R, Milling TJ Jr, Refaai MA, Mangione A, Schneider A, Durn BL, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate
in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation. 2013;128:1234–1243. doi: 10.1161/CIRCULATIONAHA.113.002283. 24. Goldstein JN, Refaai MA, Milling TJ Jr, Lewis B, Goldberg-Alberts R, Hug BA, et al. Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomised trial. Lancet. 2015;385:2077–2087. doi: 10.1016/S0140-6736(14)61685-8. 25. Skolnick BE, Mathews DR, Khutoryansky NM, Pusateri AE, Carr ME. Exploratory study on the reversal of warfarin with rFVIIa in healthy subjects. Blood. 2010;116:693–701. doi: 10.1182/blood-2009-11-253492. 26. Diringer MN, Skolnick BE, Mayer SA, Steiner T, Davis SM, Brun NC, et al. Thromboembolic events with recombinant activated factor VII in spontaneous intracerebral hemorrhage: results from the Factor Seven for Acute Hemorrhagic Stroke (FAST) trial. Stroke. 2010;41:48–53. doi: 10.1161/STROKEAHA.109.561712. 27. Schiele F, van Ryn J, Canada K, Newsome C, Sepulveda E, Park J, et al. A specific antidote for dabigatran: functional and structural characterization. Blood. 2013;121:3554–3562. doi: 10.1182/blood-2012-11-468207. 28. Glund S, Stangier J, van Ryn J, Schmohl M, Moschetti V, Haazen W, et al. Restarting dabigatran etexilate 24 h after reversal with idarucizumab and redosing idarucizumab in healthy volunteers. J Am Coll Cardiol. 2016;67:1654–1656. doi: 10.1016/j.jacc.2016.01.043. 29. Pollack CV Jr, Reilly PA, Bernstein R, Dubiel R, Eikelboom J, Glund S, et al. Design and rationale for RE-VERSE AD: a phase 3 study of idarucizumab, a specific reversal agent for dabigatran. Thromb Haemost. 2015;114:198–205. doi: 10.1160/TH15-03-0192. 30. Bernstein R, Bushi W, Dubiel R, Eikelboom J, Huisman MV, Hylek E, et al. Effect of idarucizumab on intracranial bleeding - first results from RE-VERSE-AD: reversal effects of Idarucizumab in patients on active dabigatran. International Stroke Conference, American Stroke Association, Los Angeles, February 17, 2016. 31. Pollack CV, Jr., Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA, et al. American Heart Association. Abstract: updated results of the RE-VERSE AD study: idarucizumab for dabigatran reversal in patients with serious bleeding or requiring urgent surgery or interventions, 2016. https://professional.heart.org/professional/EducationMeetings/ MeetingsLiveCME/ScientificSessions/UCM_489715_Science-News— SS16-Clinical-Science-Special-Reports.jsp. Accessed January 28, 2017. 32. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–1151. doi: 10.1056/NEJMoa0905561. 33. Lu G, DeGuzman FR, Hollenbach SJ, Karbarz MJ, Abe K, Lee G, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med. 2013;19:446–451. doi: 10.1038/nm.3102. 34. Connolly SJ, Milling TJ Jr, Eikelboom JW, Gibson CM, Curnutte JT, Gold A, et al; ANNEXA-4 Investigators. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med. 2016;375:1131–1141. doi: 10.1056/NEJMoa1607887. 35. Ansell JE, Bakhru SH, Laulicht BE, Steiner SS, Grosso M, Brown K, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med. 2014;371:2141–2142. doi: 10.1056/NEJMc1411800. 36. Zahir H, Brown KS, Vandell AG, Desai M, Maa JF, Dishy V, et al. Edoxaban effects on bleeding following punch biopsy and reversal by a 4-factor prothrombin complex concentrate. Circulation. 2015;131:82– 90. doi: 10.1161/CIRCULATIONAHA.114.013445. 37. Dibu JR, Weimer JM, Ahrens C, Manno E, Frontera JA. The role of FEIBA in reversing novel oral anticoagulants in intracerebral hemorrhage. Neurocrit Care. 2016;24:413–419. doi: 10.1007/s12028-015-0213-y. 38. Faust AC, Peterson EJ. Management of dabigatran-associated intracerebral and intraventricular hemorrhage: a case report. J Emerg Med. 2014;46:525–529. doi: 10.1016/j.jemermed.2013.11.097. 39. Zhou W, Zorn M, Nawroth P, Bütehorn U, Perzborn E, Heitmeier S, et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with rivaroxaban. Stroke. 2013;44:771–778. doi: 10.1161/ STROKEAHA.112.675231. 40. Zhou W, Schwarting S, Illanes S, Liesz A, Middelhoff M, Zorn M, et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke. 2011;42:3594– 3599. doi: 10.1161/STROKEAHA.111.624650. Key Words: intracerebral hemorrhage ◼ oral anticoagulant ◼ reversal agent ◼ vitamin K antagonist
Anticoagulant-Associated Intracranial Hemorrhage in the Era of Reversal Agents Thorsten Steiner, Jeffrey I. Weitz and Roland Veltkamp
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Stroke. 2017;48:1432-1437; originally published online April 11, 2017; doi: 10.1161/STROKEAHA.116.013343 Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2017 American Heart Association, Inc. All rights reserved. Print ISSN: 0039-2499. Online ISSN: 1524-4628
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Data Supplement (unedited) at: http://stroke.ahajournals.org/content/suppl/2017/04/11/STROKEAHA.116.013343.DC1
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SUPPLEMENTAL MATERIAL
Supplemental table I: Practically relevant characteristics of oral anticogulants
Peak values (hrs) Half-life (hrs)
Excretion
Dabigatran
Apixaban
Rivaroxaban
Edoxaban
2–3
1–4
2–4
1–2
12–17
9 - 14
5 - 13
10 – 14
80% renal
30% renal
70% liver, 30% renal
50 % renal
P-gp P-gp competition, competition, CYP3A4 CYP3A4 CYP3A4 inhibitors inhibitors inhibitors P-gp: P-glycoprotein; CYP3A4: cytochrome P450 3A4 Drug-drug interaction
P-gp competition, no data
Vitamin-K-antagonists
Acenocoumarol: 9 hours Warfarin : 2 days Phenprocoumon: 7 days Hepatic, (warfarin in parts renal) Numerous
1
Supplemental table II: Effects of DOACs on coagulation tests and expert recommendation for the indication for reversal agents modified according to 1 Dabigatran
Rivaroxaban
Apixaban
Edoxaban
VKA
(é) to é
(é)
(é)
(é)
(é)
Prothrombin time (PT)
(é)
é to éé
(é)
é to éé
ééé
INR
(é)
é to éé
(é)
é to éé
ééé
Activated partial thromboplastin time (aPTT)
Global routine tests
Guide for indication for a reversal agents
Not specific but sensitive tests
Sensitive and specific tests
Insufficiently sensitive/specific
INR > 1.2
Thrombin time (TT)
ééé
Not applicable
Not applicable
Ecarin clotting time (ECT)
ééé
Not applicable
Not applicable
Heparin anti-Xa activity
Not applicable
Guide for indication for a reversal agents
TT < 3 x upper b limit of normal
Guide for indication a reversal agents
for
ééé
ééé
Anti Xa < 0.3 U LMWH
ééé
Not applicable
c
Diluted thrombin time
anti- factorXa activity calibrated for rivaroxaban
anti-factor Xa activity calibrated for apixaban
anti-factor Xa activity calibrated for edoxaban
INR
TT < 3 x upper b limit of normal
Functional concentration < 30 d ng/ml
Functional concentration < 30 d ng/ml
Functional concentration < 30 d ng/ml
> 1.2
aThese
are guidelines only and management must be individualized to each patient. recommendation by the authors. cCorresponds to 30 ng/ml; NOAC-calibrated assays should be used whenever possible. dIf measured>4 h after drug administration; extrapolated from published recommendations for surgery25 and supersedes older recommendations. INR, international normalized ratio; LMWH, low-molecular weight heparin; N/A: Not applicable bExpert
2
References 1.
Drouet L, Bal Dit Sollier C, Steiner T, Purrucker J. Measuring non-vitamin K antagonist oral anticoagulant levels: When is it appropriate and which methods should be used? Int J Stroke. 2016;11:748-758
3
