Overview of Oral Anticoagulation Agents

Anticoagulants are among the most frequently prescribed drugs in the United States. They are indicated for prevention and treatment of venous thromboembolism (VTE) and pulmonary embolism (PE), stroke prevention in the setting of atrial fibrillation (AF), prevention of thromboembolism in patients with prosthetic heart valves, prophylaxis after joint replacement surgery, and reduction in the risk of thromboembolic events after myocardial infarction.

About 900,000 people are affected by VTE/ PE in the United States each year, and about 100,000 people die as a result, according to the CDC.¹ One-third of those with VTE/PE will have a recurrence within 10 years.¹ AF affects up to 6 million Americans every year, and this number is expected to increase with the aging of the population.

Historically, warfarin has been the most commonly prescribed oral anticoagulant. Approved by the FDA in 1954, the vitamin K antagonist (VKA) has been extensively studied, and the benefits and risks are well known.² Although warfarin is an effective anticoagulant, management and safe use can be challenging, especially in certain populations. Since 2010, 5 direct oral anticoagulants (DOACs) have been approved that target the activity of thrombin or factor Xa: apixaban, betrixaban, dabigatran, edoxaban, and rivaroxaban.³ Collectively, as a class, the DOACs have less need for laboratory monitoring, minimal drug—drug and food interactions, and more predictable dosing.^3,4 However, they come with a higher cost and varying degrees of risk, and most lack a reversal agent.^3,4

PATHOPHYSIOLOGY

Hemostasis is the normal physiologic response that promotes blood clot formation at the site of vascular injury to prevent blood loss and promote healing.⁵ Clot formation involves several different system reactions, including activation of the coagulation cascade, platelet plug formation, and vasoconstriction.⁵ The response must be localized and tightly regulated to prevent widespread clotting. Once blood flow has ceased, tissue repair can begin.

The coagulation cascade involves a series of biochemical reactions that lead to the activation of thrombin. The cascade is divided into 2 pathways, extrinsic and intrinsic, which converge to a common pathway at the activation of factor X, which converts prothrombin to thrombin. Thrombin then converts fibrinogen to fibrin, which forms the matrix of the clot.⁶

In thrombosis, coagulation reactions are inappropriately regulated so that the clot expands and occludes the lumen of the blood vessel. Three major factors, called Virchow’s triad, predispose to thrombus formation: blood hypercoagulability, vascular wall damage or injury, and venous stasis.⁷

PHARMACOKINETICS

VKAs, such as warfarin, inhibit the vitamin K— dependent synthesis of clotting factors II, VII, IX, and X, as well as the regulatory proteins C, S, and Z.² Warfarin has a narrow therapeutic window, and doses are individually tailored, based on laboratory monitoring of the international normalized ratio (INR), the universal monitoring index based on prothrombin time. The half-life of warfarin ranges from 20 to 60 hours, and the duration of effect is 2 to 5 days. It is primarily metabolized through the cytochrome P450 system, and induction or inhibition of the enzymes involved in metabolism can increase the INR significantly.^2,4

Dabigatran acts as an oral direct thrombin inhibitor that prevents thrombin from cleaving fibrinogen to fibrin. The half-life is about 12 to 17 hours in patients with normal renal function, with maximum anticoagulant effects 2 to 3 hours after ingestion.^3,8

Direct factor Xa inhibitors, which prevent factor Xa from converting prothrombin to thrombin by binding directly to factor Xa, are metabolized by the kidney and liver, and severe liver disease can result in accumulation. The DOACs have more predictable pharmacokinetic profiles than warfarin, with shorter half-lives and less need for routine laboratory monitoring, as drug levels are foreseeable for a given dose.^3,9

Betrixaban, dabigatran, and edoxaban are substrates for P-glycoprotein (P-gp), and concomitant use with P-gp inducers (eg, rifampin) reduces the anticoagulant effect.^3,8 In patients with renal failure, concomitant use with P-gp may increase the anticoagulant effect. Apixaban and rivaroxaban interact with inhibitors of CYP3A4 and P-gp, such as ketoconazole and ritonavir, and inducers, such as carbamazepine and rifampin.^3,9

EFFICACY

Anticoagulants have varying degrees of efficacy, depending on the clinical setting. There are also differences in adverse effects, cost, dosing, and monitoring. For these reasons, recommendations must be individualized, based on the indication and patient.¹⁰

When a DOAC is preferred, individual patient characteristics will determine which should be prescribed, as no head-to-head trials have been done that compare their clinical outcomes.³

VKAs are preferred over DOACs in several different settings. DOACs are not used in patients with prosthetic heart valves because of a greater risk of valve thrombosis.¹⁰ In patients with renal insufficiency, warfarin may be the preferred oral agent. For patients with creatinine clearance (CrCl) <30 mL/min, there is insufficient evidence compared with warfarin, and the DOACs must be dose adjusted. DOACs are not recommended in patients with CrCl <15 mL/min.³

DOACs also are not used during pregnancy because of the lack of clinical experience. In pregnant women, low molecular weight heparin (LMWH) is usually the preferred agent.^3,10

Randomized, double-blind, double-dummy, noninferiority trials have investigated the newer anticoagulants compared with warfarin for indications of nonvalvular AF and VTE. Based on the findings, the 2016 American College of Chest Physicians guidelines for antithrombotic therapy recommended that in patients with VTE or PE and no cancer, the use of apixaban, dabigatran, edoxaban, or rivaroxaban be selected over VKA therapy, and in patients with VTE or PE and cancer, LMWH be used over apixaban, dabigatran, edoxaban, rivaroxaban, or VKA therapy.^10,11

Bevixaban was not included in the recommendations because it had not been approved at the time. It received approval with an indication for VTE prophylaxis in hospitalized adults in 2017.

BLEEDING RISKS

Intracerebral bleeding is a major concern with warfarin, especially in older adults who have AF and are at risk of falling. The bleeding risk of dabigatran has been noted in several large observational studies, and findings have shown that overall bleeding with dabigatran is similar to warfarin, with lower rates of death and intracranial hemorrhage.^8,12 Major bleeding risk of apixaban (5 or 2.5 mg) twice daily and edoxaban (30 or 60 mg) daily has been shown to be similar compared with warfarin and rivaroxaban (20 or 15 mg) daily and dabigatran (150 mg) twice daily, which had similar risks versus warfarin.¹² The risk of gastrointestinal bleeding is slightly higher with dabigatran when using the dose of 150 mg twice daily and rivaroxaban (20 or 15 mg) daily versus warfarin.^8,12 The risk of intracranial bleeding was reduced with all DOACs versus warfarin.¹²

DOSING REVERSAL

The anticoagulant effect sometimes requires rapid reversal if major bleeding occurs or emergency surgery is needed. Warfarin toxicity can be treated by holding doses or administering fresh frozen plasma, phytonadione (vitamin K), or prothrombin complex concentrate. Guidelines have been developed to help select treatment based on the INR and if bleeding is present.¹⁰

Idarucizumab received FDA approval in 2017 as a reversal agent for dabigatran. The drug is a humanized monoclonal antibody fragment that binds to dabigatran with a higher affinity than to thrombin, thus neutralizing its activity. Reversal agents for other DOACs are in development.

ROLE OF PHARMACISTS

A 2017 report involving more than 1500 patients who were being treated for VTE with a DOAC highlighted the lack of clinician familiarity with recommended dosing.¹³ Pharmacists are well positioned to educate and guide providers on the benefits and risks of each oral anticoagulant. Patients also need to be counseled on adherence, drug interactions, and what to do when doses are missed.

New oral anticoagulants offer many advantages over warfarin, with faster onset, predictable anticoagulant effects, fewer drug interactions and dietary restrictions, lack of required monitoring, and a lower risk of intracranial bleeding. However, they do have higher costs and depend on renal elimination, and some lack an effective reversal agent.

Joanna Lewis, PharmD, MBA, is a clinical pharmacist and an active member of the American Society of Health-System Pharmacists. She has worked in a variety of practice settings, most recently as a coordinator at Duke University Hospital in Durham, North Carolina.

References

1.CDC. Venous thromboembolism (blood clots) - data and statistics. cdc.gov/ncbddd/dvt/data.html. Updated February 5, 2018. Accessed February 8, 2018.

2. Harter K, Levine M, Anderson SO. Anticoagulation drug therapy: a review. West J Emerg Med. 2015;16(1):11-7. doi: 10.5811/westjem.2014.12.22933.

3. Steuber, T. The role of direct oral anticoagulants in the management of venous thromboembolism. Am J Manag Care. 2017;23(20 Suppl):S383-S390.

4. Alquwaizani M, Buckley L, Adams C, Fanikos J. Anticoagulants: A review of pharmacology, dosing, and complications. Curr Emerg Hosp Med Rep. 2013;1(2):83-97.

5. Crawley JTB, Zanardelli S, Chion CK, Lane DA. The central role of thrombin in hemostasis. J Throm Haemost. 2007;5 Suppl 1:95-101.

6. Palta S, Saroa R, Palta A. Overview of the coagulation system. Indian J Anaesth. 2014;58(5): 515-23. doi: 10.4103/0019-5049.144643.

7. Anderson FA Jr, Spencer FA. Risk factors for venous thromboembolism. Circulation. 2003; 107(23 suppl 1): 19-16.

8. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-51. doi: 10.1056/NEJMoa0905561.

9. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in patients with nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-91. doi: 10.1056/NEJMoa1009638.

10. Vandvik PO, Lincoff AM, Gore JM, et al. Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141 (2 Suppl):e637S-e668S. doi: 10.1378/chest.11-2306.

11. Kearon C, Akl EA, Ornelas J. Antithrombotic therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016;149(2):315-352. doi: 10.1016/j.chest.2015.11.026.

12. Eikelboom, J and Merli, G. Bleeding with direct oral anticoagulants vs. warfarin: clinical experience. Am J Med. 2016.129(11S):S33-S40. doi: 10.1016/j.amjmed.2016.06.003.

13. Trujillo-Santos J, Di Micco P, Dentali F, et al. Real-life treatment of venous thromboembolism with direct oral anticoagulants: The influence of recommended dosing and regimens. Thromb Haemost. 2017;117(2):382-389. doi: 10.1160/TH16-07-0494.