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Reversing Anticoagulation to Administer Systemic Fibrinolytics for Ischemic Stroke: Pump the Brakes

2018-11-11T02:28:19+00:00

Care of acute ischemic stroke patients is a complex and time-sensitive team effort. There is a potentially dangerous trend in the medical literature over the past few years that seems to be increasing as of late: reversing anticoagulation in order to administer systemic thrombolytic therapy. The purpose of this post is to highlight the available literature on this topic, specifically related to the direct acting oral anticoagulants (DOACs), and discuss why we should not support this practice (at least as of today).

Reversing Dabigatran with Idarucizumab

Until recently, dabigatran was the only DOAC with an approved reversal agent, idarucizumab. A 2016 case claims to be the first to successfully reverse dabigatran-induced anticoagulation in order to administer systemic thrombolytics.1 It’s not always best to be first and many others have since followed. There are at least 16 additional patients reported in single case reports and small case series.2–14 There are even 3 cases of prehospital reversal in Australian mobile stroke units.15

Nineteen patients from a German registry were given idarucizumab followed by alteplase.16 The authors reported that 79% benefited from IV thrombolysis with a median improvement of 5 points in NIHSS. No bleeding complications were documented.

A 2017 systematic review identified 21 patients (including 5 from the authors’ institution).17 The time from symptom onset to start of tPA was 155 min. Three of 19 (16%) had an unfavorable outcome. There was 1 fatality as a result of symptomatic, post-thrombolysis, intracranial hemorrhage (ICH). Two patients experienced an increase in the NIHSS compared with baseline. One patient had a recurrent stroke. No systemic bleeding, venous thrombosis, or allergic reactions were reported.

Finally, a Czech Republic national registry identified 13 patients.18 Two had ICH and 1 had symptomatic ICH. No other bleeding complications were reported. Nine had a good 3-month clinical outcome and 3 patients died. Recurrent ischemic stroke occurred in 2 patients.

Why Is This Practice an Issue?

There are at least 6 major reasons we should not be adopting this practice at this point:

  1. Positive publication bias. Single case reports, small case series, and retrospective registry data cannot be used to determine the safety of an intervention. A similar parallel exists in the toxicology arena with lipid emulsion for oral drug overdoses.19 We have a tendency to only publish results when a good outcome is achieved. How many more cases exist where patients were harmed or, at the very least, did not benefit? We need well-designed trials to elucidate the real outcomes associated with this intervention.
  2. 2018 AHA/ASA Acute Ischemic Stroke Guidelines. In a climate where contraindications to administering alteplase are rapidly being eliminated or downplayed (in large part from alteplase manufacturer-directed changes to product labeling), these guidelines20 still give Class III: Harm; LOE C recommendations as follows: “IV alteplase should not be administered to patients taking direct thrombin inhibitors or direct factor Xa inhibitors unless laboratory tests such as aPTT, INR, platelet count, ecarin clotting time, thrombin time, or appropriate direct factor Xa activity assays are normal or the patient has not received a dose of these agents for >48 hours (assuming normal renal metabolizing function).”
  3. Limited idarucizumab data. We still do not fully understand the role of idarucizumab in reversing dabigatran.21 The data supporting idarucizumab have significant limitations, not the least of which was no control group in the largest human cohort study.22
  4. Resources. Most hospitals do not have timely, appropriate laboratory monitoring capabilities to test for the true degree of anticoagulation of DOACs and their reversal.
  5. Cost. Idarucizumab costs at least $5,000 per dose, with the potential for a much larger number charged to the patient. Alteplase is even more expensive. Is it ethical to pass along this financial burden to patients and their families without knowing true benefit vs. risk?
  6. Rebound anticoagulation. Rebound dabigatran concentrations may occur after idarucizumab administration in the setting of severe renal failure.23 And, paradoxical increases in dabigatran concentrations have been reported in the setting of stroke thrombolysis.24 In a well-designed study of actual stroke patients, would the potential for rebound increases in dabigatran concentrations in a subset of patients lead to a higher risk of symptomatic ICH?

To be fair, there are some advocating that this practice needs further investigation.25

Additional Concerns with Andexanet Alfa

In 2018, andexanet alfa was approved for reversal of anticoagulation from apixaban or rivaroxaban. This drug costs >$50,000 per dose, is more challenging to prepare and administer than idarucizumab, and its effect lasts only about 4 hours after the end of the infusion (meaning that the degree of anticoagulation could increase again shortly after alteplase administration).

Four-Factor Prothrombin Complex Concentrate (4F-PCC) for Warfarin Reversal

Reversing anticoagulation prior to thrombolysis is not unique to DOACs. There are emerging investigations evaluating warfarin reversal with 4F-PCC as well, though still only in one-armed trials.

Looking Ahead

Aside from any disagreement regarding the benefit of IV alteplase in acute ischemic stroke, the bottom line is that we should not be reversing anticoagulation in this setting until there is solid evidence that the benefits outweigh the risks. Transparent discussions with patients and their families are important for shared decision making.

1.
Berrouschot J, Stoll A, Hogh T, Eschenfelder C. Intravenous Thrombolysis With Recombinant Tissue-Type Plasminogen Activator in a Stroke Patient Receiving Dabigatran Anticoagulant After Antagonization With Idarucizumab. Stroke. 2016;47(7):1936-1938. [PubMed]
2.
Meyer D, Chu F, Derry K, Hailey L. Acute reversal of dabigatran with Idarucizumab for intravenous thrombolysis as acute stroke treatment. J Clin Neurosci. October 2018. [PubMed]
3.
Tireli D, He J, Nordling M, Wienecke T. Systemic Thrombolysis in Acute Ischemic Stroke after Dabigatran Etexilate Reversal with Idarucizumab-A Case Report. J Stroke Cerebrovasc Dis. 2017;26(7):e123-e125. [PubMed]
4.
Bissig D, Manjunath R, Traylor B, Richman D, Ng K. Acute Stroke Despite Dabigatran Anticoagulation Treated with Idarucizumab and Intravenous Tissue Plasminogen Activator. J Stroke Cerebrovasc Dis. 2017;26(6):e102-e104. [PubMed]
5.
Agosti S, Casalino L, Rocci E, Zaccone G, Rota E. Successful intravenous thrombolysis for ischemic stroke after reversal of dabigatran anticoagulation with idarucizumab: a case report. J Med Case Rep. 2017;11(1):224. [PubMed]
6.
Alvarez B, Orts C, Carvalho M, López Z. Intravenous Fibrinolysis in Ischemic Stroke of Large Vessel after Reversing Effect of Dabigatran with Idarucizumab. J Stroke Cerebrovasc Dis. 2017;26(9):e192-e193. [PubMed]
7.
Ohya Y, Makihara N, Wakisaka K, et al. Thrombolytic Therapy in Severe Cardioembolic Stroke After Reversal of Dabigatran with Idarucizumab: Case Report and Literature Review. J Stroke Cerebrovasc Dis. 2018;27(7):e128-e131. [PubMed]
8.
Gawehn A, Ayari Y, Heuschkel C, Kaste M, Kermer P. Successful thrombolysis with recombinant tissue plasminogen activator after antagonizing dabigatran by idarucizumab: a case report. J Med Case Rep. 2016;10(1):269. [PubMed]
9.
Kafke W, Kraft P. Intravenous Thrombolysis after Reversal of Dabigatran by Idarucizumab: A Case Report. Case Rep Neurol. 2016;8(2):140-144. [PubMed]
10.
Schäfer N, Müller A, Wüllner U. Systemic Thrombolysis for Ischemic Stroke after Antagonizing Dabigatran with Idarucizumab-A Case Report. J Stroke Cerebrovasc Dis. 2016;25(8):e126-7. [PubMed]
11.
Facchinetti R, DeGuidi G, Pitoni F, Ricci G, Lippi G. Rapid and well tolerated action of idarucizumab for antagonizing dabigatran in a patient needing urgent thrombolysis: a case report. Blood Coagul Fibrinolysis. 2017;28(7):576-579. [PubMed]
12.
Hieber M, Hollasch H, Heck D, et al. Reversal of dabigatran using idarucizumab: single center experience in four acute stroke patients. J Thromb Thrombolysis. 2018;46(1):12-15. [PubMed]
13.
Mutzenbach J, Pikija S, Otto F, Halwachs U, Weymayr F, Sellner J. Intravenous thrombolysis in acute ischemic stroke after dabigatran reversal with idarucizumab – a case report. Ann Clin Transl Neurol. 2016;3(11):889-892. [PubMed]
14.
Binet Q, Hammer F, Rocrelle O, Peeters A, Scavée C, Hermans C. Systemic thrombolysis and endovascular thrombectomy in severe acute ischemic stroke after dabigatran reversal with idarucizumab. Clin Case Rep. 2018;6(4):698-701. [PubMed]
15.
Zhao H, Coote S, Pesavento L, et al. Prehospital idarucizumab prior to intravenous thrombolysis in a mobile stroke unit. Int J Stroke. July 2018:1747493018790081. [PubMed]
16.
Kermer P, Eschenfelder C, Diener H, et al. Antagonizing dabigatran by idarucizumab in cases of ischemic stroke or intracranial hemorrhage in Germany – A national case collection. Int J Stroke. 2017;12(4):383-391. [PubMed]
17.
Pikija S, Sztriha L, Sebastian M, Golaszewski S, Sellner J. Idarucizumab in Dabigatran-Treated Patients with Acute Ischemic Stroke Receiving Alteplase: A Systematic Review of the Available Evidence. CNS Drugs. 2017;31(9):747-757. [PubMed]
18.
Šaňák D, Jakubíček S, Černík D, et al. Intravenous Thrombolysis in Patients with Acute Ischemic Stroke after a Reversal of Dabigatran Anticoagulation with Idarucizumab: A Real-World Clinical Experience. J Stroke Cerebrovasc Dis. 2018;27(9):2479-2483. [PubMed]
19.
Smolinske S, Hoffman R, Villeneuve E, Hoegberg L, Gosselin S. Utilization of lipid emulsion therapy in fatal overdose cases: an observational study. Clin Toxicol (Phila). September 2018:1-6. [PubMed]
20.
Powers W, Rabinstein A, Ackerson T, et al. 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2018;49(3):e46-e110. [PubMed]
21.
Hayes B, Winters M, Rosenbaum S, Allehyani M, Vilke G. What is the Role of Reversal Agents in the Management of Emergency Department Patients with Dabigatran-Associated Hemorrhage? J Emerg Med. 2018;54(4):571-575. [PubMed]
22.
Pollack C, Reilly P, van R, et al. Idarucizumab for Dabigatran Reversal – Full Cohort Analysis. N Engl J Med. 2017;377(5):431-441. [PubMed]
23.
Stecher A, Vene N, Mavri A, Mijovski M, Krevel B, Gradišek P. Late rebound of dabigatran levels after idarucizumab reversal in two patients with severe renal failure. Eur J Anaesthesiol. 2017;34(6):400-402. [PubMed]
24.
Hosoki S, Takagi M, Yamagami H, Ando D, Toyoda K, Koga M. Paradoxical elevation of plasma dabigatran after reversal with idarucizumab in stroke thrombolysis. J Neurol. 2018;265(10):2451-2453. [PubMed]
25.
Hsiao Y, Tsai Y, Tsai L, Fang C. Idarucizumab-facilitated intravenous thrombolysis in acute ischemic stroke: A therapeutic strategy requiring further investigation. J Neurol Sci. 2018;394:144-145. [PubMed]
Bryan D. Hayes, PharmD, FAACT, FASHP

Bryan D. Hayes, PharmD, FAACT, FASHP

Leadership Team, ALiEM
Creator and Lead Editor, Capsules series, ALiEMU
Attending Pharmacist, EM and Toxicology, MGH
Assistant Professor of EM, Harvard Medical School