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

Research grants to CPC Clinical Research from Bayer and Merck

Dis isclosures

Peripheral Artery Revascularization

• Indications for revascularization

in PAD:

• Symptom relief in claudication

unresponsive to medical treatment

• Relief of ischemic pain, healing
• f 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 amputation
• Major adverse cardiovascular

events (MACE)

• Bleeding

Major adverse limb events (MALE)

}

Device Trials Focused on Patency

Freedom from: Trial (device) Primary Outcome Restenosis TLR Death Amputation Target limb ischemia requiring surgical intervention Surgical vessel repair SUPERB (Nitinol stent) Primary patency X X Zilver PTX (DES) Composite of patency/death X X X X X IN.PACT SFA (DCB) Primary patency X X LEVANT 2 (DCB) Primary patency X X POPUP (Dacron vs PTFE fem-pop bypass) Primary patency Klinkert et al (PTFE vs vein fem-pop bypass) Primary 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

5.1 3.0 2.7 0.3 0.2 2.7 18.8 12.8 10.3 2.0 1.0 11.0

2 4 6 8 10 12 14 16 18 20 Limb-related hospitalization Cardiovascular hospitalization MALE MI CVA Outpatient endovascular revascularization

30-day 1-year % patients

381,415 Pts Undergoing Peripheral Artery Revascularization in the US

Hess CN et al. J Am Coll Cardiol 2018;72:999-1011

MALE component 30-day 1-year ALI 0.6% 2.6% Major amputation 0.9% 3.5% Surgical revascularization 1.4% 6.0%

Post-procedure Medication Use

Medication Use after Peripheral Revascularization

67.3 57.7 14.3 61.7 10.8 47.6 62.6

10 20 30 40 50 60 70 80

Aspirin P2Y12 Inhibitor Oral anticoagulant Statin Non-statin lipid-lowering therapy ACEI/ARB Beta blocker

254,385 Inpatients Undergoing Peripheral Artery Revascularization in the US

Hess CN et al. J Am Coll Cardiol 2018;72:999-1011

% patients

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 Zilver PTX (DES) Indefinite ASA + Clopidogrel/ticlopidine ≥60 days IN.PACT SFA (DCB) ASA at least 6 mos + clopidogrel (≥1 mo without stenting or ≥3 mos if stenting) LEVANT 2 (DCB) ASA indefinitely + clopidogrel/prasugrel ≥1 mo 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?

• 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 Trials in PAD

Dutch BOA CASPAR

Antithrombotic Therapy after Surgical Revascularization

J Vasc Surg 2010;52:825-33 Lancet 2000;355:346-51

Anticoagulation after Endovascular Revascularization: ePAD

Femoropopliteal EVT

R

Clopidogrel Edoxaban RR Restenosis/occlusion 33 (34.7%) 29 (30.9%) 0.89 (0.59-1.34) Restenosis/occlusion/ TLR/amputation/MACE 41 (42.3%) 32 (33.7%) 0.80 (0.55-1.15)

6 months

Moll F et al. J Endovasc Ther 2018

Clopidogrel + ASA (n=102) Edoxaban + ASA (n=101) RR 0.56 (0.19-1.62)

A

1

B

RR 1.39 (0.58-3.31)

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

Thrombin Generation Platelet Activation Low-dose Aspirin Low-dose Rivaroxaban

Rivaroxaban is a potent and selective oral direct factor Xa inhibitor which blocks initiation

• f the final common

coagulation pathway

COMPASS PAD: Rivaroxaban 2.5 and 5.0 mg doses

MACE MALE

Lancet 2018;391:219-29

7,470 patients with stable PAD (majority also with CAD)

ATLAS ACS 2-TIMI 51

Months

CV Death / MI / Stroke

Estimated Cumulative incidence (%)

HR 0.84 mITT p=0.020

ITT p=0.007

10.7% 9.1% 24

Rivaroxaban 2.5 mg BID Placebo

NNT = 63

12

12%

Mega JL et al. NEJM 2012 Gibson CM et al. JACC 2013

Stent thrombosis* Primary results

*Rivaroxaban 2.5 mg bid and 5.0 mg bid

Adapted slide from M. Bonaca

Subjective Objective Symptom Relief Prevent Irreversible Tissue Loss Multifactorial / Atherosclerotic Thrombotically Mediated Definition Reason for Intervention Etiology

Limb ischemic events occur on a spectrum similar to cardiac ischemic events

Elective coronary revascularization Severe stable angina Myocardial infarction Stable angina UA --> urgent coronary revasc Elective peripheral revascularization Chronic critical limb ischemia Acute limb ischemia Claudication Urgent peripheral revasc

Spectrum of Atherothrombosis

Symptomatic PAD undergoing peripheral revascularization

R

Placebo + ASA 100 mg Rivaroxaban 2.5 mg bid + ASA 100 mg

Stratification by procedure and clopidogrel use

Placebo Rivaroxaban Placebo Rivaroxaban Placebo Rivaroxaban Surgical Endovascular without clopidogrel Endovascular with clopidogrel

Clinicaltrials.gov NCT02504216

VOYAGER PAD Study Design

• Composite primary endpoint:
• MI
• Ischemic stroke
• Vascular death
• ALI
• Major amputation of a vascular cause
• Event-driven trial (1015 events)
• ~6500 patients
• Mean treatment duration 30 months

VOYAGER PAD Study Design

FDA and EMA accepted these 5 components as all representing approximately equal severity of ‘irreversible harm’ events Allows a large CV outcome trial to include major cardiac and limb events

• 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

Conclusions