Since 2008, when NOACs were approved by regulatory agencies in both the European Union (EU) and the US, they have been recommended for a variety of thromboembolic indications. Large, randomized, Phase 3 clinical trials evaluated apixaban, betrixaban, dabigatran, edoxaban, and rivaroxaban versus conventional therapy for the treatment of VTE in the AMPLIFY (NCT00643201), APEX (NCT01583218), RE-COVER I (NCT00291330), RE-MEDY (NCT00329238), RE-SONATE (NCT00558259), Hokusai-VTE (NCT00986154), and EINSTEIN-DVT (NCT00440193)/-PE (NCT00439777) trials, respectively. Data revealed that NOACs were noninferior to LMWH/VKA/placebo for primary prophylaxis, treatment, and secondary prevention of VTE. The risk of major bleeding and/or clinically relevant nonmajor bleeding (CRNM) is also comparable or decreased with NOAC use (Agnelli, Buller, Cohen, Curto, Gallus, Johnson, Masiukiewicz, et al., 2013; Cohen et al., 2016; Einstein–PE Investigators, 2012; Einstein Investigators, 2010; Hokusai-VTE Investigators, 2013; Schulman et al., 2009, 2014). A recent meta-analysis compared the efficacy and safety of apixaban, dabigatran, edoxaban, and rivaroxaban across the six major Phase 3 clinical trials for initial and long-term VTE treatment and reported no statistically significant differences in the risk of VTE and VTE-related death among them (Cohen et al., 2015). Further, NOAC use reduces the risk of all-cause mortality and intracranial hemorrhage—the most feared complication of VKA usage (Robinson, 2015).
Real-world evidence, although limited, supports data from phase 3 randomized controlled trials. XALIA (NCT01619007), a noninterventional study comparing standard therapy (initial unfractionated heparin, LMWH, or fondaparinux, overlapping with a VKA) with rivaroxaban for long-term and initial anticoagulation for VTE, demonstrated lower rates of major bleeding and recurrent VTE with rivaroxaban (Turpie et al., 2015). The Dresden NOAC registry study (NCT01588119) is currently examining treatment of acute VTE with rivaroxaban. Initial findings revealed that rivaroxaban is effective and has acceptable major bleeding rates in unselected patients in daily care (Keller et al., 2016). Also underway, the Global Anticoagulant Registry in the FIELD–Venous Thromboembolism (GARFIELD-VTE; NCT02155491) is an observational study investigating acute and long-term VTE management among ∼500 sites across 28 countries (Weitz et al., 2016). PREFER, in VTE (DRKS register, ID number: DRKS00004795), is an ongoing, multicenter, prospective, observational disease study of quality of life and treatment satisfaction of ∼3,500 patients with VTE across Europe (Agnelli et al., 2015). Recently, a population-based observational study, using health care data from Canada and the United States, found that the risk of major bleeding and all-cause mortality was not increased with NOAC use compared with warfarin for VTE (Jun et al., 2017). Data from these registry studies will help us better understand variation in real-world treatment of VTE and assess its effect on clinical and economic outcomes.
While advising and prescribing NOACs to patients, it is important to identify populations that may be difficult to manage as well as those that may benefit. Patients who are elderly or present with diabetes, heart failure, renal impairment, and/or had experienced a previous stroke or ischemic attack can complicate the management of VTE (Robinson, 2015). NOACs are not recommended for patients with mechanical valves or severe valvular disease and are contraindicated for patients with moderate-to-severe hepatic impairment (Bentz, 2015). In addition, patients with clotting disorders or who present with abnormal clotting test results should consult a hematologist before starting anticoagulation therapy (Sumnig et al., 2014).
Patients being treated with VKAs who may be considered for NOAC therapy include those taking medications that interact with VKAs, those who have a poorly controlled INR on VKA, or those who have a history of a previous thromboembolic event on VKA. Patient convenience, such as geographic location to provider office, lifestyle choices including diet, and costs should also be considered when choosing between an NOAC and VKA (Robinson, 2015). Selecting an appropriate NOAC agent for eligible patients is challenging in the absence of direct comparative trials. However, considering agent pharmacokinetics, metabolism, and adverse effects can assist in the decision-making process (Millar & Laffan, 2017).
Although NOACs do not require routine coagulation monitoring, regular contact with health care providers is needed to ensure safe and effective management of anticoagulation therapy. Regularly scheduled visits provide an opportunity for ongoing risk assessments and to address issues with compliance or adherence, adverse effects, alterations in renal or liver function, and signs of bleeding or thromboembolic events, which may require switching to an alternative anticoagulant. Drug–drug interactions as a result of concurrent medications should be considered alongside the duration of interaction exposure and risk of bleeding in a patient-specific manner. Concurrent use of NOACs with common medications, such as nonsteroidal anti-inflammatory agents (NSAIDs) or aspirin, can be associated with a higher risk of bleeding. Clinicians are advised to closely follow the product label regarding dose adjustments or discontinuation wherever necessary, unless the potential benefit justifies the increased risk of bleeding (Burnett et al., 2016). Substitution with acetaminophen, which does not have an antiplatelet effect, may be considered (Douketis, Bell, Eikelboom, & Liew, 2014). Continued patient education is also imperative and can be conducted through leaflets and brochures complemented with face-to-face educational sessions to answer patients’ questions regarding practical issues that can affect their everyday life (Robinson, 2015). Although the frequency of follow-up visits depends on a number of factors, patient visits should begin when transitioning from a parenteral anticoagulant to dabigatran or edoxaban or when changing doses of apixaban (after 7 days) or rivaroxaban (after 21 days) (Heidbuchel et al., 2015). After this transition, follow-up visits should occur every 3–6 months. Because all NOACs are to some extent excreted by the kidneys, kidney function and periodic creatinine clearance (CrCl) level evaluation should be completed, as well as complete blood counts to check for anemia and thrombocytopenia (Robinson, 2015).
Appropriate periprocedural management of NOAC therapy is also important as ∼10% of patients on long-term anticoagulation require surgery (Raval et al., 2017). To dissipate the anticoagulation effect before surgery, the current labeling for each NOAC recommends discontinuation 24–48 hours for apixaban (Bristol-Myers Squibb Company, 2012), 1–2 days (CrCl ≥ 50 ml/min) or 3–5 days (CrCl < 50 ml/min) for dabigatran (Boehringer Ingelheim Pharmaceuticals, 2010), and at least 24 hours for edoxaban (Daiichi Sankyo Inc, 2015) or rivaroxaban (Janssen Pharmaceuticals Inc, 2011). NOAC therapy should resume once adequate hemostasis has been established after the surgical procedure. Pre- or postprocedural bridging with heparin is not required in patients with low thromboembolic risk (Raval et al., 2017). However, a parenteral anticoagulant should be considered if an NOAC cannot be orally administered after surgery.
Current literature indicates that the primary consideration for continued anticoagulation should balance the risk of bleeding versus the risk of VTE recurrence for each individual patient (Joseph & Bartholomew, 2016). Major bleeding in patients receiving a VKA is usually managed with a reversal agent that increases vitamin K–dependent coagulation factors, such as fresh frozen plasma or factor concentrates (Ruff, Giugliano, & Antman, 2016). Although major bleeding is higher with VKAs than with NOACs, life-threatening bleeding can occur with NOACs, necessitating anticoagulant reversal. A specific antidote to dabigatran, idarucizumab, has been approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). Idarucizumab reverses the anticoagulation effects of dabigatran, acting immediately when given as two consecutive bolus intravenous injections no more than 15 minutes apart (Pollack Jr et al., 2015). However, there are currently no specific reversal agents approved for apixaban, betrixaban, edoxaban, or rivaroxaban (Ruff et al., 2016). A factor Xa inhibitor antidote, andexanet alfa, is currently under investigation in clinical trials. Andexanet alfa is a recombinant modified human factor Xa decoy protein that binds to factor Xa inhibitors to counteract the anticoagulant effect. Also in development is ciraparantag, a universal antidote intended to reverse the effects of unfractionated heparin and LMWH in addition to all NOACs. Ciraparantag is a synthetic cationic molecule that binds to anticoagulants through noncovalent hydrogen bonding and charge–charge interactions; however, the exact mechanism is not fully known. Of note, NOACs have a much shorter half-life than VKAs, so non–life-threatening bleeding can often be more easily controlled once the drug has been eliminated. Current options for NOAC management of life-threatening bleeding include supportive measures, repletion of clotting factors (e.g., prothrombin complex concentrates, activated prothrombin complex concentrates, or recombinant factor VIIa), blood transfusion, or surgery to repair the source of bleeding (Ruff et al., 2016).
There are more than 3,000 anticoagulation clinics (ACs) in the US that treat millions of Americans on anticoagulant therapy (Barnes, Nallamothu, Sales, & Froehlich, 2016). Historically, ACs were designed to address the challenges with VKA treatment and provide organized, systematic management for anticoagulation therapy. Typically run by nurses, pharmacists, NPs, or physician assistants, the services provided by ACs include educational programs for patients, verifying clinical indications, reviewing laboratory tests and anticoagulation regimens involved in treatment, assessing pharmacologic interactions, and supervising patients undergoing surgery to reduce harm and risks often associated with periprocedural periods (Testa et al., 2012).
Assessment of the global anticoagulant market from 2008 to 2014 demonstrated the declining use of warfarin, from 87.5% to 72%, as more providers prescribe NOACs. Comparing direct thrombin inhibitors versus factor Xa inhibitors revealed a 1.35-fold increase in factor Xa inhibitor usage in 2014, with a preference for rivaroxaban (Oktay, 2015). This calls for expanding the traditional role of ACs to integrate patients with VTE on NOAC therapy. Anticoagulation clinics provide several advantages over traditional physician-managed practices, including managing patient anticoagulant therapy in one central location, skilled personnel to assist in clinical decision-making of anticoagulant dosage depending on personal characteristics and comorbidities, monitoring potential interactions with comedications, minimizing bleeding complications, and encouraging adherence (Barnes et al., 2016; Sylvester et al., 2017).
Although reimagined ACs would provide invaluable services, financing remains the largest barrier to this transition. Considering the lower risk of thrombosis and bleeding complications and no need for routine INR monitoring with NOACs, many health care systems and insurers may not see the financial value of NOAC management within these specialized clinics. As more patients are treated with NOACs, it will become imperative to adapt the services provided by ACs to decrease the number of adverse events related to NOACs and to support the financial investment (Barnes et al., 2016).
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