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Manesh R. Patel, MD; Deepak L. Bhatt, MD, MPH; Jeffrey Weitz, MD; Barry H. Greenberg, MD

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The goal of this activity is to increase knowledge regarding new data regarding efficacy and safety of NOACs.

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

Posted: 11/9/2017

IN THIS PRESENTATION

Introduction

Emerging Clinical Trial Data

NOAC Trials in Process

Concluding Remarks

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

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Program Goals

Evidence for NOACs in Patients With NVAF-PCI



PIONEER AF-PCI: Study Design[1-4]

About one-third of patients with atrial fibrillation (AF) have concomitant coronary heart disease (CHD); some will requirepercutaneous coronary intervention (PCI)PIONEER study looks at different strategies to manage antithrombotic therapy after PCI, including triple therapy (vitaminK 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]



In PIONEER AF-PCI, both rivaroxaban groups had lower rates of clinically significant bleeding than triple therapyImportant to balance safety with efficacyDr Weitz: From a thrombosis standpoint, the 15-mg rivaroxaban is more attractive than the 2.5-mg dose (ie, data instroke prevention, widely used, maximizes safety)Dose reduction to 15 mg for renal impairment in ROCKET-AF and J-ROCKETDAPT 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 warfarinMore antithrombotic agents = more bleeding = no evident benefit with respect to reducing ischemic or thromboemboliccomplicationsDr Bhatt: How much is enough, tough to determine (15 mg may be just as good as 20 mg rivaroxaban in a particularsetting)Dr Weitz: As soon as you do not need DAPT or even the P2Y12 inhibitor, you can go back to aspirin and then ramp upthe dose of your anticoagulant to full dose



RE-DUAL-PCI: Trial Design[9]

About 10% of patients who come in for an intervention are already on an anticoagulant, usually for AFRE-DUAL-PCI included control arm of full-dose anticoagulation with warfarin and 2 experimental arms with dabigatran110 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 Thrombosisand Haemostasis [ISTH] and thrombolysis in myocardial infarction [TIMI])



Compelling safety results, consistent with prior workDr 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 ofthromboembolic 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 wellDr. Bhatt: If one is using dabigatran in this situation, use 150 mg plus an antiplatelet; if there is a good reason to doseadjust (eg, elderly, high-risk bleeding), then there is the flexibility of using 110 mgDabigatran 110 mg is not available in the United States



Choosing the Right Dose[11]

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



AUGUSTUS Trial: Study Design[12]

Contemporary design -- shows evolution in clinical management and trial designAUGUSTUS trial: apixaban or warfarin with aspirin or placebo, no full-dose triple therapy armDr Patel: As we go into practice, we are using evidence to inform ourselves rather than simply choosing what we thinkis our best choiceTrials 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



COMPASS Trial: Baseline Characteristics[13]

Enrolled patients with established coronary artery disease (CAD), peripheral artery disease (PAD), and carotid diseasePatients with atherosclerosis in multiple vascular beds are at high risk for recurrent ischemic eventsPatients 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 myocardialinfarction (MI)

COMPASS -- Primary Endpoint: Rivaroxaban Plus Aspirin vs Aspirin Alone[13]



Dr Patel: There is certainly a trend for significance with the 5-mg dose, but does not seem to be as efficacious as the2.5-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]



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 eventsPowerful finding with the curves and consistency, in a large population with many potential patients affected



COMPASS Trial: Subgroup Analysis[13-15]

Rivaroxaban plus aspirin gives "bang for your buck" in PAD group: reduction in triple endpoint (CV death, MI, andstroke) and limb eventsRivaroxaban may be another option for PAD besides ticagrelor, clopidogrel, and vorapaxar

NOAC Trials in Process



COMMANDER HF[16]

Important study in a special group of patients with HF and coexisting CHD, receiving low-dose rivaroxaban or placeboon top of standard therapy

NOAC Trials in Process: Unresolved Issues in Established Indications[17-27]



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 randomlyinterchangeDr Bhatt: Too much antithrombotic therapy on board, whether antiplatelet or anticoagulant, the sum of the two...can leadto bleeding that overwhelms any potential effects



Thank You

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Abbreviations

ACS = acute coronary syndromeADP = adenosine diphosphateAF = atrial fibrillationCAD = coronary artery diseaseCHD = coronary heart diseaseCRNM = clinically relevant nonmajorCV = cardiovascularCVD = cardiovascular diseaseDAPT = dual antiplatelet therapyDES = drug-eluting stenteGFR = estimated glomerular filtration rateHF = heart failureHR = hazard ratioINR = international normalized ratioISTH = International Society on Thrombosis and HaemostasisMI = myocardial infarctionNOAC = non-vitamin K antagonist oral anticoagulantNVAF = nonvalvular atrial fibrillationOAC = oral anticoagulantPAD = peripheral artery disease



PCI = percutaneous coronary interventionR = randomizationRiva = rivaroxabanSAPT = single antiplatelet therapySE = systemic embolismTAVR = transcatheter aortic valve replacementTIMI = thrombolysis in myocardial infarctionVKA = vitamin K antagonistVTE = venous thromboembolism

References

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2. Gibson CM, Mehran R, Bode C, et al. An open-label, randomized, controlled, multicenter study exploring two treatmentstrategies of rivaroxaban and a dose-adjusted oral vitamin K antagonist treatment strategy in subjects with atrialfibrillation who undergo percutaneous coronary intervention (PIONEER AF-PCI). Am Heart J. 2015;169:472-478.e5.

3. Dewilde WJ, Oirbans T, Verheugt FW, et al. Use of clopidogrel with or without aspirin in patients taking oralanticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial.Lancet. 2013;381:1107-1115. Abstract

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5. ROCKET AF Study Investigators. Rivaroxaban-once daily, oral, direct factor Xa inhibition compared with vitamin Kantagonism for prevention of stroke and embolism trial in atrial fibrillation: rationale and design of the ROCKET AF study.Am Heart J. 2010;159:340-347.e1.

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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 versuswarfarin triple therapy in patients with nonvalvular atrial fibrillation who have undergone percutaneous coronaryintervention with stenting. Clin Cardiol. 2016;39:555-564. Abstract

10. Cannon CP, Bhatt DL, Oldgren J, et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N EnglJ Med. 2017. doi: 10.1056/NEJMoa1708454. [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;66:777-787. Abstract

12. ClinicalTrials.gov. A Study of Apixaban in Patients With Atrial Fibrillation, Not Caused by a Heart Valve Problem, WhoAre at Risk for Thrombosis (Blood Clots) Due to Having Had a Recent Coronary Event, Such as a Heart Attack or aProcedure to Open the Vessels of the Heart. NCT0215400. https://clinicaltrials.gov/ct2/show/NCT02415400. AccessedSeptember 28, 2017.

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14. Bhatt DL, Flather MD, Hacke W, et al. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterialdisease in the CHARISMA trial. J Am Coll Cardiol. 2007;49:1982-1988. Abstract

15. Bonaca MP, Bhatt DL, Storey RF, et al. Ticagrelor for prevention of ischemic events after myocardial infarction inpatients with peripheral artery disease. J Am Coll Cardiol. 2016;67:2719-2728. Abstract

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https://www.medscape.org/medline/abstract/23415013












This article is a CME certified activity. To earn credit for this activity visit:http://www.medscape.org/viewarticle/884772

Hip and Knee Arthroplasty. NCT01720108. https://clinicaltrials.gov/ct2/show/NCT01720108. Accessed October 4, 2017.20. ClinicalTrials.gov. CANVAS - CANagliflozin cardioVascular Assessment Study. NCT01032629.

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