in High Bleeding Risk Patients: Primary Results of Onyx ONE Clear - - PowerPoint PPT Presentation

One Month Dual Antiplatelet Therapy in High Bleeding Risk Patients: Primary Results of Onyx ONE Clear

Ajay J. Kirtane, MD, SM

Columbia University Irving Medical Center /New York-Presbyterian Hospital and the Cardiovascular Research Foundation, New York, NY, USA email: akirtane@columbia.edu twitter: @ajaykirtane and David E. Kandzari, Roxana Mehran, Matthew J. Price, Daniel Simon, Azeem Latib, Elvin Kedhi, Alexandre Abizaid, Stephen Worthley, Azfar Zaman, Lisa Bousquette, Lilian Lee, Te-Hsin Lung, Stephan Windecker and Gregg W. Stone

• n behalf of the Onyx ONE and Onyx ONE Clear Investigators

Disclosure Statement of Financial Interest Ajay J. Kirtane

Institutional funding to Columbia University and/or Cardiovascular Research Foundation from: – Medtronic, Boston Scientific Corporation, Abbott Vascular, Abiomed, CSI, CathWorks, Siemens, Philips, ReCor Medical Personal: CME/conference honoraria and travel/meals only

Onyx ONE Clear

Background

• Up to 40% of patients undergoing PCI have high bleeding risk (HBR)

characteristics

• Guidelines recommend 3-6 months of DAPT for HBR patients undergoing PCI with

consideration for DAPT duration as short as 1 month in selected patients

• Resolute Onyx™ is a thin strutted, conformable stent with a biocompatible (Biolinx™)

polymer and sustained drug elution over several months

• The Onyx ONE RCT demonstrated noninferior outcomes of Resolute Onyx

compared with a polymer-free drug-coated stent in a broad range of HBR patients receiving 1-month DAPT1

1Windecker S, et al. N Engl J Med. 2020. doi: 10.1056/NEJMoa1910021. [Epub ahead of print]

Onyx ONE Clear

Objective

To evaluate the safety and efficacy of the Resolute Onyx stent among HBR patients undergoing PCI with planned 1-month DAPT

• 1. Extension of Onyx ONE RCT results
• 2. Patient enrollment from USA and Japan
• 3. Prospective, single arm trial design
• 4. Powered analysis to support indication approval

Onyx ONE Clear

Rationale for Prospective Single Arm Design in US/Japan

• No approved DES with 1-month DAPT in conjunction with limited BMS use

precluding 1-month RCT designs like Onyx ONE RCT

• Extension of Onyx ONE RCT data to US and Japan with

– Similar inclusion / exclusion criteria – Similar case report forms – Same endpoint definitions – Same angiographic core laboratory – Same CEC adjudication processes

Onyx ONE Clear

“1-month clear” is defined as patients who were adherent to DAPT within the 1st month after PCI and free of events that would preclude 1-month DAPT cessation NCT03647475

Clinical Follow-up

Resolute Onyx™ ZES

with 1 Month DAPT US & Japan (N=700 + max 100) 2mo 2yr 1yr 1mo 6mo

Primary endpoint: Cardiac death/MI assessed in “1-month clear” patients from 1-12 Mo

compared to a 9.7% performance goal from HBR short DAPT studies Secondary endpoints: Acute success rates, BARC bleeding, TVF, death, MI, stent thrombosis, stroke, revascularizations, MACE and TLF Antiplatelet Therapy: DAPT for 1 month, thereafter SAPT only

High Bleeding Risk patients undergoing PCI (no lesion, vessel limitations)

Study Design

Prospective, Multicenter, Single-arm Study Resolute Onyx ZES

with 1 Month DAPT from Onyx ONE RCT (N=1000)

Onyx ONE Clear

 Elderly (age ≥75 years)  Thrombocytopenia (<100,000/mm3)  OAC planned after PCI  Cancer diagnosed or treated within 3 yrs  Renal failure (CrCl <40 ml/min)  Stroke within 1 year or any prior ICH  Planned surgery <1 year  Severe chronic liver disease  Anemia (Hgb <11 g/dl)  Long-term NSAID or steroid use  Hospitalization for bleeding within 1 year  Expected DAPT non-compliance

HBR Inclusion Criteria (One or More)

Onyx ONE Clear

Antithrombotic Therapy

• After PCI, DAPT was prescribed for 1-month, including:

– Daily dose of aspirin (75-100 mg) AND – P2Y12 inhibitor (clopidogrel preferred, others allowed)

• Patients receiving OAC could receive single or dual antiplatelet therapy

during this 1st month after PCI

• After 1-month DAPT, single antiplatelet therapy was prescribed with

either (at physician discretion):

– Aspirin OR – P2Y12 inhibitor

PCI 1M P2Y12 ASA ASA / P2Y12

Onyx ONE Clear

Sample Size Calculation

Definition “1-month clear”

• Event-free2 in 1st month
• Adherent to DAPT for 1st month

= Effective analysis population

1 Based on adjusted data from LEADERS-FREE, ZEUS and Senior short DAPT studies 2 Events that would preclude DAPT discontinuation at 1 month

Primary Endpoint Cardiac death or MI Expected event rate1 6.8% Performance goal 9.7% One-sided type I error (α) 0.025 Power >97% Effective sample size 1360 patients “1-month clear” attrition rate 20% Total sample size 1700 enrolled patients

(1000 Onyx ONE RCT and 700 from Onyx ONE Clear)

Onyx ONE Clear

Trial Organization

Principal Investigators

• D. Kandzari, A. Kirtane (Co-PIs)

Executive Committee

• G. Stone (Program Chair), A. Abizaid, E. Kedhi, A. Latib, R. Mehran, M. Price,
• D. Simon, S. Windecker, S. Worthley, A. Zaman

DSMB

• JP. Carrozza (Chair)

Cardiovascular Research Foundation, New York NY, USA CEC

• S. Marx (Chair)

Cardiovascular Research Foundation, New York NY, USA Angiographic Core Lab Cardiovascular Research Foundation, New York NY, USA Statistics Medtronic (Analysis) and Baim Institute for Clinical Research, Boston MA, USA (Independent Validation) Data Management & Monitoring Medtronic, Santa Rosa CA, USA Sponsor Medtronic, Santa Rosa CA, USA

Onyx ONE Clear

United States

▪ Texas: J Choi, S Potluri, T Tolleson, A Shah ▪ New York: R Caputo, T Nazif, L Gruberg ▪ Alabama: M Kanitkar ▪ South Carolina: B McLaurin ▪ Ohio: T Smith, NH Kander, J Li, J Khatri ▪ Florida: D Spriggs, S Singh, M Tulli, T Noel ▪ Georgia: D Kandzari, H Liberman ▪ California: MJ Price, S Brar, A Loussararian, D Lee, W Lim ▪ Wisconsin: G Larrain, T Nfor ▪ Washington, DC: R Waksman ▪ Virginia: M Ragosta, M Arcarese, D Talreja ▪ Oregon: H Golwala ▪ Michigan: S Chetcuti ▪ Tennessee: J Webber, E Haddad ▪ Illinois: A Shroff ▪ Missouri: A Salisbury ▪ Minnesota: J Dutcher, J Chambers, W Ginete ▪ North Dakota: T Haldis ▪ New Jersey: K Sanghvi ▪ Massachusetts: D Pinto

Participating Centers

Japan

▪ Fukuoka: K Ando ▪ Kanagawa: S Saito, Y Ikari ▪ Tokyo: K Kozuma ▪ Kumamoto: T Sakamoto Onyx ONE RCT Onyx ONE US/Japan

Onyx ONE Clear

Site PI Hospital Location Patients

Choi, James Baylor Heart & Vascular Hospital Dallas, TX 78 Caputo, Ronald Saint Joseph's Hospital Health Center Syracuse, NY 71 Kanitkar, Mihir Huntsville Hospital Huntsville, AL 57 McLaurin, Brent AnMed Health Medical Center Anderson, SC 54 Potluri, Srinivasa The Heart Hospital Baylor Plano Plano, TX 48 Smith, Timothy The Christ Hospital Cincinnati, OH 25 Spriggs, Douglas Morton Plant Hospital Clearwater, FL 24 Tolleson, Thaddeus UT Health East Texas Tyler, TX 24 Kandzari, David Piedmont Atlanta Hospital Atlanta, GA 22 Nazif, Tamim New York-Presbyterian Hospital/ Columbia University Medical Center New York, NY 20 Price, Matthew J. Scripps Green Hospital La Jolla, CA 19 Gruberg, Luis Southside Hospital Manhasset, NY 19 Ando, Kenji Kokura Memorial Hospital Kitakyushu, Fukuoka 18 Larrain, German Aspirus Wausau Hospital Wausau, WI 18

Top Enrolling Sites

Onyx ONE Clear

Patient Flowchart

Onyx ONE RCT Resolute Onyx pts (N=1019)

263 Not “1-month Clear”: ▪ 116 Experienced event within 30 days

▪ 147 Not adherent to DAPT protocol

Onyx ONE Clear (N=1506) Primary analysis population

9 Withdrawal 6 Visit not done

1-Year Follow-up Analysis n=1491 (99.0%) Onyx ONE US/Japan (N=752: US 713 + Japan 39) Onyx ONE As-Treated population (N=1769)

1 Japanese patient not eligible yet for 1-yr follow-up at time of database snapshot 1 patient did not consent for data use outside of Onyx ONE RCT

“1-month clear” is defined as patients who were adherent to DAPT within the 1st month after PCI and free of events that would preclude 1-month DAPT cessation

Onyx ONE Clear

Baseline Characteristics

% or mean ± SD Onyx ONE Clear (N=1506) Onyx ONE RCT1 (N=905) Onyx ONE US/Japan1 (N= 601) Age (yrs) 74.0 ± 9.5 73.8 ± 9.6 74.2 ± 9.5 Female 32.3 32.2 32.6 Diabetes 39.4 37.2 42.6 Hypertension 84.0 80.0 90.0 Hyperlipidemia 72.4 64.4 84.5 Previous MI 26.3 26.0 26.8 Previous revascularization 36.2 27.6 49.1 Atrial fibrillation 35.6 33.4 38.9 Silent ischemia 10.8 9.5 12.8 Chronic coronary syndrome 40.5 39.1 42.7 Acute coronary syndrome 48.6 51.4 44.5 STEMI 4.2 5.7 1.8 Non-STEMI 21.7 26.0 15.2 Unstable angina 22.8 19.7 27.5

1 Onyx patients meeting “1-month clear” definition

Onyx ONE Clear

HBR Inclusion Criteria

0.9 1.7 1.7 2.6 2.8 3.1 4.2 6.6 7.4 12.5 14.4 41.0 59.0

10 20 30 40 50 60 70

Severe liver disease Thrombocytopenia Prior ICH Stroke < 1yr Hospital for bleeding Long-term NSAID or steroids Expected DAPT non-compliance Planned surgery Active or recent cancer Renal failure Anemia or transfusion OAC Elderly (age ≥75 yr)

Patients meeting criteria (%) N = 1506

Mean 1.6 criteria / pt 44% met ≥ 2 HBR criteria

Onyx ONE Clear

Lesion Characteristics

% or mean ± SD Onyx ONE Clear (N=1506) Onyx ONE RCT1 (N=905) Onyx ONE US/Japan1 (N= 601) Radial access 65.8 75.3 51.7 Staged procedure (performed) 3.3 2.8 4.0 Lesion location LAD 52.5 54.6 49.3 LCX 27.8 26.6 29.6 RCA 34.2 35.4 32.4 Left main 1.3 1.3 1.2 Bypass graft 4.1 2.5 6.5 Bifurcation 11.5 14.7 6.7 Moderate/severe calcification 50.0 45.6 56.7 B2/C lesion class 78.6 78.9 78.1 Number of treated lesions per patient 1.3 ± 0.6 1.3 ± 0.6 1.3 ± 0.6 Number of stents per patient 1.7 ± 1.0 1.7 ± 1.0 1.6 ± 0.9 Total stent length per patient (mm) 36.9 ± 26.3 38.7 ± 26.6 34.3 ± 25.7

1 Onyx patients meeting “1-month clear” definition

Onyx ONE Clear

Procedural Characteristics

% or mean ± SD Onyx ONE Clear (N=1506) Onyx ONE RCT1 (N=905) Onyx ONE US/Japan1 (N= 601) Pre-procedural QCA Lesion length (mm) 20.8 ± 13.0 21.2 ± 12.7 20.1 ± 13.5 RVD (mm) 2.82 ± 0.48 2.83 ± 0.46 2.80 ± 0.51 MLD (mm) 0.89 ± 0.41 0.88 ± 0.41 0.91 ± 0.40 % Diameter stenosis 68.3 ± 13.3 68.8 ± 13.5 67.5 ± 12.9 Post-procedural QCA % Diameter stenosis (in-stent) 10.1 ± 8.9 9.8 ± 8.8 10.4 ± 9.1 % Diameter stenosis (in-segment) 19.8 ± 9.5 20.3 ± 9.9 19.1 ± 8.9 Acute gain (mm, in-stent) 1.69 ± 0.49 1.72 ± 0.48 1.64 ± 0.51 Acute gain (mm, in-segment) 1.42 ± 0.50 1.43 ± 0.50 1.40 ± 0.51 Lesion success2 94.6 93.9 95.7 Device success3 93.3 93.0 93.7 Procedure success4 88.5 85.4 93.2

1 Onyx patients meeting “1-month clear” definition 2 The attainment of <30% residual stenosis by QCA (or <20% by visual assessment) and TIMI flow 3 after the procedure, using any percutaneous method. 3 The attainment of <30% residual stenosis by QCA (or <20% by visual assessment) and TIMI flow 3 after the procedure, using the assigned device only. 4 The attainment of <30% residual stenosis by QCA (or <20% by visual assessment) and TIMI flow 3 after the procedure, using any percutaneous method without

the occurrence of MACE during the hospital stay.

Onyx ONE Clear

Antithrombotic Therapy Transition After PCI

96.9%

ASA

57%

P2Y12

43%

89.3%

ASA

59%

P2Y12

41%

N = 1506

100% 80% 60% 40% 20% 0% 0 1 2 3 4 5 6 7 8 9 10 11 12 Percent of Patients Months Post-Index Procedure

SAPT DAPT OAC only

Onyx ONE Clear

Primary Endpoint: Cardiac death or MI between 1-12 months

Onyx ONE Clear (N=1506)

7.0%

Performance Goal

9.7%

Upper 1-sided 97.5% CI:

8.4%

P-value

<0.001

2% 4% 6% 8% 10%

Primary Endpoint Met

Onyx ONE Clear

Number at risk ZES 1506 1439 1352

“1-Month clear” is determined on day of transition from DAPT to SAPT (between days 27-35 post-PCI)

Kaplan Meier Estimate: Cardiac death or MI between 1-12 months

Cumulative Incidence of Cardiac Death or MI (%) 1 10 20 30 2 4 8 10 12 6 Months after PCI

7.4%

Onyx ONE Clear

Patients meeting “One-Month Clear” definition

Clinical Outcomes

between 1-12 months

Event rates (%) n = 1491 7.0 2.6 3.4 4.8 3.4 0.7 1.5 4.0 5 10 15

Cardiac death/ MI Cardiac death Non-cardiac death MI TLR Def/Prob ST Stroke BARC 3-5 Bleeding

ONE Clear

Primary Endpoint

BARC 1-5 bleeding: 13.1% BARC 2-5 bleeding: 11.7%

(clinically driven)

Onyx ONE Clear

Number at risk MI 1506 1439 1352 ST 1506 1466 1403

Kaplan Meier Estimate: MI and ST

between 1-12 months

Cumulative Incidence (%) Months after PCI 1 2 4 8 10 12 6 10 8 6 4 2 Myocardial Infarction Stent Thrombosis (ARC definite/probable)

0.7% 5.1%

Onyx ONE Clear

Subgroup Results

Cardiac Death / MI between 1-12 months

Event rates (%) n = 1491

1 Complex patient definition: bifurcation, bypass grafts, ISR, AMI <72 hr, LVEF <30%, unprotected LM, >2 vessels stented, renal insufficiency or

failure (creatinine >140 µmol/L), lesion length >27 mm, >1 lesion per vessel, lesion with thrombus or total occlusion (preprocedure TIMI = 0).

1

7.5 7.9 9.1 5.6 8.5 13.4 7.9 6.7 6.0 5.6 7.6 4.8 6.1 6.2 10 20 30

US region ACS Diabetes Female sex Complex Renal failure Stent length >30mm

Yes No

N

559 932 694 733 583 908 481 1010 869 622 187 1304 655 836

Onyx ONE Clear

Limitations

• While prospectively enrolled, Onyx ONE CLEAR employed a non-

randomized study design with pooling of patient data across different geographies from the Onyx ONE RCT

• The study was underpowered for low frequency events such as ST
• The tradeoff between ischemic events and bleeding events is often an

individualized decision and these data should be considered within that context

Onyx ONE Clear

Conclusions

• Onyx ONE Clear extends the findings of the Onyx ONE Global RCT to

HBR patients treated with 1-month of DAPT in the United States/Japan

• Onyx ONE Clear met its primary endpoint, with favorable rates of

ischemic outcomes from 1-12 months after DAPT discontinuation within a high risk population of HBR patients

• These data, in conjunction with the randomized data from the Onyx

ONE RCT, support the use of 1-month of DAPT for appropriately selected patients treated with the Resolute Onyx DES