VOYAGER PAD V ascular O utcomes Stud y of A SA Alon g with Rivaroxaban in E ndovascular or Surgical Limb R evascularizations for Peripheral Artery Disease Marc P. Bonaca, Rupert M. Bauersachs, Manesh R. Patel, Sonia S. Anand, Eike Sebastian Debus, Mark N. Nehler, Fabrizio Fanelli, Warren H. Capell, Nicole Jaeger, Lihong Diao, Connie N. Hess, John M. Kittelson, Lloyd P. Haskell, Scott D. Berkowitz, William R. Hiatt, for the VOYAGER PAD Steering Committee & Investigators American College of Cardiology Virtual Scientific Sessions 2020 Late-Breaking Clinical Trial March 28, 2020 An Academic Research Organization Affiliated with the University of Colorado School of Medicine
Background Risk in Patients Undergoing Outcomes in Patients with Peripheral Revascularization Acute Limb Ischemia N=393,017 • Median hospitalization 8 days (IQR 5-15) “Acute” Post “Stable” Revascularization Phase Cumulative Incidence • ~4% die at presentation Major Adverse Limb Events • ~1/5 major amputation 4x risk of ALI Long-term vs. no Revascularization • ~1/3 prolonged ICU stay MACE • ~3/4 major surgery • Outcomes after hospitalization are poor with ~15% disabled or dead Years from Index Revascularization Hess…Hiatt et al. JACC 2020 Jones…Fowkes et al. Circulation 2017 Bonaca…Sabatine et al. JACC 2017 2 Bonaca…Morrow et al. Circulation 2016
Background Despite the high risk, currently there is no proven antithrombotic strategy that has demonstrated efficacy for reducing major adverse limb and cardiovascular events after peripheral intervention for ischemia Graft Index-graft occlusion, revascularization, major amputation, or death Occlusions HR 0.98 HR 0.95 (95% CI 0.78 – 1.23), P=NS (95% CI 0.82 – 1.11), P=NS DAPT with Aspirin and Clopidogrel Full Intensity Oral anticoagulation Increased GUSTO bleeding Increased risk of Hemorrhagic Stroke HR 2.84 (1.32 – 6.08) HR 3.48 (1.14 – 10.60) Belch et al. Journal of Vascular Surgery. 2010 Dutch Bypass Oral anticoagulants or Aspirin (BOA) Study Group. Lancet. 2000 3
Trial Design *Ankle Brachial 6,564 Patients with Symptomatic Lower Extremity NCT02504216 Index < 0.90 and PAD* Undergoing Peripheral Revascularization Imaging Evidence of Occlusive Disease ASA 100 daily for all Patients Clopidogrel at Investigator’s Discretion Randomized 1:1 Double Blind Rivaroxaban 2.5 mg Stratified by Placebo twice daily Revascularization Approach (Surgical or Endovascular) and Use of Clopidogrel Follow up Q6 Months, Event Driven, Median f/u 28 Months Primary Efficacy Endpoint : Acute limb ischemia, major amputation of vascular etiology, myocardial infarction, ischemic stroke or cardiovascular death Principal Safety Outcome: TIMI Major Bleeding Capell WH, Bonaca MP, Nehler MR…Hiatt WR. AHJ 2018 4
Objectives In patients undergoing lower extremity revascularization for ischemic symptoms: • Test whether rivaroxaban 2.5 mg twice daily added to low dose aspirin reduces the risk of major adverse limb and cardiovascular events compared to aspirin alone • To evaluate the safety of rivaroxaban 2.5 mg twice daily added to low dose aspirin compared to aspirin alone 5
Inclusion & Exclusion Inclusion Exclusion • Age ≥ 50 • Revascularization for asymptomatic disease • Documented PAD including: • Recent revascularization (within 10 days) or ALI (2 weeks) or ACS (30 days) • Ischemic symptoms (functional limitation, rest pain or ischemic • Current major tissue loss ulceration) AND • Need for antiplatelet or anticoagulant Imaging evidence of occlusion AND • other than aspirin and/or clopidogrel • Abnormal ABI • Need for long-term DAPT (intended > 6 months) • Successful lower extremity • High risk for bleeding (significant revascularization for ischemia bleeding in last 6 months, prior stroke or other high-risk condition) 6
Outcomes Efficacy Primary: acute limb ischemia (ALI), major amputation for vascular cause (amputation), myocardial infarction (MI), ischemic stroke or CV death Secondary (hierarchical): 1. ALI, amputation, MI, ischemic stroke or coronary heart death 2. Unplanned index limb revascularization for ischemia 3. Vascular hospitalization for a coronary or peripheral event of thrombotic nature 4. ALI, amputation, MI, ischemic stroke or all-cause mortality 5. ALI, amputation, MI, all stroke or CV death 6. All-cause mortality 7. Venous thromboembolism Safety Principal: TIMI major bleeding Secondary: ISTH major bleeding, BARC 3b or above 7 CPC Clinical Events Committee (CEC) adjudicated all efficacy and safety events
Trial Organization Executive Committee William R. Hiatt (Chair) Rupert M. Bauersachs (Co-Chair) Marc P. Bonaca Sonia S. Anand Manesh R. Patel Eike Sebastian Debus Mark R. Nehler Fabrizio Fanelli Lloyd P. Haskell Scott D. Berkowitz CPC Clinical Research Warren H. Capell (ICAC Chair), Jennifer Armstrong (ICAC Member), Natalia Glebova, (ICAC Member), Connie N. Hess (ICAC Member), Mori Krantz (ICAC Member), Cecilia Low-Wang (ICAC Member), Lisa Cox (Executive Project Manager), Nicole Jaeger (Project Manager), Robin White (Director, Biostatistics and Programming), and Lihong Diao (Biostatistician). Sponsors: Bayer & Janssen Scott D. Berkowitz, Lloyd Haskell, Eva Muehlhofer, James Hung, Aneta Woroniecka-Osio MD, Uma Balasubramanian, Juliette Dehay, Alexandra Kley, Claudia Vogt, Akos Ferenc Pap Independent Data Monitoring Committee John Dormandy (Chair)*, Joshua Beckman (Chair), Scott Kinlay, Robert McLafferty, Robin Roberts, (Statistician), and William Robinson. *Deceased 8
Steering Committee and National Lead Investigators Argentina Finland Netherlands Switzerland M. Venermo F. Moll I. Baumgartner R. Diaz Austria France Poland Taiwan M. Brodmann A. Bura-Rivière A. Jawien S. Shen Wang Belgium J. Baptiste Ricco Portugal Thailand F. Vermassen Germany A. Mansilha P. Mutirangura Brazil D. Scheinert (Co-Chair) Romania Ukraine H. Lawall I. Coman I. Gudz D. Brasil United Kingdom Bulgaria Hungary Russia V. Chervenkoff L. Matyas A. Svetlikov G. Hamilton Canada Italy Serbia United States D. Szalay C. Rabbia I. Koncar A. Hirsch (Co-Chair)* Czech Republic M. Antonella Ruffino Slovokia R. Powell (Co-Chair) K. Roztocil F. Violi J. Maďarič J. Chung South Korea J. Kittelson (Biostatistician) China Japan W. Fu / Z. Shi H. Shigematsu D. Choi J. Mills Denmark Y. Soga Spain J. Mustapha H. Sillesen Y. Yonemitsu V. Riambau Alonso F. Saab Estonia Latvia/Lithuania Sweden P. Põder D. Krievins L. Norgren *Deceased 9
Global Enrollment 6,564 patients randomized at 534 sites in 34 countries between 7/2015 – 1/2018 Finland: 17 Czech Republic: 243 Hungary: 261 Denmark: 78 Ukraine: 299 Estonia: 9 Sweden: 42 Slovakia: Germany: 594 Latvia: Belgium: 126 Poland: 203 126 Netherlands: 78 168 Bulgaria: 737 Lithuania: 84 Romania: 214 Russia: 188 Canada: 170 United Kingdom: 129 Austria: 212 South Korea: 148 France: 107 United States: 524 Japan: 459 Portugal: 75 China: 211 Spain: 96 Switzerland: 91 Taiwan: 76 Serbia: Italy: 184 Thailand: 67 68 Brazil: 185 Argentina: 299 10
Disposition 6,772 Patients Not Randomized = 208 Enrolled Inclusion/Exclusion 167 Subject decision 29 Adverse event 2 6,564 Patients Physician decision 1 Other 9 Randomized Placebo Rivaroxaban N=3278 N=3286 Premature Drug Discontinuation = 1080 (33.2%) Premature Drug Discontinuation = 1011 (31.1%) 14.2% Annualized 13.2% Annualized Median Follow-up Withdrawal of Consent = 37 (1.13%) Withdrawal of Consent = 32 (0.97%) 28 Months 0.48% Annualized 0.42% Annualized Vital status unknown = 12 (0.37%) Vital status unknown = 8 (0.24%) Lost to Follow up = 3 (0.09%) Lost to Follow up = 3 (0.09%) Vital Status Known = 3263 (99.5%) Vital Status Known = 3275 (99.7%) Analyzed Analyzed ITT = 3286 (100%) ITT = 3278 (100%) Safety = 3256 (99.1%) Safety = 3248 (99.1%) Complete primary efficacy and principal safety outcome ascertainment in 98.8% of potential patient-years of follow up 11
Baseline Characteristics Characteristics at Randomization Rivaroxaban 2.5 mg Placebo + aspirin twice daily + aspirin N=3286 N=3278 % % Age, Yrs Median 67 67 Female 26 26 Caucasian 81 81 Diabetes Mellitus 40 40 Current Smoking 35 35 COPD 11 11 eGFR < 60 ml/min/1.73m 2 20 20 Coronary Artery Disease 32 31 Prior MI 11 11 Known Carotid Stenosis 9 9 Clopidogrel 51 51 P>0.05 for all Statin 79 81 comparisons ACEi or ARB 64 63 12
PAD & Procedural Characteristics Characteristics at Randomization Rivaroxaban 2.5 mg Placebo + aspirin twice daily + aspirin N=3286 N=3278 % % Prior Peripheral Artery Disease History History of Claudication 95 96 History of Revascularization 36 35 History of Amputation 6 6 Ankle Brachial Index, Median (IQR) 0.56 (0.42 – 0.67) 0.56 (0.42 – 0.67) Indication for Revascularization Critical limb ischemia 23 24 Claudication 77 76 Type of Revascularization Surgical 35 35 Endovascular or Hybrid 66 65 P>0.05 for all comparisons Days from Procedure to Randomization 5 (2 – 7) 5 (2 – 7) Median, (IQR) 13
Primary Endpoint Acute limb ischemia, major amputation for vascular cause, myocardial infarction, ischemic stroke, CV death 19.9% 20 Placebo Rivaroxaban 18 17.3% 16 Cumulative Incidence (KM%) 14 12 10 HR 0.85 8 95% CI 0.76 – 0.96 6 P=0.0085 4 2 0 0 3 90 182 6 274 9 12 366 456 15 18 547 639 21 24 731 27 821 912 30 1004 33 36 Months from Randomization 14
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