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Coronary Stents: Understanding Differences in Design, Material, Drug, Usage
Alexandra Lansky, MD Yale School of Medicine University College of London Director Interventional Cardiology Research New Haven, CT
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I have no real or apparent conflicts of interest to report.
Alexandra J. Lansky, MD I have no real or apparent conflicts of interest to report.
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Network meta-analysis: 38 trials, 18,023 pts
TLR Frequency Stettler C et al. Lancet 2007;370: 2 2
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Network meta-analysis: 38 trials, 18,023 pts
BMS PES SES 10 SES vs. BMS: HR 1.00 ( ), p=0.89 PES vs. BMS: HR 1.03 ( ), p=0.75 SES vs. PES: HR 0.96 ( ), p=0.80 8 6 All cause death (%) 4 Mortality 2 1 2 3 4 Years after initial procedure BMS / / / /1875 PES / / / /869 SES / / / /10810 Stettler C et al. Lancet 2007;370: 3 3
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DES Efficacy - Safety Balance 1st Generation
Attribute Bare Metal Stents CYPHER & TAXUS Efficacy ++ ++++ Safety +++ Deliverability Improved efficacy, but diminished deliverability and similar safety
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Second Generation DES 81 mm 7.8 mm 132 mm 19.6 mm Strut Thickness:
XIENCE V Strut Thickness: 81 mm Polymer Thickness: 7.8 mm Structure of Everolimus, rapamycine derivative Stent Material: Cobalt Chromium (CoCr) Alloy Strut & polymer thickness, 3.0 mm, 500x TAXUS EXPRESS Strut Thickness: 132 mm Polymer Thickness: 19.6 mm Modified on 2/12/10 Structure of Paclitaxel, cyclodecane isolated from Taxus brevifolia Stent Material: Stainless Steel Strut & polymer thickness, 3.0 mm, 500x
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Target lesion failure (%)
SPIRIT IV: TLF* Through 3 Years (N=3690) 25 XIENCE V (n=2458) TAXUS Express (n=1229) 20 HR [95%CI] = [0.63, 0.97] p=0.004 HR [95%CI] = 0.71 [0.56, 0.90] p=0.02 p=0.001 HR [95%CI] = 0.61 [0.46, 0.81] 15 11.7% Target lesion failure (%) 9.9% Δ 2.5% 10 Δ 2.9% 6.7% 9.2% Δ 2.7% 7.0% 5 4.0% 3 6 9 12 15 18 21 24 27 30 33 36 Months Number at risk XIENCE V 2458 2390 2364 2323 2281 2238 2212 2187 2162 2132 2116 2095 2074 TAXUS 1229 1166 1138 1119 1095 1069 1060 1049 1029 1019 1008 994 979 TLF (primary endpoint at 1 year) = cardiac death, target vessel MI, or ischemia-driven TLR
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SPIRIT IV: Cardiac Death and TV MI @ 3 Years
2 4 6 8 10 12 14 3 9 15 18 21 24 27 30 33 36 XIENCE V (n=2458) TAXUS Express (n=1229) HR [95%CI] = [0.52, 0.85] p=0.001 HR [95%CI] = 0.77 [0.57, 1.04] 9.1% p=0.08 HR [95%CI] = 0.72 [0.50, 1.03] Δ 3.2% All Death or MI (%) 5.9% p=0.07 Δ 1.4% 4.0% 5.9% Δ 1.1% 4.5% 2.9% Months Number at risk XIENCE V 2458 2392 2378 2350 2319 2291 2276 2264 2247 2223 2214 2202 2187 TAXUS 1229 1179 1165 1153 1136 1114 1108 1104 1090 1080 1070 1057 1043
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Stent Thrombosis (Protocol Definition)*
Early (0 – 30 days) Late (>30 days – 1 year) Very Late (>1 year) 0.08 XIENCE V N=2458 0.79% p=0.004 TAXUS N=1229 1.99% Stent thrombosis (%) *ACS + angiographic thrombus, or unexplained death or STEMI/Q-wave MI in TL distribution within 30 days
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Zotarolimus Release (%)
Resolute DES System Components Established Components Unique Polymer Technology Driver cobalt alloy stent BioLinx polymer is a unique blend of three polymers to control drug release, support biocompatibility and enhance elution rate Sprint delivery system Drug-release kinetics: complete elution by 180 days 100 80 60 40 20 Zotarolimus Release (%) 50 150 200 Days % eluted Zotarolimus antiproliferative drug Udipi K, et al. EuroIntervention. 2007; 3:137-9 Meredith IT, et al. J Am Coll Cardiol Intv. 2009; 2:977-85 Meredith IT, et al. EuroIntervention. 2007; 3:50-53
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RESOLUTE All Comers : 12 month TLF
(Cardiac Death, Target Vessel MI, and Clinically Driven TLR) at 1 Year Resolute (N = 1140) Xience V (N = 1152) Log-Rank P = 0.92 20 Resolute 8.2% vs. Xience V 8.3% Pnon-inferiority <0.001 Primary Non-Inferiority Clinical Endpoint Met 15 10 8.3% Cumulative incidence of events [%] 8.2% 5 180 360 Time after initial procedure [days] No. at risk 30 60 90 120 150 180 210 240 270 300 330 360 ZES 1140 1110 1084 1076 1070 1062 1060 1058 1051 1042 1038 1037 1025 EES 1152 1123 1088 1080 1078 1074 1068 1061 1047 1046 1032 1019 Error bars indicate a point-wise two-sided 95% confidence interval (±1.96*SE). Standard Error based on the Greenwood Formula. Serruys PW, Silber S, et al., N Engl J Med. 2010;363:136-46 10
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RESOLUTE All Comers Stent Thrombosis and Cardiac Death / MI
ARC Definite/Probable ST Cardiac Death and Target Vessel MI 10 10 Resolute ZES Resolute ZES Xience V EES Xience V EES Log Rank P = 0.05 Log Rank P = 0.96 5.4% 5.3% 5 5 Cumulative incidence of events [%] Early stent thrombosis events did not translate into differences in cardiac death or TVMI rates for the Resolute stent 1.6% 0.7% 180 360 180 360 Time after initial procedure [days] Time after initial procedure [days] Error bars indicate a point-wise two-sided 95% confidence interval (±1.96*SE). Standard Error based on the Greenwood Formula Serruys PW, et al. Presented at EuroPCR LBCT, 2010.
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Everolimus-Eluting Stents
Everolimus concentration: 100 ug/cm2 Polymer: PBMA & PVDF‑HFP (7m thickness) 10% Nickel XIENCE V / PROMUS (CoCr-EES) 3% Iron 15% Tungsten 52% Cobalt 20% Chromium 1.5% Manganese PROMUS Element (PtCr-EES) 2.6% Molybdenum 18% Chromium 9% Nickel 0.05% Manganese 33% Platinum 37% Iron PBMA=poly (n‑butyl methacrylate) (primer layer); PVDF-HFP=poly (vinylidene fluoride‑co‑hexafluoropropylene) (drug matrix layer)
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PLATINUM: Target Lesion Failure
Time-to-event analysis Per Protocol Intention-to-Treat CoCr-EES (N=747) PtCr-EES (N=756) CoCr-EES (N=762) PtCr-EES (N=768) 10 3 6 9 12 2 4 10 8 8 HR [95% CI] = 1.17 [0.66, 2.09] P = 0.59 HR [95% CI] = 1.12 [0.64, 1.95] P = 0.70 6 Target Lesion Failure (%) 3.4% 3.5% 4 3.0% 3.2% 2 PLATINUM ACC Presentation Analysis r016-validated, Exhibits 1, 2, 3; PLATINUM 12-Month RCT Manuscript Analysis r007: exhibit 5 3 6 9 12 Months Months No. at risk CoCr EES 747 735 731 723 707 756 745 740 734 719 762 747 743 735 718 768 756 751 745 730 PtCr EES
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ARC Stent Thrombosis Definite/Probable (%)*
PLATINUM: Stent Thrombosis – ARC Def/Prob 12 Months – Intent-to-Treat 10 CoCr-EES (N=762) PtCr-EES (N=768) 8 6 HR [95% CI] = 0.99 [0.20, 4.91] P = 0.99 ARC Stent Thrombosis Definite/Probable (%)* 4 2 0.4% 0.4% 3 6 9 12 Months No. at risk CoCr-EES 762 755 752 745 728 768 761 758 741 PtCr-EES * All were definite ST
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Design Features of the Ideal DES
Desired Attributes Attributes and Design Goals Acute Performance Stent & Delivery System Deliverable Visible Trackable Conformable Thinner Struts Fewer connectors Improved Deliverability Efficacy Low Drug Load Good Clinical Outcomes Low TLR Low Clinical Symptom Recurrence Drug Load = PROMUS™/Xience™ Release kinetics similar to PROMUS™/Xience™ Safety Reduced Polymer Load Bioabsorbable Polymer Rapid BMS conversion (4mo) Abluminal Polymer Coating Low Polymer Mass No Stent Thrombosis Shortened DAPT Requirement Safer for DAPT Interruption 15 15 15
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ION™ / TAXUS® Element™ Stent
DES Evolution to Thinner Strut Thickness 1st Generation 2nd Generation 3rd Generation 4th Generation Xience V® and Xience Prime® Stents ION™ / TAXUS® Element™ Stent PROMUS Element™ Stent TAXUS® Express® Stent TAXUS® Liberté® Stent SYNERGY™ Stent Cypher® Stent Endeavor® Stent current benchmark for lowest strut thickness 0.140 μm (0.0055” ) 0.132 μm (0.0052”) 0.096 μm (0.0038”) 0.091 μm (0.0036”) 0.081 μm (0.0032”) 0.081 μm (0.0032”) 0.081 μm (0.0032”) 0.074 μm (0.0029”) Coating Thickness: 12.6 µm 19.6 µm 4.8 µm 7.8 µm Stainless Steel Cobalt Alloys Platinum Chromium Reported strut thicknesses are for 3.0mm diameter 16
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Xience V® (PROMUS®) Stent
Radiopacity Can Help Identify Procedural Complications Easier identification of stent deformation PtCr Stent 3.0x16 (0.0032” (0.081mm)) TAXUS® Liberté® Stent 3.0x16 (0.0038” (0.097mm)) Xience V® (PROMUS®) Stent 3.0x15 (0.0032” (0.081mm)) Endeavor® Stent 3.0x18 (0.0036” 0.091mm)) Stent deformation occurs infrequently with all thin strut stents. Bench x-ray C-arm w/ PMMA phantom Data on File. X-ray images of stents without a phantom and with a 25cm PMMA phantom. The PtCr Stent Series includes PROMUS Element, TAXUS Element (ION) and OMEGA. Bench test conducted on the PROMUS Element Stent. PROMUS Stent is a private-labeled Xience V Everolimus Eluting Coronary Stent System manufactured by Abbott and distributed by Boston Scientific Corporation. Xience V is a trademark of Abbott Laboratories group of companies. 17 17
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Stent Geometry & Design 101
Hoops provide radial strength Connections hold hoops together and provide longitudinal strength Hoop strength (radial strength) and longitudinal strength are independent Connectors play major role in flexibility Connectors control cell size and SB access Bridges/connectors link hoops Prime/ Vision Multi- Link Element Cinatra Velocity/ Select Driver Welds link hoops
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6 connectors 3 connectors 3 2 2 (3) 140µ 100µ 81µ 91µ Cypher Select
Liberte Vision Xience V Promus MultiLInk Xience Prime Driver Endeavor Integrity Resolute Omega ION Element Stainless steel Cobalt Chromium Platinum Chromium 140µ 100µ 81µ 91µ 6 connectors 3 connectors 3 connectors 2 2 (3)
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Radial Strength Amount of radial compression force the stent resists
More Compression Resistance Radial Force (Newtons/mm) Less Compression Resistance TAXUS® Liberté® Stent Cypher® Stent Endeavor® Stent Xience V® Stent TAXUS™ Element™ / ION™Stent PtCr Alloy Stainless Steel Alloy CoCr Alloy Data on File. Stent Performance Summary April mm Stents. TAXUS Element / ION n=15. TAXUS Liberté n=10. Cypher n=3. Xience Prime n=5. Endeavor n=7. Bench test results may not necessarily be indicative of clinical performance. Xience V n=10. The ION™ stent is commercialized as the TAXUS™ Element™ stent outside the US.
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Stent Recoil Percent decrease in stent diameter after balloon deflation More Recoil Percent (%) Recoil Less Recoil Xience V® Stent Endeavor® Stent Cypher® Stent TAXUS® Liberté® Stent TAXUS™ Element™ / ION™ Stent CoCr Alloy Stainless Steel Alloy PtCr Alloy Data on File. Stent Performance Summary April mm Stents. TAXUS Element n=15. TAXUS Liberté n=10. Cypher n=3. Xience Prime n=5. Xience V n=10. Endeavor n=7. Bench test results may not necessarily be indicative of clinical performance. The ION™ stent is commercialized as the TAXUS™ Element™ stent outside the US.
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Conformability Amount of force required to bend the stent
Less Conformability Conformability Newtons/mm More Conformability Cypher® Stent Xience V® Stent TAXUS® Liberté® Stent Endeavor® Stent TAXUS™ Element™ / ION™ Stent Stainless Steel Alloy CoCr Alloy Stainless Steel Alloy CoCr Alloy PtCr Alloy Data on File. Stent Performance Summary April mm Stents. TAXUS Element n=15. TAXUS Liberté n=10. Cypher n=3. Xience Prime n=5. Xience V n=10. Endeavor n=7. Bench test results may not necessarily be indicative of clinical performance.
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How far are stents compressed with 0.5N force ?
The Cypher Select did not shorten The Element shortened 5mm Xience 1mm
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Profound differences in longitudinal strength of contemporary DES
Performance Characteristics: Flexibility and longitudinal strength are trade off, mostly function of # connectors Consequences: stent compression, elongation and mal-apposition Radial Strength and recoil considerations Device Selection and Strategies to limit distortion: Stent selection in ostial and highly calcified lesions Meticulous Technique to avoid deep guide engagement, full balloon deflation prior to withdrawal
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Current Problems with Polymers
Shortcomings often associated with polymers during stent delivery “Webbed” polymer surface leading to stent expansion issues” Non uniform polymer coating Polymer delamination ● Durable Coatings-Potential for: - Continuing source of inflammation - Poor healing/thrombosis risk
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Drug-Eluting Technology Progression
Abluminal Bioabsorbable Polymer Fully Bioresorbable Polymer DES Polymer Free DES Current DES Biostable Polymer Vessel Wall Polymer + Drug Polymer + Drug Polymer + Drug BVS REVA Biotronic Synergy BioMatrix FireHawk Freedom Translumina Drug Filled stent Xience/Promus Resolute SYNERGY™ Stent Everolimus Drug PLGA Polymer Ultrathin Abluminal, Bioerodable Polymer (Rollcoat Technology) Platinum Chromium Platform Bioabsorbable PLGA polymer is only applied to the abluminal surface of the stent Maximum coating thickness 3μm (1/2 dose) and 4μm (standard dose) Check mags 26
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Coating Weight (µg, 16 mm Stent)
DES Coating Weight SYNERGY™ Stent* BioMatrix™ Stent PROMUS™ Stent BVS Stent + Coating Bare-Metal Stent BVS – paper in EuroIntervention (PCR) “Design principles and performance of bioresorbable polymeric vascular scaffolds”, James P. Oberhauser, PhD; Syed Hossainy, PhD; Richard J. Rapoza, PhD, by Abbott Vascular, Santa Clara, CA, states that an entire 3.0x18mm BVS scaffold includes 8.74mg of L-lactate and 76µg of D-lactate. Paper also states PLA in coating is equimolar, so total polymer weight in the coating should be 152µg on an 18mm stent. // l l l l l l l l l l l ,700 7,800 7,900 Coating Weight (µg, 16 mm Stent) Data on file Boston Scientific Corporation. Coating weights for BioMatrix and PROMUS Element are estimates for a 16mm stent based on published coat weights for 3.0x18mm stents. The SYNERGY stent is an investigational device limited by law to investigational use. Not for sale. 27 27 27
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Drug Release Kinetics In Vivo
Noninjured Porcine Model 2 4 6 8 10 20 40 60 80 PROMUS Element EES PROMUS EES Everolimus (ng/mg) Arterial Tissue Levels* Release (%) In Vivo Cumulative Release* 15 30 45 60 75 90 Time (Days) * Boston Scientific Corporation in-house testing; N=9-12 stents per time point; data are meanSD; EES=everolimus-eluting stent
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Bioabsorbable Everolimus-Eluting Scaffold (BVS)
The Cohort A device lost radial strength earlier than expected (Possibly in weeks) Bioresorption largely complete by 2 yrs Drug Elution Radial strength Cohort A ? Full Bioresorption Mass Loss 1 3 6 Mos 2 Yrs
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Vessel and stent area changes at 6 months and two years
Serruys et al Lancet 2009 Post-stenting 6 months 2 years LLL=0.40 LLL=0.42 Vessel size (EEL) did not change (although trend to reducing size between 6 months and 2 years (white)) Stent (broken line) shrank 12% by 6 months then disappeared Lumen (blue) shrank in area by 16% by 6 mo then increased by 12%
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Bioabsorbable and Polymer-Free Stents Design Features
Platform Strut Thickness Polymer / Carrier Drug / Coating Synergy™ (Boston Scientific) Bioabsorbable PLGA Everolimus Abluminal PtCr 0.0029” (74µm) BioMatrix Flex™ (Biosensors) Stainless Steel Bioabsorbable PLA Biolimus-A9™ Abluminal 0.0044” (112µm) Nobori™ (Terumo) Stainless Steel 0.0049” (125µm) Bioabsorbable PLA with Parylene C Tie-Layer Biolimus-A9™ Abluminal Orsiro™ (Biotronik) CoCr Bioabsorbable PLA Sirolimus Conformal 0.0024” (60µm) Yukon Choice™ (Translumina) Sirolimus Conformal Stainless Steel 0.0034” (87µm) N/A BioMatrix Flex (Dr. Volvker Klauss, TCT 2009) Nobori (Catheterization and Cardiovascular Interventions publication by Otsuka et. al in 2011) CRE8™ (CID) Non-polymeric amphiphilic carriers Sirolimus Abluminal CoCr 0.0031” (80µm) BVS™ (Abbott) Bioabsorbable PLA Everolimus Conformal PLA 0.0059” (150µm) Bioabsorbable Abluminal Polymer Bioabsorbable Conformal Polymer Polymer Free Fully Bioabsorbable Strut thickness values are based on workhorse designs. The SYNERGY stent is an investigational device. Not for sale. 31
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Future DES Summary Conclusions…1
Next generation DES (Endeavor, Xience V/Promus, Element) have already demonstrated superior performance characteristics, including enhanced deliverability, improved safety, and increased anti- restenosis efficacy. Future DES are focusing largely on drug carrier enhancements to reduce safety concerns Bioabsorbable polymer drug delivery – many versions, much promise, insufficient long-term clinical data to assess incremental value
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Future DES Summary Conclusions…2
Polymer-free drug delivery – more difficult to achieve optimal drug elution profiles, best chance for “BMS-like” safety profile, BUT almost no clinical data thus far Bioabsorbable stents have important potential advantages, each system is unique (all will require iterative stent designs and drug elution), but early proof-of-concept has already been accomplished (BVS) suggesting a more biocompatible solution with excellent safety and efficacy; may represent a breakthrough DES technology in the future!
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