A New Era for NOACs: What Does the Future Hold? CME

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1 This article is a CME certified activity. To earn credit for this activity visit: A New Era for NOACs: What Does the Future Hold? CME Manesh R. Patel, MD; Deepak L. Bhatt, MD, MPH; Jeffrey Weitz, MD; Barry H. Greenberg, MD Posted: 11/9/2017 Educational Impact Challenge The goal of this activity is to increase knowledge regarding new data regarding efficacy and safety of NOACs. Before you begin this activity, please assess your clinical knowledge by completing this brief survey. Answering these questions again after the activity will allow you to see what you learned and to compare your answers with those of your peers. «Back Next» IN THIS PRESENTATION Introduction Emerging Clinical Trial Data NOAC Trials in Process Concluding Remarks

2 play M FS Adobe AudienceManager ZOOM THUMBNAILS A New Era for NOACs: What Does the Future Hold? Panelists NEXT 00:00 / 32:11

3 Program Goals Evidence for NOACs in Patients With NVAF-PCI

4 PIONEER AF-PCI: Study Design [1-4] About one-third of patients with atrial fibrillation (AF) have concomitant coronary heart disease (CHD); some will require percutaneous coronary intervention (PCI) PIONEER study looks at different strategies to manage antithrombotic therapy after PCI, including triple therapy (vitamin K antagonist [VKA] plus dual antiplatelet therapy [DAPT]) Experimental arms derived from WOEST-like and ATLAS-like strategies PIONEER AF-PCI: Clinically Significant Bleeding [2,5-7]

5 In PIONEER AF-PCI, both rivaroxaban groups had lower rates of clinically significant bleeding than triple therapy Important to balance safety with efficacy Dr Weitz: From a thrombosis standpoint, the 15-mg rivaroxaban is more attractive than the 2.5-mg dose (ie, data in stroke prevention, widely used, maximizes safety) Dose reduction to 15 mg for renal impairment in ROCKET-AF and J-ROCKET DAPT associated with twofold or threefold increase in bleeding risk Assessing Competing Risks [3,8] WOEST and ISAR-TRIPLE trials brought attention to triple therapy bleeding risk with warfarin More antithrombotic agents = more bleeding = no evident benefit with respect to reducing ischemic or thromboembolic complications Dr Bhatt: How much is enough, tough to determine (15 mg may be just as good as 20 mg rivaroxaban in a particular setting) Dr Weitz: As soon as you do not need DAPT or even the P2Y 12 inhibitor, you can go back to aspirin and then ramp up the dose of your anticoagulant to full dose

6 RE-DUAL-PCI: Trial Design [9] About 10% of patients who come in for an intervention are already on an anticoagulant, usually for AF RE-DUAL-PCI included control arm of full-dose anticoagulation with warfarin and 2 experimental arms with dabigatran 110 mg twice daily or 150 mg twice daily plus adenosine diphosphate (ADP) receptor antagonists RE-DUAL-PCI: Primary Endpoint: ISTH Major or CRNM Bleeding Event [10] Bleeding rates almost halved in RE-DUAL-PCI across a variety of definitions (ie, International Society on Thrombosis and Haemostasis [ISTH] and thrombolysis in myocardial infarction [TIMI])

7 Compelling safety results, consistent with prior work Dr Bhatt: Two is better than three for bleeding, at least when the three includes full-dose anticoagulation RE-DUAL-PCI: Efficacy End Points [10] Dual therapy noninferior to triple therapy for risk of thromboembolic events [incidence of composite efficacy endpoint of thromboembolic events: 13.7% in combined dual therapy groups vs 13.4% in triple therapy group (hazard ratio [HR], 1.04; 95% CI: 0.84, 1.29; P =.005 for noninferiority) 150-mg dose balances efficacy with bleeding risk well Dr. Bhatt: If one is using dabigatran in this situation, use 150 mg plus an antiplatelet; if there is a good reason to dose adjust (eg, elderly, high-risk bleeding), then there is the flexibility of using 110 mg Dabigatran 110 mg is not available in the United States

8 Choosing the Right Dose [11] New era of non-vitamin K antagonist oral anticoagulants (NOACs): trials are making us think about dosing more -- right reason? right dose? Important to reassess if patient who comes in on low-dose NOAC needs to continue low dose Triple therapy (aspirin, second antiplatelet, and full-dose anticoagulant) is "too much" for elderly Also, may not be well-tolerated in younger patients, as seen in APPRAISE-2 Dr Weitz: If you are going to use warfarin, use a WOEST-like approach (for stroke prevention in patients with comorbidities precluding NOAC use)

9 AUGUSTUS Trial: Study Design [12] Contemporary design -- shows evolution in clinical management and trial design AUGUSTUS trial: apixaban or warfarin with aspirin or placebo, no full-dose triple therapy arm Dr Patel: As we go into practice, we are using evidence to inform ourselves rather than simply choosing what we think is our best choice Trials in the setting of PCI for all 4 NOACs COMPASS Trial: Study Design [4,13] Trial stopped early in February 2017 due to "overwhelming efficacy" Rivaroxaban doses based on ATLAS investigative group

10 COMPASS Trial: Baseline Characteristics [13] Enrolled patients with established coronary artery disease (CAD), peripheral artery disease (PAD), and carotid disease Patients with atherosclerosis in multiple vascular beds are at high risk for recurrent ischemic events Patients with high-risk bleeding excluded (recent stroke or previous hemorrhagic or lunar stroke, severe heart failure (HF), estimated glomerular filtration rate (egfr <15 ml/min) Not an acute coronary syndrome (ACS) population, even though there were patients with and without prior myocardial infarction (MI) COMPASS -- Primary Endpoint: Rivaroxaban Plus Aspirin vs Aspirin Alone [13]

11 Dr Patel: There is certainly a trend for significance with the 5-mg dose, but does not seem to be as efficacious as the 2.5-mg twice daily rivaroxaban plus aspirin dose COMPASS Trial: Efficacy Outcomes [13] Rivaroxaban plus aspirin vs aspirin alone: substantial reductions in stroke and cardiovascular (CV) death, and almost MI; overall positive broad composite COMPASS Trial: Major Bleeding [13]

12 COMPASS Trial: Net Clinical Benefit [13] COMPASS Trial: Cumulative Incidence of Primary Efficacy Outcome [4,13] 2.5 mg rivaroxaban = same winning dose as ATLAS but associated with lower mortality in COMPASS (plus aspirin) Dr Weitz: Somehow, adding low-dose anticoagulant to aspirin must enable plaque stabilization to prevent those events Powerful finding with the curves and consistency, in a large population with many potential patients affected

13 COMPASS Trial: Subgroup Analysis [13-15] Rivaroxaban plus aspirin gives "bang for your buck" in PAD group: reduction in triple endpoint (CV death, MI, and stroke) and limb events Rivaroxaban may be another option for PAD besides ticagrelor, clopidogrel, and vorapaxar NOAC Trials in Process

14 COMMANDER HF [16] Important study in a special group of patients with HF and coexisting CHD, receiving low-dose rivaroxaban or placebo on top of standard therapy NOAC Trials in Process: Unresolved Issues in Established Indications [17-27]

15 NOAC Trials in Process: Potential New Indications [12, 28-36] Concluding Remarks Revolution in use of anticoagulants (ie, right drug, right dose, right indication, right duration) -- cannot randomly interchange Dr Bhatt: Too much antithrombotic therapy on board, whether antiplatelet or anticoagulant, the sum of the two...can lead to bleeding that overwhelms any potential effects

16 Thank You This content has been condensed for improved clarity. Educational Impact Challenge What did you learn from this activity? Please click on the "Next" button to proceed to a brief survey to see how your knowledge improved after the education. You can also see how your answer compares with those of your peers. Educational Impact Challenge Abbreviations ACS = acute coronary syndrome ADP = adenosine diphosphate AF = atrial fibrillation CAD = coronary artery disease CHD = coronary heart disease CRNM = clinically relevant nonmajor CV = cardiovascular CVD = cardiovascular disease DAPT = dual antiplatelet therapy DES = drug-eluting stent egfr = estimated glomerular filtration rate HF = heart failure HR = hazard ratio INR = international normalized ratio ISTH = International Society on Thrombosis and Haemostasis MI = myocardial infarction NOAC = non-vitamin K antagonist oral anticoagulant NVAF = nonvalvular atrial fibrillation OAC = oral anticoagulant PAD = peripheral artery disease

17 PCI = percutaneous coronary intervention R = randomization Riva = rivaroxaban SAPT = single antiplatelet therapy SE = systemic embolism TAVR = transcatheter aortic valve replacement TIMI = thrombolysis in myocardial infarction VKA = vitamin K antagonist VTE = venous thromboembolism References 1. Kralev S, Schneider K, Lang S, et al. Incidence and severity of coronary artery disease in patients with atrial fibrillation undergoing first-time coronary angiography. PLoS One. 2011;6:e Gibson CM, Mehran R, Bode C, et al. An open-label, randomized, controlled, multicenter study exploring two treatment strategies of rivaroxaban and a dose-adjusted oral vitamin K antagonist treatment strategy in subjects with atrial fibrillation who undergo percutaneous coronary intervention (PIONEER AF-PCI). Am Heart J. 2015;169: e5. 3. Dewilde WJ, Oirbans T, Verheugt FW, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet. 2013;381: Abstract 4. Mega JL, Braunwald E, Wiviott SD, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012;366:9-19. Abstract 5. ROCKET AF Study Investigators. Rivaroxaban-once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation: rationale and design of the ROCKET AF study. Am Heart J. 2010;159: e1. 6. Hori M, Matsumoto M, Tanahashi N, et al. Rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation the J- ROCKET AF study --. Circ J. 2012;76: Abstract 7. Yamamoto K, Wada H, Sakakura K, et al. Cardiovascular and bleeding risk of non-cardiac surgery in patients on antiplatelet therapy. J Cardiol. 2014;64: Abstract 8. Fiedler KA, Maeng M, Mehilli J, et al. Duration of triple therapy in patients requiring oral anticoagulation after drugeluting stent implantation: the ISAR-TRIPLE trial. J Am Coll Cardiol. 2015;65: Abstract 9. Cannon CP, Gropper S, Bhatt DL, et al. Design and rationale of the RE-DUAL PCI trial: a prospective, randomized, phase 3b study comparing the safety and efficacy of dual antithrombotic therapy with dabigatran etexilate versus warfarin triple therapy in patients with nonvalvular atrial fibrillation who have undergone percutaneous coronary intervention with stenting. Clin Cardiol. 2016;39: Abstract 10. Cannon CP, Bhatt DL, Oldgren J, et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med doi: /NEJMoa [Epub ahead of print] 11. Hess CN, James S, Lopes RD, et al. Apixaban plus mono versus dual antiplatelet therapy in acute coronary syndromes: insights from the APPRAISE-2 trial. J Am Coll Cardiol. 2015;66: Abstract 12. ClinicalTrials.gov. A Study of Apixaban in Patients With Atrial Fibrillation, Not Caused by a Heart Valve Problem, Who Are at Risk for Thrombosis (Blood Clots) Due to Having Had a Recent Coronary Event, Such as a Heart Attack or a Procedure to Open the Vessels of the Heart. NCT Accessed September 28, Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med doi: /NEJMoa [Epub ahead of print] 14. Bhatt DL, Flather MD, Hacke W, et al. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol. 2007;49: Abstract 15. Bonaca MP, Bhatt DL, Storey RF, et al. Ticagrelor for prevention of ischemic events after myocardial infarction in patients with peripheral artery disease. J Am Coll Cardiol. 2016;67: Abstract 16. Zannad F, Greenberg B, Cleland JG, et al. Rationale and design of a randomized, double-blind, event-driven, multicentre study comparing the efficacy and safety of oral rivaroxaban with placebo for reducing the risk of death, myocardial infarction or stroke in subjects with heart failure and significant coronary artery disease following an exacerbation of heart failure: the COMMANDER HF trial. Eur J Heart Fail. 2015;17: Abstract 17. ClinicalTrials.gov. A Study Exploring Two Treatment Strategies in Patients With Atrial Fibrillation Who Undergo Catheter Ablation Therapy. NCT Accessed October 4, ClinicalTrials.gov. A Study of Rivaroxaban (JNJ ) on the Venous Thromboembolic Risk in Post-Hospital Discharge Patients. NCT Accessed October 4, ClinicalTrials.gov. Extended Venous Thromboembolism Prophylaxis Comparing Rivaroxaban to Aspirin Following Total

18 Hip and Knee Arthroplasty. NCT Accessed October 4, ClinicalTrials.gov. CANVAS - CANagliflozin cardiovascular Assessment Study. NCT Accessed October 4, ClinicalTrials.gov. Comparative Investigation of Low Molecular Weight (LMW) Heparin/Edoxaban Tosylate (DU176b) Versus (LMW) Heparin/Warfarin in the Treatment of Symptomatic Deep-Vein Blood Clots and/or Lung Blood Clots. (The Edoxaban Hokusai-VTE Study). NCT Accessed October 4, ClinicalTrials.gov. Trial to Evaluate Anticoagulation Therapy in Hemodialysis Patients With Atrial Fibrillation. NCT Accessed October 4, Study to Compare the Safety of Rivaroxaban Versus Acetylsalicylic Acid in Addition to Either Clopidogrel or Ticagrelor Therapy in Participants With Acute Coronary Syndrome (GEMINI ACS 1) Accessed October 4, ClinicalTrials.gov. Exploring the Efficacy and Safety of Rivaroxaban to Support Elective Percutaneous Coronary Intervention. NCT Accessed October 4, ClinicalTrials.gov. Global Study Comparing a rivaroxaban-based Antithrombotic Strategy to an antiplatelet-based Strategy After Transcatheter aortic valve replacement to Optimize Clinical Outcomes. NCT Accessed October 4, ClinicalTrials.gov. Anti-Thrombotic Strategy After Trans-Aortic Valve Implantation for Aortic Stenosis. NCT Accessed October 4, ClinicalTrials.gov. Edoxaban Compared to Standard Care After Heart Valve Replacement Using a Catheter in Patients With Atrial Fibrillation (ENVISAGE-TAVI AF). NCT Accessed October 4, ClinicalTrials.gov. Rivaroxaban Versus Aspirin in Secondary Prevention of Stroke and Prevention of Systemic Embolism in Patients With Recent Embolic Stroke of Undetermined Source (ESUS). NCT Accessed October 4, ClinicalTrials.gov. Dabigatran Etexilate for Secondary Stroke Prevention in Patients With Embolic Stroke of Undetermined Source (RE-SPECT ESUS). NCT Accessed October 4, ClinicalTrials.gov. Apixaban for Treatment of Embolic Stroke of Undetermined Source. NCT Accessed October 4, ClinicalTrials.gov. Valsartan Optimal Therapy Against Elevated Home Blood Pressure Research (VOYAGER) Study. NCT Accessed October 4, ClinicalTrials.gov. Study of Reduced Anti-coagulation/Anti-platelet Therapy in Patients With the HeartMate II Left Ventricular Assist System (LVAS) (TRACE). NCT Accessed October 4, ClinicalTrials.gov. Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation. NCT Accessed October 4, ClinicalTrials.gov. Edoxaban Treatment Versus Vitamin K Antagonist (VKA) in Patients With Atrial Fibrillation (AF) Undergoing Catheter Ablation. NCT Accessed October 4, ClinicalTrials.gov. Efficacy and Safety of Rivaroxaban in Reducing the Risk of Major Thrombotic Vascular Events in Subjects With Symptomatic Peripheral Artery Disease Undergoing Peripheral Revascularization Procedures of the Lower Extremities. NCT Accessed October 4, ClinicalTrials.gov. Edoxaban Treatment Versus Vitamin K Antagonist in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention. NCT Accessed October 4, This article is a CME certified activity. To earn credit for this activity visit: