Anticoagulant Therapies Aft fter Endovascular In Interv rvention - PowerPoint PPT Presentation

Anticoagulant Therapies Aft fter Endovascular In Interv rvention Connie N. Hess, MD, MHS University of Colorado School of Medicine CPC Clinical Research

Dis isclosures Research grants to CPC Clinical Research from Bayer and Merck

Peripheral Artery Revascularization • Indications for revascularization in PAD: • Symptom relief in claudication unresponsive to medical treatment • Relief of ischemic pain, healing of ischemic ulcers, and limb salvage in critical limb ischemia • Increasing rates of peripheral revascularization in U.S. Goodney PP et al. J Vasc Surg 2009;50:54-60

Key Post-Procedure Outcomes • Vessel patency • Acute limb ischemia (ALI) } Major adverse limb events • Major amputation (MALE) • Major adverse cardiovascular events (MACE) • Bleeding

Device Trials Focused on Patency Freedom from: Trial (device) Primary Restenosis TLR Death Amputation Target limb Surgical Outcome ischemia vessel requiring repair surgical intervention SUPERB (Nitinol stent) Primary X X patency Zilver PTX (DES) Composite of X X X X X patency/death IN.PACT SFA (DCB) Primary X X patency LEVANT 2 (DCB) Primary X X patency POPUP (Dacron vs Primary PTFE fem-pop bypass) patency Klinkert et al (PTFE vs Primary vein fem-pop bypass) patency 1. Circ Cardiovasc Interv 2015;8:e00093; 2. Circ Cardiovasc Interv 2011;4:495-504; 3; Circulation 2015;131:495-502; 4. N Engl J Med 2015;373:145-153; 5. Eur J Vasc Endovasc Surg 2007;34:44-9; 6. J Vasc Surg 2003;37:149-55

Patients Undergoing Peripheral Revascularization are at Heightened Risk of Cardiovascular and Limb Complications Early and Late After Intervention

Outcomes after Peripheral Artery Revascularization 381,415 Pts Undergoing Peripheral Artery Revascularization in the US 20 18.8 18 MALE component 30-day 1-year 16 % patients ALI 0.6% 2.6% 14 12.8 11.0 12 Major amputation 0.9% 3.5% 10.3 10 Surgical 1.4% 6.0% 8 revascularization 5.1 6 3.0 4 2.7 2.7 2.0 1.0 2 0.3 0.2 0 Limb-related Cardiovascular MALE MI CVA Outpatient hospitalization hospitalization endovascular revascularization 30-day 1-year Hess CN et al. J Am Coll Cardiol 2018;72:999-1011

Post-procedure Medication Use

Medication Use after Peripheral Revascularization 254,385 Inpatients Undergoing Peripheral Artery Revascularization in the US 80 70 67.3 62.6 61.7 57.7 60 47.6 50 % patients 40 30 20 14.3 10.8 10 0 Aspirin P2Y12 Inhibitor Oral Statin Non-statin ACEI/ARB Beta blocker anticoagulant lipid-lowering therapy Hess CN et al. J Am Coll Cardiol 2018;72:999-1011

P2Y12 Inhibitor Use after PVI in Medicare Beneficiaries Jones WS et al. Am Heart J 2016;179:10-8

Antithrombotic Therapy in Device Trials Trial (device) Post-procedure Antithrombotic Therapy SUPERB (Nitinol stent) Per operator Indefinite ASA + Clopidogrel/ticlopidine ≥60 days Zilver PTX (DES) ASA at least 6 mos + clopidogrel (≥1 mo without IN.PACT SFA (DCB) stenting or ≥3 mos if stenting) ASA indefinitely + clopidogrel/prasugrel ≥1 mo LEVANT 2 (DCB) POPUP (Dacron vs PTFE fem-pop bypass) Per operator Klinkert et al (PTFE vs vein fem-pop bypass) Warfarin POD 1 through 6 mos, ASA thereafter 1. Circ Cardiovasc Interv 2015;8:e000937; 2.Circ Cardiovasc Interv 2011;4:495-504; 3. Circulation 2015;131:495-502; 4. N Engl J Med 2015;373:145-153; 5. Eur J Vasc Endovasc Surg 2007;34:44-9; 6. J Vasc Surg 2003;37:149-55

Antithrombotic Therapy is Routinely Used After Intervention … But What Do The Data Support?

Antithrombotic Trials in PAD • Most PAD evidence derived from subgroups of larger cardiovascular (CAD) outcome trials and/or stable PAD • Primary focus has been MACE • New evidence supports including MALE, including ALI and major amputation • Post-revascularization setting not well-studied

Antithrombotic Therapy after Surgical Revascularization CASPAR Dutch BOA J Vasc Surg 2010;52:825-33 Lancet 2000;355:346-51

Anticoagulation after Endovascular Revascularization: ePAD A Clopidogrel + ASA RR 0.56 (0.19-1.62) (n=102) Femoropopliteal R 6 months EVT Edoxaban + ASA (n=101) 1 B RR 1.39 (0.58-3.31) Clopidogrel Edoxaban RR Restenosis/occlusion 33 (34.7%) 29 (30.9%) 0.89 (0.59-1.34) Restenosis/occlusion/ 41 (42.3%) 32 (33.7%) 0.80 (0.55-1.15) TLR/amputation/MACE Moll F et al. J Endovasc Ther 2018

Guideline on the Management of Patients with Lower Extremity PAD Gerhard-Herman MD et al. Circulation 2017;135:686-725

Factor Xa Inhibition: A New Approach to Arterial Thrombosis Low-dose Low-dose Rivaroxaban Aspirin Rivaroxaban is a potent and selective oral direct factor Xa inhibitor which blocks initiation of the final common Thrombin Platelet coagulation pathway Generation Activation

COMPASS PAD: Rivaroxaban 2.5 and 5.0 mg doses 7,470 patients with stable PAD (majority also with CAD) MACE MALE Lancet 2018;391:219-29

ATLAS ACS 2-TIMI 51 Primary results Stent thrombosis* CV Death / MI / Stroke 12% HR 0.84 Placebo Estimated Cumulative incidence (%) 10.7% mITT p=0.020 9.1% ITT p=0.007 Rivaroxaban 2.5 mg BID NNT = 63 12 0 24 Months Mega JL et al. NEJM 2012 *Rivaroxaban 2.5 mg bid and 5.0 mg bid Gibson CM et al. JACC 2013

Spectrum of Atherothrombosis Limb ischemic events occur on a spectrum similar to cardiac ischemic events UA --> urgent Myocardial Stable Elective coronary Severe stable angina coronary revasc infarction angina revascularization Chronic critical Urgent peripheral Acute limb Elective peripheral Claudication limb ischemia revasc ischemia revascularization Definition Subjective Objective Reason for Intervention Prevent Symptom Irreversible Relief Tissue Loss Etiology Thrombotically Multifactorial / Mediated Atherosclerotic Adapted slide from M. Bonaca

VOYAGER PAD Study Design Symptomatic PAD undergoing peripheral revascularization R Rivaroxaban 2.5 mg Placebo + ASA bid + ASA 100 mg 100 mg Stratification by procedure and clopidogrel use Endovascular with Endovascular Surgical clopidogrel without clopidogrel Rivaroxaban Placebo Rivaroxaban Placebo Rivaroxaban Placebo Clinicaltrials.gov NCT02504216

VOYAGER PAD Study Design • Composite primary endpoint: FDA and EMA accepted these 5 • MI components as all representing • Ischemic stroke approximately equal severity of • Vascular death ‘irreversible harm’ events • ALI • Major amputation of a vascular cause Allows a large CV outcome trial to • Event-driven trial (1015 events) include major cardiac and limb events • ~6500 patients • Mean treatment duration 30 months

Conclusions • Key post-peripheral revascularization outcomes include vessel patency, MALE, and MACE • Antithrombotic therapies in PAD studied in stable PAD and mainly target systemic CV risk reduction • Use of post-procedure antithrombotic agents (primarily antiplatelet) is common but not evidence-based • Post-procedure CV and limb ischemic risk remains high • Current data do not support use of anticoagulation after peripheral revascularization • Direct Factor Xa inhibition on background ASA effective in stable PAD and ACS • Await results of VOYAGER for use after peripheral revascularization