The Newer Anticoagulants and Agents Used for Reversing Their Action

The development of novel anticoagulants (NOACs) has provided a great alternative to the cumbersome use of warfarin. There are now many choices with different dosing regimens as well as modes of metabolism and excretion to choose from. This has made it even more crucial to know what drugs and interventions can be used in a bleeding crisis situation. This article will review the available NOACs, and discuss methods that can be utilized to reverse their effects.

The presence of atrial fibrillation (AFib) raises the risk of ischemic stroke fivefold. The left atrial appendage is believed to be the source for most of these clots. Oral anticoagulants are highly effective and reasonably safe for reducing risk of stroke.

The CHA₂DS₂-VASc score is used to stratify risk of stroke in those with persistent or paroxysmal AFib (Figure 1). The 2014 AHA/ACC/HRS Guidelines for the Management of Patients With Atrial Fibrillation¹ recommended the use of warfarin, dabigatran, rivaroxaban, and apixaban as Class I for the prevention of thromboembolism in patients with AFib in those with specific CHA₂DS₂-VASc scores. (An update in these guidelines is expected soon, and will probably address the use of edoxaban). A partial list of Class 1 recommendations includes:

• CHA₂DS₂-VASc score recommended to assess stroke risk.
• Warfarin is recommended with mechanical heart valves. Target INR intensity should be based on the type and location of prosthesis.
• With prior stroke, TIA, or CHA₂DS₂-VASc score ≥2, oral anticoagulants are recommended. Options include: warfarin, dabigatran, rivaroxaban, or apixaban.
• With warfarin, determine INR at least weekly during initiation and monthly when stable.
• Direct thrombin or factor Xa inhibitor recommended, if unable to maintain therapeutic INR.
• Evaluate renal function prior to initiation of direct thrombin or factor Xa inhibitors, and re-evaluate when clinically indicated and at least annually.¹

The NOACs approach the coagulation cascade to exert their effects in a totally different direction from warfarin. While warfarin acts on factors II, IX, and X, dabigatran acts on factor IIa, and rivaroxaban, apixaban, and edoxaban act on factor Xa (Figure 2). So, while vitamin K can reverse the effects of warfarin in an emergency situation, it is virtually useless in reversing the newer agents.

The approach to reversing the newer agents in an emergency is based on an understanding of their pharmacokinetics and pharmacodynamics. Specific reversal agents have finally been developed for these drugs, but their availability may be limited. A brief review of the NOACs follows, as well as a review of reversal agents and interventions.

Dabigatran

Dabigatran etexilate (Pradaxa, Boehringer Ingelheim), 75-150 mg twice daily, is a direct thrombin inhibitor affecting factor IIa of the coagulation cascade. Maximal drug concentration is reached in about 1-3 hours.² The drug is not metabolized by the cytochrome P450 system. The half-life of the drug is 12 to 17 hours, and it is 80% renally excreted. Therefore, the drug may accumulate in the setting of abnormal renal function.

Drug therapy with dabigatran does not require regular monitoring. INR is insensitive to dabigatran. The level of anticoagulation can be assessed by activated partial thromboplastin time (aPTT). Dabigatran prolongs aPTT at therapeutic doses. It is also important to ascertain the time of the last dose relative to time of the blood sample. The median trough aPTT in a 150 mg dabigatran dose was 52 (40-76) seconds in the RE-LY trial. Thrombin time (TT) is very sensitive to dabigatran levels. A normal TT excludes dabigatran levels that are relevant. However, a prolonged TT does not discriminate between important and insignificant concentrations. Ecarin clotting time (ECT) can also assess the anticoagulation level and is actually a more specific measure of effect than aPTT. Ecarin chromogenic assay is also correlated closely with dabigatran activity. In those with normal renal function, plasma concentration levels do decline relatively quickly after discontinuation of the drug.^2-3

Xa Inhibitors

Xa inhibition prevents prothrombin from being generated from thrombin, and inhibits the generation of tissue factor-induced thrombin.⁴ Rivaroxaban, apixaban, and edoxaban are the drugs which inhibit factor Xa.

Rivaroxaban

Rivaroxaban (Xarelto, Janssen, a Johnson & Johnson company) was approved for use in patients with non-valvular atrial fibrillation. The U.S. FDA requires that patients getting this drug must receive a Medication Guide describing the associated risks and adverse reactions. Rivaroxaban should be taken one time a day with the evening meal to ensure complete absorption.

Rivaroxaban is 80% bioavailable. Maximal plasma concentrations are reached after 2-4 hours, and rivaroxaban has a plasma half-life of 5 to 9 hours in healthy patients and 11-13 hours in the elderly. Two-thirds of the drug is metabolized by the kidneys, and the other third is excreted via feces. Concomitant use with P-gp and strong CYP3A inhibitors and inducers should be avoided. The drug is not recommended for those receiving ketoconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, conivaptan, HIV protease inhibitors, rifampin, itraconazole, voriconazole, or posaconazole. Also, use should be avoided with moderate and severe hepatic impairment or with any hepatic disease associated with coagulopathy.⁵

Apixaban

Apixaban (Eliquis, Bristol-Myers Squibb and Pfizer) has a rapid onset of action and high oral bioavailability. The half-life is ~12 hours. Food does not affect absorption and the drug is not altered by pH changes. Elimination is 25% renal, and 75% nonrenal.^6-7 This suggests it would be a preferred Xa drug when renal impairment is present. Apixaban is not to be taken in combination with inhibitors of CYP3A4 (azole antifungals, macrolide antibiotics, protease inhibitors); these agents increase apixaban levels.⁸

Edoxaban

Edoxaban (Savaysa, Daiichi Sankyo) is the most recent addition to the Xa inhibitors. It is given once daily, which helps with compliance. Peak concentration occurs within 1-2 hours and half-life is 10-14 hours. The drug elimination is about 50% renal and 50% biliary intestinal excretion.⁹

Monitoring Anticoagulant Activity

Monitoring the anticoagulant activity of the Xa agents is best performed with the chromogenic anti-Xa assay. Calibration with the drug of interest should correlate well with drug levels measured by liquid chromatography-tandem mass spectrometry. In the absence of this test, prothrombin time (PT) can be used to assess for edoxaban and rivaroxaban. Elevated or prolonged levels of the PT may be present in therapy and above therapy levels of these drugs. A normal PT does not exclude a therapeutic level.¹⁰ For apixaban, PT and aPTT are not very helpful. A prolonged PT is found with therapeutic or above therapeutic levels, and a normal PT does not exclude either.

Reversal Interventions and Agents

In 2017, the ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants was published.¹⁰ This group reviewed scientific evidence and expert opinions, and developed a decision pathway for bleeding management. Elements considered in the decision pathway included severity of the bleed, acute medical and surgical management, need for reversal, appropriateness and time of restarting anticoagulation, and the impact of pertinent comorbidities and concomitant drug therapy.¹⁰

Major bleeds were defined as those that occurred with hemodynamic compromise, located in a critical location (intracranial), required a transfusion of ≥2 U of packed red blood cells (RBCs), or associated with a ≥2 g/dL decrease in hemoglobin.¹⁰ Non-major bleeds were those not classified as major, although some required intervention or hospitalization.

For patients with major bleeding who are on dabigatran, the following should be done: discontinue the drug, institute mechanical compression, surgical hemostasis if needed, transfusion of RBC or PT (if concomitant antiplatelet use), and administer 5 g idarucizumab (Praxbind, Boehringer Ingelheim) IV. If the drug is not available, administer four-factor prothrombin complex concentrate (4F-PCC) or activated prothrombin complex concentrate (aPCC) 50 units/kg IV. Activated charcoal should also be considered if last ingestion was between 2-4 hours. Hemodialysis may be recommended if the drug level is high, especially in the setting of impaired renal function. It should be noted that idarucizumab may not universally be available in every hospital pharmacy.¹⁰

For those with major bleeding who are on a Xa inhibitor (rivaroxaban, apixaban), the following should be done: discontinue the drug, institute mechanical compression, surgical hemostasis, transfusion of RBC or PT (if concomitant antiplatelet use), and administer andexanet alfa (AndexXa, Portola Pharmaceuticals) bolus and infusion. If andexanet alfa is not available, administer 4F-PCC or aPCC 50 units/kg IV. Activated charcoal should also be considered if last ingestion was between 2-4 hours. Use of andexanet alfa for edoxaban would be off-label at this time.¹⁰

Idarucizumab is a humanized, monoclonal antibody fragment. Peak plasma concentrations occur at the end of a 5-minute infusion. The half-life of the drug is 47 minutes. It acts by binding the dabigatran. The agent is excreted by the kidneys.²

Andexanet alfa was approved by the FDA in 2018. It is the first antidote for factor Xa inhibitors. It was able to achieve effective hemostasis 12 hours after infusion in 79% of patients with a serious acute bleed (usually GI or intracranial). It is approved for use with rivaroxaban and apixaban, but not yet for edoxaban.

In studies with healthy volunteers, the only adverse events were infusion reactions. No antibodies to factor X developed in healthy volunteers and no neutralizing antibodies against andexanet alfa were detected.

Andexanet alfa comes in a carton with four 100 mg single-use vials. Dosage is based on which factor Xa agent was taken, the dosage, and the time since the last dose. The supply is limited until early 2019. In July 2018, the drug was available at 10 institutions in the U.S. A bolus is given, followed by a 2-hour infusion. The drug has a 5- to 7-hour half-life, and some anticoagulant effect returns 1-3 hours after stopping infusion, possibly necessitating a longer infusion.¹¹

Ciraparantag (PER977) is in development for use with all NOACs plus unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and fondaparinux (a factor Xa drug). It is a small, synthetic, water-soluble molecule.¹⁰

Should the NOAC be Restarted?

The determination to restart the anticoagulant should be based on the area where bleeding occurred, the risk of rebleeding, whether a surgical procedure is planned, and the initial rationale for placing the patient on the anticoagulant. Patients at higher risk if the medication is not restarted would be those with mechanical valve prosthesis, atrial fibrillation, VTE, prior thromboembolism, left ventricular or atrial thrombus, or those with an LVAD.¹⁰

NOACs have proven to be a great addition to the treatment armamentarium for patients at risk for clot formation. The ability to stop an adverse bleeding situation in patients on these drugs helps to close the circle for safe and effective care. The development of the new drug antidotes, along with careful analysis and supportive interventions, makes this a reality. 

Disclosure: The author has no conflicts of interest to report regarding the content herein.   

1. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology, American Heart Association Task Force in Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014;64:e1-76.

2. Boehringer Ingelheim Pharmaceuticals, Inc. Prescribing Information. Ridgefield, CT; 2018.

3. van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010;103:1116-1127.

4. Gerotziafas GT, Elalamy I, Depasse F, et al. In vitro inhibition of thrombin generation, after tissue factor pathway activation, by the oral, direct factor Xa inhibitor rivaroxaban. J Thromb Haemost. 2007;5:886-888.

5. Janssen Pharmaceuticals, Inc. Prescribing Information. Titusville, NJ; 2018.

6. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981-992.

7. Lopes RD, Alexander JH, Al-Khatib SM, et al. Apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation (ARISTOTLE) trial: Design and rationale. Am Heart J. 2010;159:331-339.

8. Carriero J, Ansell J. Apixaban, an oral direct Factor Xa inhibitor: awaiting the verdict. Expert Opin Investig Drugs. 2008;17:1937-1945.

9. Daiichi Sankyo, Inc. Prescribing Information. Chuo, Japan; 2018. Available at https://bit.ly/2SHAlMr.

10. Tomaselli GF, Mahaffey KW, Cuker A, et al. 2017 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2017;70:3042-3067.

11. Medical Letter on Drugs and Therapeutics: Andexxa-An antidote for apixaban and rivaroxaban. JAMA. 2018;320(4):399-400.