Journal of the American Heart Association CONTEMPORARY REVIEW Direct Oral Anticoagulant Use: A Practical Guide to Common Clinical Challenges Ashley Chen, PharmD; Eric Stecker, MD, MPH; Bruce A. Warden , PharmD, BCPS-AQ Cardiology, CLS ABSTRACT: Direct oral anticoagulants (DOACs) have quickly become attractive alternatives to the long- standing standard of care in anticoagulation, vitamin K antagonist. DOACs are indicated for prevention and treatment of several cardiovascular con- ditions. Since the first approval in 2010, DOACs have emerged as leading therapeutic alternatives that provide both clinicians and patients with more effective, safe, and convenient treatment options in thromboembolic settings. With the expanding role of DOACs, clinicians are faced with increasingly complex decisions relating to appropriate agent, duration of treatment, and use in special populations. This review will provide an overview of DOACs and act as a practical reference for clinicians to optimize DOAC use among common challenging scenarios. Topics addressed include (1) appropriate indications; (2) use in patients with specific comorbidities; (3) monitoring parameters; (4) transitioning between anticoagulant regimens; (5) major drug interactions; and (6) cost considerations. Key Words: anticoagulation ■ oral direct thrombin inhibitor ■ oral factor Xa inhibitors ■ pharmacotherapy irect oral anticoagulants (DOACs)—dabigatran those for warfarin by 2013, with apixaban being the most (Pradaxa), rivaroxaban (Xarelto), apixaban (Eliquis), frequently prescribed DOAC for patients with nonvalvular Downloaded from http://ahajournals.org by on June 23, 2020 Dedoxaban (Savaysa), and betrixaban (Bevyxxa) are atrial fibrillation (NVAF).7 anticoagulation pharmacotherapy used for the preven- Over the past decade, DOACs have been the sub- tion of thrombosis in several cardiovascular contexts.1 ject of extensive investigation in many clinical scenarios. DOACs are categorized into 2 main classes: oral direct Though guidelines and review articles have provided factor Xa inhibitors (ie, rivaroxaban, apixaban, edoxaban, detailed and in- depth analyses of the immense literature and betrixaban) and direct thrombin inhibitors (ie, dab- base, these can be too cumbersome and challenging igatran). In 2010, the US Food and Drug Administration to integrate into everyday clinical use. The purpose of (FDA) approved its first DOAC, dabigatran, followed by this review is to be a practical reference or algorithm for rivaroxaban, apixaban, edoxaban, and betrixaban in the the busy clinician to navigate key aspects of effective following years. DOACs are relatively new agents demon- DOAC prescribing, with an emphasis on addressing strating superiority or noninferiority to prior standards of key situations where clinical uncertainty exists. This re- care, anticoagulation with vitamin K antagonists (VKA; ie, view will provide recommendations to address special warfarin), or low- molecular- weight heparins (LMWHs), in clinical situations to include indications, use in specific reducing risk of thromboembolic complications with sim- comorbidities, monitoring parameters, transitioning to ilar or reduced bleeding risk.2–5 Advantages of DOACs or off of therapy, drug interactions, and cost. compared with VKAs include fewer monitoring require- ments, less frequent follow- up, more immediate drug onset and offset effects (important for periprocedural and INDICATIONS FOR USE acute bleeding management), and fewer drug and food In general, FDA- approved indications for each of the interactions.6 As a result, DOAC prescriptions exceeded DOACs are comparable (see Table 1). Dabigatran, Correspondence to: Bruce A. Warden, PharmD, BCPS-AQ Cardiology, CLS, FNLA, 3181 SW Sam Jackson Park Rd, Mail Code HRC5N, Portland, OR 97239. E-mail: [email protected] Current address: Ashley Chen, PharmD, St. Joseph Medical Center, Tacoma, WA. For Sources of Funding and Disclosures, see page 15. © 2020 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. JAHA is available at: www.ahajournals.org/journal/jaha J Am Heart Assoc. 2020;9:e017559. DOI: 10.1161/JAHA.120.017559 1 Chen et al Practical Guide to DOAC Use added; however, trade- offs regarding thrombosis are Nonstandard Abbreviations and Acronyms not as clear cut.15 Recent investigations shed light on this common AF atrial fibrillation clinical scenario. The PIONEER AF- PCI (Prevention of ASCVD atherosclerotic cardiovascular disease Bleeding in Patients With Atrial Fibrillation Undergoing CAD coronary artery disease PCI) trial revealed that dual therapy with rivaroxaban CKD chronic kidney disease dosed at nonstandardized AF dosing (15 mg daily, or CrCl creatinine clearance 10 mg daily if renal impairment) and a P2Y12 inhibitor (predominantly clopidogrel) or triple therapy with rivar- CYP cytochrome P450 oxaban 2.5 mg twice daily plus DAPT was associated DAPT dual-antiplatelet therapy with lower bleeding risk in comparison to triple therapy DOAC direct oral anticoagulant (VKA at standard AF dosing, aspirin, and clopidogrel; FDA US Food and Drug Administration hazard ratio [HR], 0.59; 95% CI, 0.47–0.76) but similar HR hazard ratio thrombotic events.16 The RE- DUAL PCI (Randomized INR international normalized ratio Evaluation of Dual Antithrombotic Therapy with LMWH low molecular weight heparin Dabigatran Versus Triple Therapy With Warfarin in NVAF nonvalvular atrial fibrillation Patients With Nonvalvular Atrial Fibrillation Undergoing PCI percutaneous coronary intervention Percutaneous Coronary Intervention) trial showed that VKA vitamin K antagonists dual therapy with dabigatran (110 and 150 mg twice- VTE venous thromboembolism daily regimens) and a P2Y12 inhibitor (predominantly clopidogrel) revealed similar results, demonstrating a lower risk of bleeding and hospitalization compared with triple therapy (VKA dose adjusted to an interna- rivaroxaban, apixaban, and edoxaban are approved for tional normalized ratio [INR] of 2–3, aspirin, clopido- the lowering the risk of stroke and embolism in NVAF as grel). The magnitude of difference in bleeding events well as deep vein thrombosis and pulmonary embolism was dose dependent (HR, 0.52; 95% CI, 0.42–0.63; treatment/prophylaxis.8–11 Unique indications include and HR, 0.72; 95% CI, 0.58–0.88 for the dabigatran betrixaban for prophylaxis of venous thromboembo- 110 and 150 mg regimens, respectively). At the same Downloaded from http://ahajournals.org by on June 23, 2020 lism (VTE) in hospitalized patients for an acute medi- time, dabigatran at both doses was noninferior with cal illness, and rivaroxaban in combination with aspirin respect to the prevention of ischemic event rates.17 to reduce major cardiovascular events in patients with The AUGUSTUS (Antithrombotic Therapy After Acute chronic coronary artery disease (CAD) or peripheral Coronary Syndrome or PCI in Atrial Fibrillation) trial di- artery disease.9,12 However, there is still uncertainty in rectly examined the benefit and risk of dropping aspirin understanding safe and effective use of DOACs in the with both warfarin and apixaban in combination with setting of patients with cardiovascular comorbidities, a P2Y inhibitor (clopidogrel). The AUGUSTUS trial specifically atrial fibrillation (AF) with recent percutane- 12 keenly addressed a key missing component to the lit- ous coronary intervention (PCI), AF with concomitant erature and criticisms of RE- DUAL PCI and PIONEER artificial heart valves, stable atherosclerotic cardiovas- AF- PCI trials by comparing triple therapy to triple ther- cular disease (ASCVD), and cancer- associated throm- apy and dual therapy to dual therapy. The trial demon- boembolism. This section aims to clarify the use of strated the antithrombotic regimens that included DOACs within these patient subgroups. apixaban in combination with a P2Y12 inhibitor (without aspirin) resulted in less bleeding (HR, 0.69; 95% CI, AF and PCI 0.58–0.81) and fewer hospitalizations (HR, 0.83; 95% The combination of AF and CAD has often led to con- CI, 0.74–0.93) without significantly effecting the num- fusion regarding the optimal antithrombotic strategy, ber of ischemic events than regimens that included a historically favoring atherothrombotic prevention to VKA, aspirin, or both.18 Clinicians should be confident bleeding complications. Patients with CAD undergo- that dropping aspirin according to clinical trial proto- ing PCI are to receive dual- antiplatelet therapy (DAPT) cols when using apixaban, dabigatran, or rivaroxaban consisting of aspirin and a P2Y inhibitor (ie, clopi- 12 in combination with a P2Y12 inhibitor will substantially dogrel, prasugrel, or ticagrelor) for prevention of re- lower bleeding risk without increasing thrombotic risk, current atherosclerosis and stent thrombosis.13 When a sentiment endorsed by recent consensus docu- this occurs in patients with comorbid AF, the poten- ments.14,19 When it comes to antithrombotic therapy in tial need for triple antithrombotic therapy consisting of this scenario, less may be more. DAPT and anticoagulation (historically VKA) arises.14 Another important consideration is the use of As several studies have shown, bleeding risk rises sig- add- on therapy to further mitigate bleeding risk, spe- nificantly with each