Novel Oral Anticoagulants:

Transcription

1 Novel Oral Anticoagulants: Transforming Stroke Prevention in Nonvalvular Atrial Fibrillation A Clinical Coffee Break Activity Jointly provided by This activity is supported by an independent educational grant from Boehringer Ingelheim Pharmaceuticals, Inc.

2 Activity Information Release date: February 5, 2016 Expiration date: February 4, 2017 Educational credits: 1.0 AMA PRA Category 1 Credit(s) TM Estimated time to complete activity: 60 minutes TARGET AUDIENCE This activity is intended for cardiologists, primary care physicians, surgeons, and other healthcare professionals who treat patients with nonvalvular atrial fibrillation at risk for stroke. PURPOSE The goal of this activity is to provide clinicians with practical information on how best to identify patients with nonvalvular atrial fibrillation who are most likely to benefit from timely initiation of novel oral anticoagulant therapy, to present an overview on the risks and benefits of current and emerging novel oral anticoagulants for patients with nonvalvular atrial fibrillation at risk for stroke, and to indicate how emerging novel oral anticoagulants and reversal therapies may affect the treatment landscape for nonvalvular atrial fibrillation. ACTIVITY OVERVIEW Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with significant morbidity and mortality. An estimated 2.7 million Americans are living with AF, and the number of patients with AF is projected to increase 150% by 2050, with >50% of these patients being older than 80 years. If untreated, patients with AF have a 5-fold or higher risk for stroke than the general population. Warfarin has been the mainstay for stroke prevention in AF for decades. Recently, 2 classes of novel oral anticoagulants (NOACs), direct thrombin inhibitors (eg, dabigatran) and factor Xa inhibitors (eg, rivaroxaban, apixaban, and edoxaban), have been approved by the US Food and Drug Administration (FDA) to prevent strokes in nonvalvular AF. The use of oral anticoagulation in patients with AF at moderate or high risk for stroke improves clinical outcomes and helps to ensure that the benefits exceed the risks of bleeding. Warfarin, an oral vitamin K antagonist, has proven efficacy it reduces stroke risk by at least 68% in patients with AF compared to placebo. However, warfarin use poses significant clinical challenges such as drug-drug, drug-food, and vitamin K interactions, which limit its use and results in low adherence to treatment. Frequent and long-term monitoring of the international normalized ratio is essential to keep warfarin in the desired therapeutic range to prevent stroke while avoiding an elevated risk of bleeding, such as intracranial hemorrhage. NOACs present advantages and disadvantages versus warfarin and should be considered as a first-line treatment for appropriate patients. For example, unlike vitamin K antagonists, NOACs do not require routine INR monitoring, have a rapid onset of action, and have a stable and predictable dose-related anticoagulant effect with few clinically relevant drug-drug interactions. In addition to the current and emerging NOACs, agents are on the horizon that hold promise for reversing the anticoagulant effects of NOACs. In fact, the first reversal agent, idarucizumab, a monoclonal antibody to dabigatran, was FDA approved in October Other reversal agents, including andexanet alfa and PER977, are being evaluated. LEARNING OBJECTIVES At the conclusion of this activity, participants should better be able to: Identify patients with nonvalvular atrial fibrillation who are most likely to benefit from timely initiation of novel oral anticoagulant therapy Analyze the risks and benefits of current and emerging novel oral anticoagulants for patients with nonvalvular atrial fibrillation at risk for stroke Discuss emerging novel oral anticoagulants and reversal therapies and their impact on the treatment landscape for nonvalvular atrial fibrillation FACULTY Michael D. Ezekowitz, MBChB, DPhil, FRCP, FACC Professor of Medicine Sidney Kimmel Medical College at Jefferson University Philadelphia, Pennsylvania Cardiovascular Research Institute New York, New York

3 Accreditation Information PHYSICIAN CONTINUING MEDICAL EDUCATION Accreditation Statement This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Postgraduate Institute for Medicine and AXIS Medical Education. The Postgraduate Institute for Medicine is accredited by the ACCME to provide continuing medical education for physicians. Credit Designation The Postgraduate Institute for Medicine designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit. Physicians should claim only the credit commensurate with the extent of their participation in the activity. METHOD OF PARTICIPATION AND REQUEST FOR CREDIT There are no fees for participating and receiving CME/CE credit for this activity. During the period February 5, 2016 through February 4, 2017, participants must read the learning objectives and faculty disclosures and study the educational activity. Upon registering and successfully completing the post-test with a score of 75% or better and the activity evaluation, your certificate will be made available immediately. To contact PIM please visit DISCLOSURE OF CONFLICTS OF INTEREST Postgraduate Institute for Medicine (PIM) requires instructors, planners, managers and other individuals who are in a position to control the content of this activity to disclose any real or apparent conflict of interest (COI) they may have as related to the content of this activity. All identified COI are thoroughly vetted and resolved according to PIM policy. PIM is committed to providing its learners with high quality CME activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest. The faculty reported the following financial relationships or relationships to products or devices they or their spouse/ life partner have with commercial interests related to the content of this CME activity: Name of Faculty Michael D. Ezekowitz, MBChB, DPhil, FRCP, FACC Reported Financial Relationship Consulting fee: Aegerion Pharmaceuticals; Amgen, Inc.; Armetheon, Inc.; Bayer Pharmaceuticals Corporation; Boehringer Ingelheim; Bristol-Myers Squibb Company; Coherex Medical; Daiichi Sankyo Company, Ltd.; Gilead; Janssen Scientific Affairs; Johnson & Johnson; Medtronic Inc.; Merck & Co., Inc.; Pfizer, Inc.; Portola Pharmaceuticals, Inc.; POZEN Inc.; sanofi-aventis The planners and managers reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity: The following PIM planners and managers, Trace Hutchison, PharmD; Samantha Mattiucci, PharmD, CHCP; Judi Smelker-Mitchek, RN, BSN; and Jan Schultz, RN, MSN, CHCP, hereby state that they or their spouse/ life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months. The following AXIS planners and managers reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity: Linda Gracie-King, MS; Ronald Viggiani, MD; Deborah Middleton, MS; Jocelyn Timko, BS; and Laura M. Healy, BS hereby state that they or their spouse/ life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months. DISCLOSURE OF UNLABELED USE This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. DISCLAIMER Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient s conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer s product information, and comparison with recommendations of other authorities. SAFEGUARDS AGAINST COMMERCIAL BIAS Postgraduate Institute for Medicine and AXIS affirm that the content and format of the CME activities and related materials promote improvements and quality in healthcare and do not promote a specific proprietary business interest of a commercial entity. To this end, Postgraduate Institute for Medicine and AXIS employ several strategies to ensure the absence of commercial bias, including, but not limited to, review of all planned content for CME activities jointly sponsored by Postgraduate Institute for Medicine and AXIS to ensure adherence to the Accreditation Council for Continuing Medical Education s content validation statements, and resolution of any actual or perceived conflicts of interest that exist. We employ three metrics as we review materials: 1. Fair balance a. Recommendations or emphasis must fairly represent and be based on a reasonable and valid interpretation of the information available on the subject matter b. No single product or service is overrepresented when other equal competing products or services are available for inclusion 2. Scientific objectivity of studies mentioned in the materials or used as the basis for content 3. Appropriateness of patient care recommendations made to learners FEE There is no fee for this educational activity

4 Novel Oral Anticoagulants: Transforming Stroke Prevention in Nonvalvular Atrial Fibrillation A Clinical Coffee Break Activity Michael D. Ezekowitz, MBChB, DPhil, FRCP, FACC Co-authors: Ronald Viggiani, MD; and Laura M. Healy, BS INTRODUCTION Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. It is associated with significant morbidity and mortality (Lewis et al, 2014). An estimated 2.7 million Americans are living with AF, and the number of patients with AF is projected to increase 150% by 2050, with >50% of these patients being older than 80 years (American Heart Association, 2014; Rao et al, 2014). If untreated, patients with AF have a 5-fold or higher risk for stroke than the general population (Rao et al, 2014). Increased life expectancies mean that AF-related stroke is a growing global public health concern. Until 2010, when dabigatran was approved for stroke prevention in AF, warfarin was the only effective option for stroke prevention (Ezekowitz et al, 1992). The use of warfarin is associated with significant challenges related to drug-drug and food-drug interactions and its use requires frequent blood monitoring to maintain anticoagulation within a narrow therapeutic window. Overall, the novel oral anticoagulants (NOACs) are as good as, or better than, warfarin therapy for stroke prevention in patients with nonvalvular AF, and they have a comparable or reduced risk of associated major bleeding. In addition, the NOACs have fewer drug-drug and food-drug interactions and do not require continuous blood monitoring. Integration of these agents into clinical practice offers patients with nonvalvular AF new treatment options, and as therapeutic use of the NOACs increases, real-world experience will add more understanding of the value of these agents. In this activity, Dr. Michael Ezekowitz reviews the importance of anticoagulation for the management of AF and discusses advances in anticoagulation therapy. WHAT IS THE RATIONALE FOR ANTICOAGULATION THERAPY IN PATIENTS WITH AF WHO ARE AT RISK FOR STROKE? Michael D. Ezekowitz, MD The rationale for anticoagulation therapy in this population is that a number of clinical trials have demonstrated that anticoagulation in appropriately selected patients dramatically reduces the incidence of stroke in patients with AF. These trials included patients who have nonvalvular AF, which is defined as, AF in the absence of rheumatic mitral stenosis, a mechanical or bioprosthetic heart valve, or mitral valve repair (January et al, 2014). But there also were a very large number of patients in these trials who had other forms of valvular disease, and they benefited from anticoagulation just as well as those who had no evidence of valvular disease (Avezum et al, 2015; Breithardt et al, 2014, Ezekowitz et al, 2014). HOW CAN CLINICIANS DETERMINE WHETHER A PATIENT WITH NONVALVULAR AF SHOULD BE RECEIVING ANTICOAGULATION THERAPY? Well, again there are considerable data from multiple sources that have led the American College of Cardiology, the American Heart Association, and the Heart Rhythm Society to produce guidelines that provide a threshold above which anticoagulation is indicated (January et al, 2014). The guidelines recommend that for patients with nonvalvular AF, the CHAD 2 DS 2 -VASc score is used to assess stroke risk (Tables 1 and 2). In the United States, oral anticoagulants are recommended for patients with nonvalvular AF and a CHA 2 DS 2 -VASc score of 2 or greater (January et al, 2014). Table 1 Stroke Risk Assessment: CHA 2 DS 2 -VASc Score C Risk Factor Congestive heart failure/left ventricular failure Points H Hypertension 1 A 2 Age 75 years 2 D Diabetes mellitus 1 S 2 Stroke/TIA/TE 2 V Vascular disease (prior MI, PAD, or aortic plaque) A Age years 1 Sc Sex category (Female) 1 Maximum score possible 9 MI, myocardial infarction; PAD, peripheral artery disease; TE, thromboembolism; TIA, transient ischemic attack. Novel Oral Anticoagulants: Transforming Stroke Prevention in Nonvalvular Atrial Fibrillation 4 1 1

5 Table 2 CHA 2 DS 2 -VASc Risk Stratification Scores for Nonvalvular AF Cumulative Score Adjusted Stroke Rate (% per year) WHAT ARE SOME OF THE SPECIFIC RECOMMENDATIONS FROM THESE GUIDELINES RELATED TO ANTITHROMBOTIC THERAPY IN PATIENTS WITH AF AND SPECIFIC RECOMMENDATIONS REGARDING THESE NOVEL ORAL ANTICOAGULANTS? There are a number of recommendations in the guidelines for risk-based antithrombotic therapy. Class I recommendations are listed in Table 3; however, learners should refer to the guidelines for a complete list of recommendations (January et al, 2014). Edoxaban was approved in January 2015 and therefore, is not included in the list of recommendations. Many clinicians think that the data from the major trials evaluating NOACs provide strong support for using the NOACs (dabigatran, rivaroxaban, apixaban, edoxaban) preferentially over warfarin for stroke prevention in AF. The RE-LY trial included 18,113 patients who had AF and were at risk for stroke to receive either 110 or 150 mg dabigatran or adjusted-dose warfarin (Connolly et al, 2009). The 150-mg dose of dabigatran was superior to warfarin regarding the primary outcome of stroke or systemic embolism (relative risk 0.66, 95% CI , P <.001), but the 110-mg dose was not (relative risk 0.91, 95% CI , P =.34). Rates of hemorrhagic stroke were 0.38% per year in the warfarin group compared with 0.10% per year in the 150-mg dabigatran group (relative risk with dabigatran 0.26, 95% CI , P <.001) and 0.12% Table 3 Summary of Recommendations Regarding Risk-based Antithrombotic Therapy in Nonvalvular AF (Class I evidence) Antithrombotic therapy based on shared decision making, discussion of risks of stroke and bleeding, and patient s preference (level of evidence: C) Selection of antithrombotic therapy based on risk of thromboembolism (level of evidence: B) CHA 2 DS 2 -VASc score recommended to assess stroke risk (level of evidence: B) Warfarin recommended for mechanical heart valves and target INR intensity based on type and location of prosthesis (level of evidence: B) With prior stroke, TIA, or CHA 2 DS 2 -VASc score 2, oral anticoagulants recommended; options include: Warfarin (level of evidence: A) Dabigatran, rivaroxaban, or apixaban (level of evidence: B) With warfarin, determine INR at least weekly during initiation of therapy and monthly when stable (level of evidence: A) Direct thrombin or factor Xa inhibitor (dabigatran, rivaroxaban, apixaban) is recommended if unable to maintain therapeutic INR with warfarin (level of evidence: C) Reevaluate the need for and choice of anticoagulation therapy at periodic intervals to reassess stroke and bleeding risks (level of evidence: C) Bridging therapy with UFH or LMWH recommended with a mechanical heart valve if warfarin is interrupted; bridging therapy should balance risks of stroke and bleeding (level of evidence: B) For patients without mechanical heart valves, bridging therapy decisions should balance stroke and bleeding risks against duration of time patient will not be receiving anticoagulation drugs (level of evidence: C) Evaluate renal function before initiation of direct thrombin or factor Xa inhibitors, and reevaluate when clinically indicated and at least annually (level of evidence: B) INR, international normalized ratio; LMWH, low-molecular-weight heparin; TIA, transient ischemic attack; UFH, unfractionated heparin. For a complete list, see January et al, per year in the 110-mg dabigatran group (relative risk 0.31, 95% CI , P <.001) (Connolly et al, 2009). These data provided very convincing evidence for the use of dabigatran. The ROCKET AF trial included 4,264 patients with nonvalvular AF who received either once-daily 20 mg rivaroxaban or dose-adjusted warfarin; the primary endpoint was stroke or systemic embolism (Patel et al, 2011). Stroke or systemic embolism occurred in Novel Oral Anticoagulants: Transforming Stroke Prevention in Nonvalvular Atrial Fibrillation 5

6 241 patients in the warfarin group (2.2%/year) and in 188 patients in the rivaroxaban group (1.7%/year) (HR in the rivaroxaban group 0.79, 95% CI , P <.001 for noninferiority) (Patel et al, 2011). The ARISTOTLE trial was a randomized, doubleblind trial that compared twice-daily 5 mg apixaban with warfarin in 18,201 patients with AF and at least 1 additional risk factor for stroke; the primary endpoint was systemic embolism or ischemic or hemorrhagic stroke (Granger et al, 2011). The rate of the occurrence of the primary outcome was 1.60% per year in the warfarin group compared with 1.27% per year in the apixaban group (HR with apixaban 0.79, 95% CI , P <.001 for noninferiority; P =.01 for superiority). The rates of death from any cause were 3.94% and 3.52%, respectively (HR 0.89, 95% CI , P =.047). The rate of hemorrhagic stroke was 0.24% per year in the apixaban group compared to 0.47% per year in the warfarin group (HR 0.51, 95% CI ; P <.001) (Granger et al, 2011). ENGAGE AF-TIMI 48 was a randomized, doubleblind, double-dummy trial comparing once-daily 30 mg (low dose) or 60 mg (high dose) edoxaban with warfarin in 21,105 patients with moderate- to high-risk AF; stroke or systemic embolism was the primary efficacy endpoint (Giugliano et al, 2013). The annualized rate of the primary endpoint was 1.50% with warfarin (median time in the therapeutic range, 68.4%) compared to 1.61% with low-dose edoxaban (HR 1.07, 97.5% CI , P =.005 for noninferiority) and 1.18% with high-dose edoxaban (HR 0.79, 97.5% CI , P <.001 for noninferiority). The rates of the secondary endpoint (composite of stroke, systemic embolism, or death from cardiovascular causes) were 4.43% for warfarin versus 3.85% with low-dose edoxaban (HR 0.87, 95% CI , P =.005), and 4.23% for high-dose edoxaban (HR 0.95, 95% CI , P =.32) (Giugliano et al, 2013). In addition to their efficacy, these novel agents, unlike warfarin, do not require routine monitoring, do not interact with other medicines or foods, and usually do not require changes in dose. The other side of the coin, of course, is bleeding. In the RE-LY trial, rates of life-threatening bleeding, intracranial bleeding, and major or minor bleeding were higher with warfarin (1.80%, 0.74%, and 18.15%, respectively) than with either the 150-mg dose of dabigatran (1.45%, 0.30%, and 16.42%, respectively) or the 110-mg dose of dabigatran (1.22%, 0.23%, and 14.62%, respectively; P <.05 for all comparisons of dabigatran with warfarin) (Connolly et al, 2009). It is also important to note that major bleeding was noninferior with the 150-mg dose of dabigatran compared to warfarin and gastrointestinal bleeding was more common in patients prescribed the 150-mg dose of dabigatran. In the ROCKET AF trial, the rates of major bleeding were comparable in the warfarin and rivaroxaban groups (3.4% and 3.6%, respectively; P =.58). Rates of intracranial hemorrhage were significantly lower in the rivaroxaban group than in the warfarin group (0.5% vs 0.7% per year, HR 0.67, 95% CI 0.47 to 0.93, P =.02). Major bleeding from a gastrointestinal site was more common in the rivaroxaban group, with 224 bleeding events (3.2%), compared with 154 events in the warfarin group (2.2%, P <.001) (Patel et al, 2011). In ARISTOTLE, the rate of major bleeding was 3.09% per year in the warfarin group compared with 2.13% per year in the apixaban group (HR 0.69, 95% CI , P <.001) (Granger et al, 2011). The ENGAGE AF-TIMI 48 study demonstrated that the annualized rate of major bleeding was 3.43% with warfarin versus 1.61% with low-dose edoxaban (HR 0.47, 95% CI , P <.001) and 2.75% with high-dose edoxaban (HR 0.80, 95% CI , P <.001) (Giugliano et al, 2013). A recent meta-analysis of all participants included in the RE-LY, ROCKET AF, ARISTOTLE, and ENGAGE AF-TIMI 48 trials reported that NOACs significantly reduced intracranial hemorrhage (HR 0.48, 95% CI ; P <.0001), but increased gastrointestinal bleeding (HR 1.25, 95% CI ; P =.04) (Ruff et al, 2014). Data from the ARISTOTLE trial indicated that apixaban was not associated with increased gastrointestinal bleeding compared with warfarin (HR 0.89, 95% CI , P =.37) (Granger et al, 2011). ARE THERE ANY SPECIFIC ISSUES TO KEEP IN MIND WHEN CONSIDERING THE USE OF A NOVEL ORAL ANTICOAGULANT? Yes, there are. There are a number of contraindications for use in the prescribing information for each of these agents. Dabigatran is contraindicated in patients with active pathologic bleeding, a history of serious sensitivity to dabigatran, and in those with mechanical prosthetic heart valves (Pradaxa Novel Oral Anticoagulants: Transforming Stroke Prevention in Nonvalvular Atrial Fibrillation 6

7 prescribing information, 2015). It should also be avoided in patients with moderate-to-severe mitral stenosis. Rivaroxaban is contraindicated in patients with active pathologic bleeding or a severe hypersensitivity to rivaroxaban; its use is not recommended in patients with prosthetic heart valves (Xarelto prescribing information, 2015). Apixaban is contraindicated in patients with active pathologic bleeding, severe hypersensitivity to the drug, and is not recommended in patients with prosthetic heart valves (Eliquis prescribing information, 2015). It should also be avoided in patients with moderate-tosevere mitral stenosis. Edoxaban is contraindicated in patients with active pathologic bleeding and its use is not recommended in patients with mechanical heart valves or moderate-to-severe stenosis (Savaysa prescribing information, 2015). Before initiating therapy with any of these agents, it is important to review the complete and most recent prescribing information. Patients with mechanical heart valves were excluded from all trials of NOACs; however, 1 study found that the use of dabigatran in patients with mechanical heart valves was associated with increased rates of bleeding and thromboembolic complications compared to warfarin (Eikelboom et al, 2013). According to the 2014 American Heart Association/American College of Cardiology Guideline for the management of patients with valvular heart disease, class I recommendations for anticoagulation in patients with a mechanical prosthetic valve include vitamin K antagonists or a vitamin K antagonist and aspirin (Nishimura et al, 2014). Class IIa recommendations for those with bioprosthetic valves include vitamin K antagonists or aspirin. Oral direct thrombin inhibitors or anti factor Xa agents should not be used in patients with mechanical valve prostheses and are listed as class III (Harm) (Nishimura et al, 2014). In addition, patients with hemodynamically significant mitral stenosis and AF should be treated with a vitamin K antagonist or heparin (Nishimura et al, 2014). Another important issue to keep in mind is the presence of renal impairment. It is important for clinicians to know a patient s creatinine clearance before administering any of these drugs because the dose may need to be adjusted (or may not be given at all) depending on a patient s renal function (Table 4). Creatinine clearance is determined by using the Cockcroft-Gault formula. Table 4 Renal Dosing for Novel Oral Anticoagulants Drug Dabigatran Apixaban Rivaroxaban Edoxaban Renal Dosing CrCl >30 ml/min: 150 mg twice daily CrCl ml/min: 75 mg twice daily CrCl <15 ml/min or on dialysis: dosing recommendations cannot be provided No dose adjustment recommended for patients with renal impairment (including those with ESRD [CrCL <15 ml/min] maintained on hemodialysis): 5 or 2.5 mg twice daily* CrCl >50 ml/min: 20 mg once daily CrCl ml/min: 15 mg once daily CrCl ml/min: 15 mg once daily CrCl <15 ml/min: dosing recommendations cannot be provided CrCl 95 ml/min: do not use CrCl >50 to 94 ml/min: 60 mg once daily CrCl ml/min: 30 mg once daily CrCl <15 ml/min: not recommended * Use apixaban 2.5 mg twice daily if any 2 characteristics are present: serum creatinine 1.5 mg/dl, 80 years old, or body weight 60 kg (132 lb). CrCl, creatinine clearance. Eliquis prescribing information, 2015; Pradaxa prescribing information, 2015; Savaysa prescribing information, 2015; Xarelto prescribing information, Women who are pregnant or lactating should not use any of the NOACs because there are no well-controlled studies of their use in this population (Bates et al, 2012). Treatment will likely increase the risk for hemorrhage during pregnancy and delivery, so NOACs should only be used if the benefit outweighs the risks. A very important group of patients are those with coronary disease who require dual antiplatelet therapy. For these patients, there are no current data that support the use of a novel agent; therefore, it is advisable to use a vitamin K antagonist. However, this is a field that is actively evolving some clinicians, based on their clinical judgment, drop the aspirin rather than use dual antiplatelet therapy if they think that an anticoagulant is needed. But that is a judgment call and is not based on evidence. Novel Oral Anticoagulants: Transforming Stroke Prevention in Nonvalvular Atrial Fibrillation 7

8 WHAT DO CLINICIANS NEED TO KNOW ABOUT THE USE OF ASPIRIN FOR STROKE PREVENTION IN AF? There are strong data that support the fact that aspirin is of no value for stroke prevention in AF (Hart et al, 2007). In fact, the risk of bleeding increases when aspirin is used concomitantly with an anticoagulant, and the risk of bleeding with aspirin, even when used alone, is not trivial. So one of the most important points of management has evolved in the past several years; namely, that the use of aspirin for primary prevention in patients at risk for coronary disease is currently discouraged because the evolving data suggest that the bleeding risk exceeds the risk of the therapeutic benefit. The bottom line is that aspirin has limited use for stroke prevention in AF. In addition, clinicians should make sure that aspirin is being used for a legitimate reason in their patients who have an indication for using anticoagulation for stroke prevention in AF. WHAT DOES THE EVIDENCE SAY REGARDING THE EFFICACY AND SAFETY OF THE NOACS COM- PARED WITH WARFARIN? I think that s best answered by looking at data from the meta-analysis that Christian Ruff and I and others published in Lancet (Ruff et al, 2014). This metaanalysis basically included all the NOAC trials and very nicely demonstrated, as I pointed out earlier, that dabigatran 150 mg twice daily is the most effective of these agents for reducing stroke, which includes ischemic stroke, and also intracerebral bleeds. However, all the remaining agents in terms of efficacy were either noninferior or superior (Figure 1). The only agent superior to warfarin at reducing ischemic stroke was dabigatran (150 mg twice daily). Apixaban was superior for reducing stroke in general, but not ischemic stroke. And stroke, of course, is accompanied by systemic embolization, so there is a similar reduction in systemic embolization, but the event rates are much lower than the stroke event rates (Ruff et al, 2014). Now it s notable and very important that all these drugs reduce intracranial hemorrhage by at least 50% (Figure 2). The mechanism by which this occurs is not clear, but it s a highly reproducible finding in all groups of patients studied and was, quite frankly, a major but pleasant surprise. It is important to recognize that with 3 of these drugs, the higher dose of dabigatran (150 mg), the 20 mg dose of rivaroxaban, and the 60 mg dose edoxaban, there is an increase in gastrointestinal bleeding (Connolly et al, 2009; Patel et al, 2011; Giugliano et al, 2013). The absolute numbers of gastrointestinal bleeds are actually quite small. It is clearly preferable if you are going to have a bleed, a complication of all effective anticoagulants, it is better to have a gastrointestinal bleed than an intracerebral bleed. Figure 1 Stroke or Systemic Embolic Events Data are n/n unless otherwise indicated. Heterogeneity: I 2 =47%; P =.13. NOAC, new oral anticoagulant; RR, risk ratio. *Dabigatran 150 mg twice daily. Rivaroxaban 20 mg once daily. Apixaban 5 mg twice daily. Edoxaban 60 mg once daily. Novel Oral Anticoagulants: Transforming Stroke Prevention in Nonvalvular Atrial Fibrillation 8

9 Figure 2 Secondary Efficacy and Safety Outcomes Data are n/n unless otherwise indicated. Heterogeneity: ischemic stroke I 2 = 32%, P =.22; hemorrhagic stroke I 2 = 34%, P =.21; myocardial infarction I 2 = 48%, P =.13; all-cause mortality I 2 = 0%, P =.81; intracranial hemorrhage I 2 = 32%, P =.22; gastrointestinal bleeding I 2 = 74%, P =.009. NOAC, new oral anticoagulant; RR, risk ratio. CAN YOU SUMMARIZE SOME OF THE BENEFITS OF THE ORAL ANTICOAGULANTS COMPARED WITH WARFARIN? It s important to recognize that the NOACs were all specifically designed to obviate the difficulties of using warfarin. Therefore, they all have a rapid onset of action after oral ingestion and they all have short halflives. The short half-life was thought to be important in that in the event of a bleed, the effect of the drugs dissipated quickly if they were discontinued, which was an easy antidote. The NOACs also all have highly predictable pharmacokinetic patterns, unlike warfarin, and therefore there s no need for routine monitoring. However, because these drugs are required twice a day or once a day, it is exceedingly important to educate patients regarding the importance of adherence to the dosing regimen. All healthcare providers who work with patients taking these agents should provide guidance to the patients and their families/caregivers about the importance of adherence. It is important for them to know that if they don t take their medication, it increases the likelihood of strokes and thrombotic events; if they don t take their medication on a regular basis, they cease to be protected. WHAT ARE SOME OF THE RISKS MORE COMMON WITH THE NOVEL ORAL ANTICOAGULANTS COMPARED WITH WARFARIN? I have emphasized the importance of adherence because these are short-acting drugs, so taking them exactly as indicated is crucial. The bleeding risks, though, in general, are either similar to warfarin or less than warfarin. So even with respect to bleeding, there are important advantages of NOACs. Clinicians should not be lulled into a false sense of security with these agents, however, thinking that these drugs are perfectly safe. They are effective anticoagulants but they are associated with an increased risk of bleeding and patients need to be made aware of that. In addition, the issue of cost is not really a risk but is something to keep in mind and is a moving target. Warfarin, of course, is a very old drug and is inexpensive. The cost of the NOACs is much higher but is covered by insurance in the United States. There is generally a copay that varies depending on the patient s insurance coverage and patients need to be made aware of that. However, there are also indirect costs associated with warfarin, including the costs associated with the need for frequent monitoring. In addition, there are indirect cost reductions that are difficult to define with the NOACs, because of reductions of events, for example, a reduced number of ischemic and bleeding events with dabigatran, apixaban, and edoxaban. Because the number of adverse events is fewer than that seen with warfarin, there are cost savings beyond the actual cost of the medication. Therefore, if you look at this globally, there actually may be potential cost savings in the long term for the NOACs compared to warfarin. Novel Oral Anticoagulants: Transforming Stroke Prevention in Nonvalvular Atrial Fibrillation 9

10 HOW DO THE DIFFERENT NOVEL ORAL ANTICO- AGULANTS COMPARE WITH EACH OTHER? Comparing the novel agents, one with another, is actually quite difficult because there has been no headto-head comparison. In addition, the characteristics of the patients in the clinical trials for each of these agents were quite different. That said, there are characteristics of the drugs that do differentiate one from another. For instance, the differences in dosing (Table 5). Dabigatran and apixaban are prescribed twice a day that s extremely important and rivaroxaban and edoxaban are prescribed once a day (Eliquis prescribing information, 2015; Pradaxa prescribing information, 2015; Savaysa prescribing information, 2015; Xarelto prescribing information, 2015). It s also important to recognize that rivaroxaban needs to be taken with food, whereas the other drugs do not. There are potential drug-drug interactions. The P-glycoprotein enzyme system promotes the excretion Table 5 Selected Features of Currently Approved NOACs Used in Nonvalvular AF of these drugs from the bloodstream by pumping them from the bloodstream into the gastrointestinal tract. Therefore, if patients are taking agents that inhibit the P-glycoprotein system concomitantly with any of the NOACs, there is a chance of increasing the blood levels of the NOACs and potentially increasing the risk of bleeding. The most commonly prescribed P-glycoprotein inhibitors in patients with cardiac issues are amiodarone, dronedarone, verapamil, and diltiazem. Others include ketoconazole, ticagrelor, and clarithromycin (Finch and Pillans, 2014). Clinicians must be aware that these drugs can have interactions with NOACs and use their clinical judgment regarding their concomitant use. CAN YOU PROVIDE SOME PRACTICAL TIPS ON HOW CLINICIANS MAY SELECT AMONG THESE DIFFERENT AGENTS FOR PARTICULAR PATIENTS? Well, I think that we have very good data to help us decide whether to use a novel agent compared to a vitamin K antagonist. As I pointed out earlier, patients with mechanical heart valves, mitral stenosis, or with Feature Dabigatran Apixaban Rivaroxaban Edoxaban Mechanism of action Thrombin inhibitor Factor Xa inhibitor Factor Xa inhibitor Factor Xa inhibitor Dosing 150 mg BID 5 mg BID 20 mg QD 60 mg QD How taken Oral Oral Orally with evening meal Oral Drug-drug interactions Geriatric use Warnings P-gp inducers rifampin: avoid coadministration P-gp inhibitors in patients with CrCl ml/min: reduce dose or avoid P-gp inhibitors in patients with CrCl <30 ml/min: not recommended Risk of bleeding increases with age Premature discontinuation increases the risk for thrombotic events; spinal/ epidural hematoma may occur Strong dual inhibitors of CYP3A4 and P-gp increase blood levels of apixaban: reduce dose or avoid coadministration Simultaneous use of strong dual inducers of CYP3A4 and P-gp reduces blood levels of apixaban: avoid concomitant use No restrictions Premature discontinuation increases the risk for thrombotic events; spinal/ epidural hematoma may occur Combined P-gp and strong CYP3A4 inhibitors and inducers: avoid concomitant use Avoid use with anticoagulants Risk of bleeding and thrombotic events increases with age Premature discontinuation increases the risk for thrombotic events; spinal/epidural hematoma may occur Avoid concomitant use with anticoagulants and rifampin No restrictions Reduced efficacy in patients with CrCl >95 ml/ min; Premature discontinuation increases the risk for ischemic events; spinal/epidural hematoma may occur BID, twice daily; CrCl, creatinine clearance; P-gp, P-glycoprotein; QD, once daily. Eliquis prescribing information, 2015; Pradaxa prescribing information, 2015; Savaysa prescribing information, 2015; Xarelto prescribing information, Novel Oral Anticoagulants: Transforming Stroke Prevention in Nonvalvular Atrial Fibrillation 10

11 significantly impaired renal function should be using vitamin K antagonists. An exciting advance, just in October 2015, was the US Food and Drug Administration approval of a reversal agent for dabigatran (Boehringer Ingelheim Press Release, 2015). This agent, idarucizumab, is most certainly now available in several hospital systems. One of the nice things about this agent is that it has highly predictable pharmacokinetics. The RE-VERSE-AD trial was a phase 3 prospective cohort study to determine the efficacy and safety of idarucizumab to reverse the anticoagulant effects of dabigatran in patients with either serious bleeding or who required an urgent procedure (Pollack et al, 2015). Results from this trial showed that when idarucizumab was given in 2 sequential doses of 2.5 g intravenously, 68 patients with an elevated dilute thrombin time and 81 with an elevated ecarin clotting time at baseline had a median maximum percentage reversal of 100% (95% CI ). Idarucizumab normalized test results in 88% to 98% of the patients, an effect that was evident within minutes (Pollack et al, 2015). Fortunately, life-threatening bleeds with dabigatran are uncommon, but what was demonstrated in this trial was that within the cohort of patients who had serious bleeding (and who could be assessed), hemostasis was restored at a median of approximately 11 hours after the administration of the reversal agent (Pollack et al, 2015). These data suggest that when a patient has a lifethreatening bleed in the presence of dabigatran, that dabigatran is only 1 contributor to the major bleed, and there are obviously other contributors. A clear example of other contributing pathologies is individuals who have, for instance, trauma from an automobile accident while taking dabigatran. Obviously, dabigatran may contribute to their bleeding, but other measures such as surgical ligation of a bleeding artery or repairing a vascular structure, if indicated, would also be needed. So I think that the availability of a reversal agent does help in selecting which of the novel agents one would want to prescribe. Now, there are reversal agents that are in development for the factor Xa inhibitors, but they are not yet approved. The ANNEXA-A and ANNEXA-R trials were randomized, double-blind, placebo-controlled studies to evaluate the efficacy and safety of andexanet alfa to reverse anticoagulation with apixaban or rivaroxaban in healthy older volunteers (50-75 years old) (Siegal et al, 2015). The study included 48 patients in the apixaban group and 53 in the rivaroxaban group who received andexanet alfa and 17 patients in the apixaban group and 27 in the rivaroxaban group who received placebo. Bolus administration of andexanet alfa reduced anti factor Xa activity rapidly (within 2-5 minutes) in the apixaban study (mean [+/- SD] reduction, 94% ± 2% vs 21% ± 9%; P <.001) and in the rivaroxaban study (92% +/- 11% vs 18% +/- 15%, P <.001) (Siegal et al, 2015). The reversal lasted for approximately 2 hours (consistent with the 1-hour half-life of the drug). There were no clinical toxic effects. Phase 3b to 4 studies are ongoing (Portola Pharmaceuticals, NCT ). A potential broad-spectrum reversal agent currently being studied is PER977 (AKA ciraparantag, aripazine; Perosphere, NCT ). The safety, side effect profile, and effect on anticoagulation reversal of escalating single intravenous doses of PER977 (5-300 mg) when administered alone and after a 60-mg dose of edoxaban were assessed in 80 healthy people (Ansell et al, 2014). Three hours after the administration of edoxaban in patients who received a single intravenous dose of PER977 ( mg), the wholeblood clotting time decreased to within 10% above the baseline value in 10 minutes; in patients receiving placebo, it took approximately 12 to 15 hours. Baseline hemostasis was sustained for 24 hours. Results of the phase 2 study are pending (Ansell et al, 2014). Other factors to consider: dabigatran does have gastrointestinal adverse symptoms, such as dyspepsia, which responds to taking the medication with fluids, or prescribing proton pump inhibitors, but there are a small number of patients who are intolerant to dabigatran and need to be switched to another novel agent because of gastrointestinal symptoms. Ultimately, it s the decision of the prescribing doctor which among these agents to use. One point that I would make is that for different reasons, these novel agents are all better than warfarin, and in my view should be used in preference to warfarin, but this is a decision that needs to be made on an individual basis. HOW SHOULD CLINICIANS SELECT AMONG THE NOACS FOR SPECIFIC TYPES OF PATIENTS? The only point that I would make here in addition to what I have already covered is that among the elderly Novel Oral Anticoagulants: Transforming Stroke Prevention in Nonvalvular Atrial Fibrillation 11

12 and the high-risk patients, the relative benefit of the novel agents is at least similar to those at lower risk. Just because a patient is elderly should not be a contraindication to anticoagulation, and certainly should not be a contraindication to using a novel oral agent. I think the issues of renal function in older patients are extremely important because we know that renal function deteriorates with age (Table 4). As I mentioned, there is an ability to down-titrate all the novel agents to a lower dose as renal function deteriorates. If the renal function reaches levels at which these drugs should not be used, then a patient can be transitioned to a vitamin K antagonist. I would also say that the use of antiplatelet agents, like aspirin, is associated with increased bleeding, so the concomitant use of aspirin with any anticoagulant is associated with increased bleeding. There is no efficacy advantage regarding stroke prevention in combining aspirin with an oral anticoagulant, so one should look very carefully at why the aspirin is being prescribed. There are good data to suggest that aspirin is often used for indications that are not supported by the literature, and one can safely discontinue the aspirin and reduce the chances of bleeding. The transition from a novel agent to a vitamin K antagonist is more difficult. Patients need to have a period of time when there is simultaneous administration of the vitamin K antagonist and the novel agent, and the novel agent should be discontinued immediately when the INR approaches 2. However, it is important that the novel agent not be discontinued prematurely to prevent patients from having a period of time when they are not anticoagulated. We all know the vitamin K antagonists take time to reach a therapeutic benefit, so this overlap of the 2 agents is very important. When transitioning from dabigatran to warfarin, administer warfarin 3 days before discontinuing dabigatran for a creatinine clearance (CrCl) >50 ml/ min; for a CrCl between 31 and 50 ml/min, start warfarin 2 days before discontinuing dabigatran; and for a CrCl of 15 to 30 ml/min, start warfarin 1 day before discontinuing dabigatran. For rivaroxaban and apixaban, discontinue the drug and begin both parenteral anticoagulation and warfarin at the time of the scheduled next dose; discontinue parenteral administration once the therapeutic INR is reached (Ezekowitz et al, 2014). YOU MENTIONED TRANSITIONING FROM A NOAC TO A VITAMIN K ANTAGONIST. WHAT DO CLINICIANS NEED TO KNOW ABOUT DRUG TRANSITIONING EITHER ON OR OFF NOVEL ORAL ANTICOAGULANTS? Drug transitioning from a vitamin K antagonist to a novel agent is important. When patients transition from a vitamin K antagonist to either dabigatran, apixaban, and edoxaban, clinicians must be sure that the international normalized ratio (INR) is less than 2 so that patients are not being double-anticoagulated. When transitioning from a vitamin K antagonist to rivaroxaban, the INR should be less than 3 prior to starting rivaroxaban. So that s relatively straight forward. There is no need for hospital admission or bridging therapy unless the NOAC cannot be given orally (Ezekowitz et al, 2014). The transition from parental heparin to a novel agent should occur when the next dose of heparin (either intravenous or subcutaneous) is due. Instead of taking the heparin, it can be immediately discontinued and the novel agent can then be given without interruption. RECENTLY THE FIRST REVERSAL AGENT WAS APPROVED. YOU HAD MENTIONED THIS AGENT BEFORE BUT CAN YOU PROVIDE SOME ADDI- TIONAL INFORMATION ABOUT THIS NEW DRUG? The approved agent, idarucizumab, is a reversal agent specific for dabigatran. It is a humanized monoclonal fragment with a very high affinity for dabigatran; it binds to dabigatran, which is cleared by the kidney. Data are now available that suggest that for patients who are bleeding and require this reversal agent, that, if clinically needed, they can restart dabigatran within 24 hours (Glund et al, 2014). The recommended dose of idarucizumab is 5 g, intravenously administered as 2 consecutive infusions of each of the 2.5 g vials or as a bolus injection by injecting both vials consecutively via syringe (Praxbind prescribing information, 2015). As I mentioned earlier, idarucizumab has almost instantaneous reversal with the bolus injection. This reversal agent, in my view, will be most effective for patients who have lifethreatening extracranial bleeds. It probably will not have much impact on intracranial bleeds because these become a neurosurgical problem rather than an Novel Oral Anticoagulants: Transforming Stroke Prevention in Nonvalvular Atrial Fibrillation 12

13 anticoagulation problem. The data on this are evolving but my sense in discussing this with neurosurgeons is that this reversal agent is unlikely to have much benefit in patients with intracranial bleeds. Another group who will, in my view, benefit from the availability of idarucizumab will be patients requiring urgent surgery for any reason. For example, patients could need surgery for an acute appendicitis and be taking dabigatran. Using this reversal agent to eliminate the dabigatran effect in these patients would clearly be an advantage. In fact, in the RE-VERSE-AD trial, data showed that for patients who were prescribed the drug in an emergency situation because the patient required surgery, 93% of those who could be evaluated had a normalized dilute thrombin time after the reversal agent was prescribed and were judged to have normal surgical bleeding (Pollack et al, 2015). So I believe this is a major step forward. I do not think that this drug will be used very commonly, but I think that from a psychological standpoint it is very important to have a reversal agent available. IS THERE ANY ADDITIONAL INFORMATION YOU WOULD LIKE TO ADD REGARDING SOME OF THE OTHER EMERGING REVERSAL AGENTS? Well, it s a very fast moving field. As I mentioned earlier, data about the uniform reversal agent, andexanet alfa, was published in The New England Journal of Medicine (Siegal et al, 2015). Patients in this study were healthy volunteers and the effect of the drug in patients being administered both apixaban and rivaroxaban showed that the factor Xa concentration was significantly reduced. It s important to recognize that andexanet alfa requires different dosing paradigms for the different novel anticoagulants and, unlike idarucizumab, requires not only an intravenous injection, but continuous infusion to maintain its inhibiting effect of the factor Xa inhibitors. It s also important to mention that as of the date of this interview, this drug is not yet approved for use. PER977 (AKA ciraparantag, aripazine) is currently being studied for use as a broad-spectrum reversal agent for low-molecular-weight heparin, unfractionated heparin, and all new NOACs (Perosphere, 2015). As I mentioned earlier, preliminary results are encouraging for the reversal of edoxaban and phase 2 trial results are forthcoming (Ansell et al, 2014). So, as I pointed out, these data are relatively new, and the field regarding the reversal agents is moving very fast, so there ll be a lot of new information regarding these drugs. IN YOUR OPINION, WHAT HAS BEEN THE IMPACT OF THESE NOACS ON THE MORBIDITY AND MOR- TALITY OF PATIENTS WITH AF WHO ARE AT RISK FOR STROKE? The impact of all the novel agents on mortality is quite interesting. In patients with AF, warfarin reduces all-cause mortality by approximately 25% to 30% compared to no treatment at all (Ezekowitz et al, 1992), but the novel agents as a class reduce all-cause mortality by approximately 10% when compared to warfarin in the populations enrolled in the clinical trials (Ruff et al, 2014). The longest continuous follow-up that we have regarding the novel oral agents comes from patients randomized into the RE-LY trial and continued without interruption into RELY-ABLE. Data from RELY-ABLE presented at AHA 2012 reported on nearly 6,000 patients from RE-LY who were followed for an additional 28 months (Boehringer Ingelheim Press Release, 2012). Results showed the rates of ischemic stroke were 1.15%/year with 150 mg twice daily of dabigatran and 1.24%/year on 110 mg twice daily of dabigatran. (Rates of hemorrhagic stroke were 0.13%/ year and 0.14%/year, respectively.) In a forthcoming paper that my colleagues and I will publish in Europace, even more long-term data from RELY-ABLE show that although the incidence of stroke continues to be dramatically reduced, all-cause mortality remains a problem for patients with AF. These patients have other comorbidities that increase their risk of dying. We still have much work to do to help these patients, but the novel agents have been a major step forward toward reducing all-cause mortality. Regarding morbidity, the strokes associated with AF are a highly morbid condition. So these strokes result in death in approximately 20% of patients within a month, but in between 50% and 60% of these patients, the AF-related strokes result in serious disability, and many of these patients are not independent following these strokes (Reiffel, 2014). So the reduction of strokes not only reduces mortality, but it also reduces serious morbidity in these patients. Novel Oral Anticoagulants: Transforming Stroke Prevention in Nonvalvular Atrial Fibrillation 13