Novel Oral Anticoagulants

Anticoagulants are used frequently to treat and prevent thromboembolism. Historically, vitamin K antagonists (VKAs; eg, warfarin) have been the standard of care and only oral option. Many limitations are associated with warfarin despite its widespread use. Warfarin has a narrow therapeutic window, requires frequent laboratory monitoring, and is affected by diet, genetics, and illnesses. Medications that do not require frequent monitoring and have less inter- and intrapatient variability could offer great potential. Novel oral anticoagulants (NOACs) are relatively new medications that offer many of these potential benefits. The 2 classes of NOACs are direct thrombin inhibitors and direct factor Xa inhibitors. Dabigatran (Pradaxa) is currently the only direct thrombin inhibitor and was the first NOAC approved in 2010. Factor Xa inhibitors include rivaroxaban (Xarelto), apixaban (Eliquis), and edoxaban (Savaysa).^1,2

PHARMACOLOGY

The coagulation cascade is an intricate pathway controlled by many factors. Inhibiting one element can turn off the entire process. The last steps of the coagulation pathway involve converting prothrombin to thrombin via prothrombinase and factor Xa. Thrombin then converts fibrinogen to fibrin, producing a clot. Direct factor Xa inhibitors reduce thrombin production by selectively inhibiting factor Xa and prothrombinase activity. Direct thrombin inhibitors, such as dabigatran, inhibit thrombin to prevent the formation of fibrin and the development of a clot.^2-6

THERAPEUTIC USE

Although nuances exist between specific medications, NOACs have overall similar indications such as to reduce the risk of stroke and systemic embolism (in nonvalvular atrial fibrillation) and to treat and prevent deep vein thrombosis and pulmonary embolism. The usual dosing and administration of each NOAC is less patient-specific than warfarin. Dabigatran 150 mg should be administered twice daily with a full glass of water. Rivaroxaban dosing varies based on indication, with a dose ranging from 10 to 20 mg and a frequency of once or twice daily. The 15- and 20-mg rivaroxaban tablets should be taken with food, although this is not a requirement for the 10-mg tablet. The apixaban dose and frequency varies based on indication, but ranges from 2.5 to 10 mg once or twice daily. Edoxaban is dosed at 60 mg once daily regardless of indication. Dosage adjustments for specific creatinine clearance or drug interaction are given in the package inserts.^2-6

COMPARATIVE EFFICACY

A lack of direct head-to-head trials makes it difficult to compare the efficacy and safety of NOACs. However, clinical trials used for the basis of approval were similar, and each study was a multinational noninferiority study comparing the medication to warfarin (dosed to a target international normalized ratio of 2:3) and using a primary composite end point of the occurrence of first stroke or systemic embolic event. Although noninferiority margins varied between studies, each new medication significantly demonstrated noninferiority to warfarin. Each study also examined the safety of each new medication compared with warfarin, specifically addressing various bleeding risks.^3-7

Although limitations exist, indirect comparisons can be helpful in determining differences between NOACs. Skjøth and colleagues compared the efficacy and safety end points of 4 clinical trials (ENGAGE-AF, RE-LY, ROCKET-AF, and ARISTOTLE) comparing NOACs with warfarin. Compared with edoxaban (60 mg), apixaban was similar in efficacy but was associated with lower clinically relevant or major bleeding (HR 0.79; 95% CI, 0.70-0.90). Dabigatran demonstrated greater efficacy than edoxaban (stroke HR 0.73; 95% CI, 0.55- 0.96), although it was also associated with more “other location bleeding.” There was no difference between edoxaban and rivaroxaban in regard to efficacy or mortality, but rivaroxaban was associated with more major or clinically relevant bleeding (HR 1.20; 95% CI, 1.08-1.32).

ADVERSE REACTIONS

The majority of adverse reactions associated with NOACs are related to an increased risk of bleeding, which can be significant and even fatal. Patients should be educated regarding the signs and symptoms of blood loss. Medications that elicit an increased risk of bleeding (antiplatelet agents, heparin, fibrinolytic therapy, and long-term, nonsteroidal anti-inflammatory drugs) increase this risk further. Dabigatran and rivaroxaban have rates of major bleeding similar to that of warfarin (dabigatran HR 0.97; 95% CI, 0.84-1.12; rivaroxaban HR 1.04; 95% CI, 0.90- 1.20). Apixaban and edoxaban have a reduced risk of bleeding compared with warfarin (apixaban HR 0.69; 95% CI, 0.60-0.80; edoxaban HR 0.84; 95% CI, 0.73-0.97). Other adverse reactions include gastrointestinal reactions such as dyspepsia and gastroesophageal reflux disease.^2-7

DRUG INTERACTIONS

All 4 NOACs are substrates of the P-glycoprotein (P-gp) transporter, and rivaroxaban and apixaban are also substrates of cytochrome P450 3A4 (CYP3A4). Any concomitantly administered medication that induces or inhibits CYP3A4 and/or P-gp will potentially alter the exposure of these agents. Rivaroxaban and apixaban should not be administered with combined P-gp and CYP3A4 inhibitors (eg, ketoconazole, ritonavir, clarithromycin) or inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s wort). Dabigatran and edoxaban should not be used with P-gp inducers, such as rifampin. A dose reduction for P-gp inhibitors and dabigatran is not necessary unless the patient has moderate renal impairment (creatinine clearance 30-50 mL/min).^2-6

SAFETY ISSUES

The main risk of NOAC agents is bleeding. Conversely, if any oral anticoagulant is discontinued prematurely, there may be an increase in the risk of thrombotic events if an alternative anticoagulant is not initiated. In the event that the effect of an anticoagulant needs to be reversed (eg, emergency surgery), VKAs can be reversed with vitamin K, fresh frozen plasma, or prothrombin complex concentrate. Reversal agents for NOACs are more limited. Idarucizumab, a reversal agent specifically for dabigatran, was approved in October 2015; reversal agents for other NOACs are in development.^1,8

References

• FDA approves new antiplatelet drug used during heart procedure. Food and Drug Administration Web site. June 22, 2015. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm452172.htm Accessed August 21, 2015.
• FDA Briefing Document: Kengreal® NDA 204-958. Food and Drug Administration Web site. April 15, 2015. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM430747.pdf. Accessed September 25, 2015.
• Kengreal™ [package insert]. Parsippany, NJ: The Medicines Company; Updated July 2015.
• Kengreal. Micromedex [online database]. Greenwood Village, CO: Truven Health Analytics. Updated June 30, 2015.
• Bhatt DL, Stone GW, Mahaffey KW, et al. Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med. March 10, 2013; 368:1303-1313.

Jennifer L. Cruz, PharmD, BCPS, is an assistant professor of clinical education at UNC Eshelman School of Pharmacy. Katherine Summers is a PharmD candidate at UNC Eshelman School of Pharmacy.