Clinical and Angiographic Outcomes of the EVOLVE Trial: A Randomized Evaluation of a Novel Bioabsorbable Polymer-Coated, Everolimus-Eluting Coronary Stent

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Clinical and Angiographic Outcomes of the EVOLVE
Trial A Randomized Evaluation of a Novel
Bioabsorbable Polymer-Coated, Everolimus-Eluting
Coronary Stent

• Ian T. Meredith,
• Stefan Verheye, Christophe L. Dubois, Joseph
  Dens, Jean Fajadet, Didier Carrié, Simon Walsh,
  Keith G. Oldroyd, Olivier Varenne, Seif El-Jack,
  Raul Moreno, Anita A. Joshi, Dominic J. Allocco,
  Keith D. Dawkins

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Introduction

• Durable polymer coatings on drug-eluting stents
  have been associated with chronic inflammation
  and impaired healing.

Potential advantages of bioabsorbable polymer
stents
may

• Reduce DAPT duration
• Reduce risk with DAPT interruption
• Decrease stent thrombosis

• Reduced Polymer Load
• Short-term Polymer Exposure

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SYNERGY Stent
Abluminal Bioabsorbable Polymer
Bioabsorbable polymer (PLGA) Applied only to the
abluminal surface (rollcoat) Thin strut (0.0029)
PtCr Stent
Abluminal Bioabsorbable Polymer
Current Durable Polymer
Durable PermanentPolymer Drug 360 AroundStent
PLGA BioabsorbablePolymer Everolimuson
Abluminal Side of Stent
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SYNERGY Polymer Mass
PLGA mass assessed in explanted stent and
adjacent tissue
Polymer Mass Remaining ()
Time (Days)
Polymer resorption is complete within 4 months
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EVOLVE Trial

• Primary Objective
• To compare the bioabsorbable polymer SYNERGY
  Everolimus-Eluting Coronary Stent System to the
  permanent polymer PROMUS Element Stent for the
  treatment of de novo atherosclerotic lesions
• Test Devices
• SYNERGY (everolimus dose and release profile
  similar to PROMUS Element)
• SYNERGY ½ Dose (half the everolimus dose and
  similar release profile to PROMUS Element)
• Control Device
• PROMUS Element

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EVOLVE Study Design
Patients with de novo native coronary lesions
28 mm in length, RVD 2.25 mm 3.5,
DSgt50 (excluded LM disease, CTO, AMI or recent
MI)
Randomized 111 at 29 sites(EU, Australia, New
Zealand)
SYNERGYN94
SYNERGY ½ DoseN99
PROMUS ElementN98
Single-blind, noninferiority design Primary
Clinical Endpoint TLF (TV-CD, TV-MI, or TLR) at
30 days Primary Angiographic Endpoint In-stent
late loss at 6 months
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Sample Size Power Calculation
Primary Angiographic Endpoint 6-month in-stent
Late Loss

• Expected rate for both groups 0.14 0.47 mm
• Non-inferiority margin (?) 0.20
• Test significance level (?) 0.048 (1-sided)
• Power (1??) approximately 0.85
• Expected rate of attrition 20
• N 291 patients (97 per group at 111 ratio)

If the P value from the one-sided Student test is
lt0.048, it will be concluded that SYNERGY is
non-inferior to PROMUS Element
From SPIRIT III (9-month endpoint)
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EVOLVE Trial Support
Co-Principal Investigators
Ian Meredith Melbourne, Australia Stefan Verheye Antwerp, Belgium
Core Labs
Angio CardioVascular Institute at BIDMC IVUS MedStar Health Research Institute
Clinical Events Committee
Joseph Kannam (Chair) Germano DiSciascio
Claude Hanet Goran Stankovic
Data Monitoring Committee
W. Douglas Weaver (Chair) David Parker Faxon
Steven R. Bailey David J. Molitemo
Jan G. P. Tijssen Adam Greenbaum
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Top 10 Enrolling Sites
EVOLVE Centers
Site PI Enrolled, n Country
UZ Gasthuisberg Christophe Dubois 30 Belgium
Ziekenhuis Oost Limburg Joseph Dens 29 Belgium
Clinique Pasteur Jean Fajadet 25 France
Centre Hôpital Universitaire Rangueil Didier Carrié 24 France
Royal Victoria Hospital Simon Walsh 15 UK
Golden Jubilee National Hospital Keith Oldroyd 14 UK
Monash Medical Centre Ian Meredith 13 Australia
Hôpital Cochin Olivier Varenne 13 France
Hospital La Paz Raul Moreno 11 Spain
Northshore Hospital Seif El-Jack 11 NZ
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Patient Flow
All Patients Randomized(N291)
SYNERGY(N94)
PROMUS Element(N98)
SYNERGY ½ Dose(N99)
No 6-Month f/u (n1) Withdrew consent 0 Missed 6
mo visit 1
No 6-month f/u (n1) Withdrew consent 0Missed 6
mo visit 1
No 6-month f/u (n3) Withdrew consent 0Missed 6
mo visit 3
6-Month Follow-up Clinical 99.9 (97/98)Angio
96.9 (95/98)
6-Month Follow-up Clinical 98.9 (93/94)Angio
93.6 (88/94)
6-Month Follow-up Clinical 97.0 (96/99)Angio
88.9 (88/99)
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Baseline Demographics
SYNERGY½ DoseN99
SYNERGYN94
PROMUSElementN98
P value
P value
Age, years 62.1 10.0 64.9 11.0 0.07 62.9 10.2 0.61
Male 79.6 69.9 0.12 69.7 0.11
Hypertension 69.4 61.3 0.24 71.7 0.72
Hyperlipidemia 70.4 68.5 0.77 72.4 0.75
Diabetes 22.4 17.2 0.36 18.2 0.46
Insulin-treated 8.2 6.5 0.65 4.0 0.23
Current smoker 27.8 21.7 0.33 20.6 0.24
Prior MI 34.4 32.3 0.76 34.7 0.96
Unstable angina 21.1 22.6 0.80 30.6 0.13
Intent-to-treat P values are versus PROMUS
Element medically treated
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Baseline Lesion Characteristics
SYNERGY½ DoseN99
SYNERGYN94
P value
P value
PROMUSElementN98
RVD, mm 2.53 0.41 2.60 0.45 0.22 2.65 0.40 0.04
MLD, mm 0.68 0.30 0.68 0.30 0.96 0.67 0.31 0.94
DS, 73.4 9.9 74.0 10.4 0.68 74.7 10.5 0.35
Lesion length, mm 14.62 5.81 13.41 6.29 0.16 13.55 5.76 0.21
Lesion location
LAD 39.8 41.8 0.78 39.4 0.95
LCx 31.6 26.4 0.43 33.3 0.80
RCA 28.6 31.9 0.62 27.3 0.84
Lesion characteristics evaluated by
QCA.Intent-to-treat P values are versus PROMUS
Element
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Procedural Characteristics
SYNERGY½ DoseN99
SYNERGYN94
PROMUSElementN98
P value
P value
Stents per lesiona 1.05 0.22 1.04 0.21 0.82 1.08 0.27 0.07
Stent length (mm)a 22.61 6.92 22.96 6.27 0.73 22.22 7.05 0.69
Pre-dilatation 100.0 97.8 0.24 99.0 1.00
Post-dilatation 58.2 60.2 0.77 64.6 0.35
Max pressure overall (atm) 18.13 4.36 17.25 3.16 0.09 17.30 3.19 0.11
Procedural successb 100.0 98.9 0.49 97.0 0.25
Technical successc 100.0 99.0 0.49 98.2 0.50
aStudy stents in target lesion onlybDefined as
DSlt30 with TIMI flow 3 and no in-hospital MI,
TVR, or cardiac deathcDefined as successful
delivery and deployment of the study stent to the
target vessel without balloon rupture or stent
embolizationIntent-to-treat P values are versus
PROMUS Element
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Post-Procedure AngiographicCharacteristics
SYNERGY½ DoseN99
SYNERGYN94
PROMUSElementN98
P value
P value
MLD, in-stent 2.44 0.36 2.51 0.37 0.17 2.58 0.36 0.008
MLD, in-segment 2.05 0.42 2.14 0.41 0.14 2.21 0.40 0.007
Acute gain, in-stent 1.76 0.38 1.83 0.39 0.20 1.90 0.38 0.01
Acute gain, in-segment 1.38 0.42 1.46 0.44 0.17 1.54 0.41 0.007
Diameter stenosis, in-stent 3.77 9.29 3.23 9.62 0.68 2.90 7.94 0.50
Diameter stenosis, in-segment 19.57 9.26 18.06 8.46 0.21 17.08 6.90 0.04
By QCAValues are mm or percentIntent-to-treat
P values are versus PROMUS Element
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Late Loss at 6 Months
Late Loss at 6 Months
Difference and 95.2 UCB
Noninferiority Threshold
P0.19
P0.56
SYNERGY
Plt0.001
Difference (SYNERGY PROMUS)
Late loss, mm
SYNERGY½ Dose
Plt0.001
SYNERGY½ Dose
PROMUSElement
SYNERGY
Noninferiority is proven because the upper 95.2
confidence bound of the difference in 6-month
late loss is lt0.20 for both SYNERGY stents
Intent-to-treat P values for superiority
comparison
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Angiographic Outcomes at 6 mo
SYNERGY½ DoseN99
SYNERGYN94
PROMUSElementN98
P value
P value
In-stent values
MLD 2.29 0.50 2.41 0.42 0.08 2.45 0.44 0.02
Late Loss 0.15 0.34 0.10 0.25 0.19 0.13 0.26 0.56
Diameter stenosis 8.95 14.97 6.59 9.90 0.18 7.27 9.47 0.34
Binary restenosis 3.2 0.0 0.25 0.0 0.25
Assessed by QCAValues are mm or
percentIntent-to-treat P values are versus
PROMUS Element
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Death and MI at 6 Months
All PN.S.
Patients,
AllDeath
CardiacDeath
NoncardiacDeath
AllMI
Q-Wave
Non-Q-Wave
The cause of the noncardiac death in the SYNERGY
group was a motor vehicle accident at 191 days
post-procedure. Intent-to-treat P values are
versus PROMUS Element (Fisher exact test)
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Revasc and ST at 6 Months
All PN.S.
Patients,
TVR
TLR
Non-TLRTVR
StentThrombosis
Intent-to-treat P values are versus PROMUS
Element (Fisher exact test)
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Target Lesion Failure
30 days
6 Months
P1.00
P0.49
P0.25
P0.72
Patients,
Patients,
PROMUSElement
SYNERGY½ Dose
SYNERGY
PROMUSElement
SYNERGY
SYNERGY½ Dose
Intent-to-treat P values are versus PROMUS
Element (Fisher exact test)
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Limitations

• The study only included patients with relatively
  simple de novo lesions
• Patients with AMI, stroke, CTO, bifurcation, LMCA
  lesion, SVG lesion, ostial lesions, or lesions
  with thrombus or excessive tortuosity or
  angulation were excluded
• The study was not powered to detect differences
  in clinical event rates
• The study was not designed to assess the risk of
  thrombosis or the required duration of dual
  antiplatelet therapy with SYNERGY
• Two additional studies planned with adequate
  power to
• Assess clinical event rates
• Assess long vs short duration of DAPT

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Conclusions

• In this prospective, randomized, multicenter,
  First Human Use trial, the two dose formulations
  of the SYNERGY stent were non-inferior to the
  PROMUS Element stent for the primary angiographic
  endpoint of in-stent late loss at 6 months.
• Clinical events were low and comparable with no
  stent thromboses in any group.
• These results support the safety and efficacy of
  the novel abluminal bioabsorbable polymer SYNERGY
  everolimus-eluting stent for the treatment of
  patients with de novo coronary artery disease.
• Additional research is needed to evaluate
  clinical event rates and the potential for dual
  antiplatelet therapy reduction with this novel
  stent.

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Thank you to the EVOLVE Site Investigators
Ian Meredith, MonashHeart Stefan Verhaye, Ziekenhuis Netwerk Antwerpen Middelheim
Adrian Banning, John Radcliffe Hospital Paul Barragan, Polyclinique Les Fleurs
Didier Carrie, Hôpital Rangueil Mariano Valdes Chavarri, Hospital Universitario Virgen
Joseph Dens, Ziekenhuis Oost-Limburg Christophe Dubois, Universitaire Ziekenhuis Gasthuisberg
Seif El-Jack, North Shore Hospital Jean Fajadet, Clinique Pasteur
Rosana Hernandez-Antolin, Hospital Clinico San Carlos Stefan James, Uppsala Akademiska Hospital
Henning Kelbaek, Rigshospitalet Copenhagen Jacek Kubica, Szpital Uniwersytecki
Victor Legrand, Centre Hospitalier Universitaire Sart Tilman Liège Monica Masotti, Hospital Clinic i Provencial de Barcelona
Raul Moreno, Hospital Universitario La Paz Keith Oldroyd, Golden Jubilee
Douglas Scott, Middlemore Hospital Iwar Sjögren, Falu Iasarett
Rod Stables, Liverpool Heart and Chest Hospital Leif Thuesen, Skejby Sygehus
Olivier Varenne, Hôpital Chocin Simon Walsh, Belfast Health Social Care Trust
Darren Walters, Prince Charles Hospital Nick West, Papworth Hospital
Alan Whelan, Fremantle Hospital Robert Whitbourn, Saint Vincents Hospital
Gerard Wilkins, Dunedin Hospital