Xience V Everolimus-Eluting and Cypher Sirolimus-Eluting Stents: There Are Clinical Differences Chuck Simonton MD, FACC, FSCAI Chief Medical Officer Abbott.

Xience V Everolimus-Eluting and Cypher Sirolimus-Eluting Stents: There Are Clinical Differences
Chuck Simonton MD, FACC, FSCAI Chief Medical Officer Abbott Vascular Santa Clara, CA CRT 2011

Preclinical Data: Optimizing Stent Design Early Cypher SES vs Taxus PES Clinical Trials Xience V EES vs Taxus Clinical Trials Recent head-to-head Cypher SES vs Xience V EES clinical trials (TCT and ESC 2010) Conclusions

XIENCE V EES Progression Towards Thinner Struts
CYPHER TAXUS Express ENDEAVOR™ XIENCE V Strut Thickness: 140 µm Coating Thickness: 12.6 µm Strut Thickness: 132 µm Coating Thickness: 19.6 µm Strut Thickness: 91 µm Coating Thickness: 4.8 µm Strut Thickness: 81 µm Coating Thickness: 7.8 µm …it is in this context that we believe that the progression towards thinner stent struts is important. Shown are the left are the actual SEM cross sections for the first generation of drug eluting stents, for which the strut thickness greatly exceeds 100um. On the right is the Xience V stent with a strut thickness of 81 um. Also of note is the thin outline of the actual polymer coating around the stent strut for Xience V. The coating thickness is about 8um for Xience V compared to 13-20um for the first generation of DES on the left. This difference is quite visible in the micrographs. Abluminal coating thickness represented Data on file at Abbott Vascular

Qualitative Assessment of Endothelial Cell Coverage: 14-day Rabbit Iliac
These are scanning electron micrographs of the luminal surface of stents cut longitudinally. These images provide a qualitative assessment of endothelial coverage. As you can see, Xience has greater coverage than the other competitive DES CYPHER TAXUS ENDEAVOR XIENCE V VISION Joner, Virmani et al, JACC 2008

Joner, Virmani et al, JACC 2008
Quantitative Assessment of Luminal Endothelialization by SEM (14 Day Rabbit Iliac) % 4 4 4 6 6 4 4 4 6 6 CYPHER TAXUS VISION CYPHER TAXUS VISION ENDEAVOR XIENCE V ENDEAVOR XIENCE V Above Struts Between Struts 14 Days Rabbit Iliac Joner, Virmani et al, JACC 2008 Error bar = ± 1 SE

Preclinical Data: Optimizing Stent Design Early Cypher SES vs Taxus PES Clinical Trials Xience V EES vs Taxus Clinical Trials Recent head-to-head Cypher SES vs Xience V EES clinical trials (TCT and ESC 2010) Strut Fractures Conclusions

SIRTAX-LATE 5-Year Clinical and Angiographic Follow-up From a Prospective, Randomized Trial Comparing Sirolimus-Eluting With Paclitaxel-Eluting Stents Lorenz Räber, MD On Behalf of the SIRTAX Investigators Dep. of Cardiology, Bern University Hospital, Switzerland Funded by Bern University Hospital, Switzerland

Major Adverse Cardiac Events @ 5 Years
1 year HR 0.59 [0.40 – 0.86] P<0.01 5 year HR 0.85 [0.65 – 1.10] P=0.21 30 24.2% 25 Δ 2.9% 20 21.3% 13.8% 15 Cumulative Incidence of MACE (%) Δ 5.5% 10 8.3% 5 SES PES 1 2 3 4 5 Years 10

Target Lesion Failure (%)
Xience V: Clinical Advantages Maintained at 2 Years in On-Label Patients: No “Late Catch-Up” SPIRIT IV: 2-Year TLF* 6.7%  2.7% 4.0% 9.9%  3.0% 6.9% p=0.0009 p=0.003 Target Lesion Failure (%) Months (N=2458) (N=1229) 30% Reduction The second key message for XIENCE V is around efficacy: clinical advantages increase over time. In SPIRIT IV, we saw the difference in the TLF rates between XIENCE V and TAXUS widening at the two year mark, with a highly significant difference in TLF rates between the two. Q&A What is Target Lesion Failure (TLF), and why is this the primary endpoint for SPIRIT IV instead of MACE? Target Lesion Failure is a composite endpoint of Cardiac Death, Target Vessel Myocardial Infarction, and Ischemia Driven TLR. The industry, based on FDA guidance, is moving toward this standard definition for clinical trials, as it more adequately addresses the performance of a stent and MACE definitions across trials often differ. In many cases, MACE includes cardiac death, ID-TLR and MI. For TLF, the main difference from MACE is the “Target Vessel MI” component (versus “All MI”). What is the definition of Ischemia Driven Target Lesion Revascularization (ID-TLR) in SPIRIT IV? Patients had to experience symptoms to receive a revascularization. This differentiates SPIRIT IV from many other trials in that in SPIRIT IV there was no pre-specified angiographic follow-up. TLR rates in SPIRIT IV are more closely linked to real world experiences. What do the results in patients with diabetes mean? Xience V was numerically lower than Taxus in all diabetics, representing the largest diabetic subset of an RCT ever presented between two DES. XIENCE V had superior outcomes in the overall population and numerically lower Target Lesion Failure in patients with diabetes, Across all subgroups, regardless of patient or lesion complexity, XIENCE V has consistently demonstrated numerically lower clinical event rates versus TAXUS. Why did XIENCE V double in TLF from non-diabetics to diabetics? Consistent with many DES trials, XIENCE V demonstrated higher event rates in patients with diabetes versus patients without diabetes. More importantly, in 1,140 patients with diabetes, XIENCE V had a low 6.4% rate of TLF (versus 6.9% for TAXUS, p=0.80) in SPIRIT IV at one year. Also, XIENCE V was superior in the primary clinical endpoint of TLF ( 39% reduction) in SPIRIT IV at one year Source: G. Stone. SPIRIT IV 2-Year Results Presentation, TCT TAXUS Express2 was the control in SPIRIT IV. *Primary endpoint of SPIRIT IV. TLF = cardiac death, ID-TLR and TLR.

Xience V: Clinical Advantages Observed to Widen Further at 2 Years in All-Comer Patients
COMPARE: 2-Year MACE** MACE (%) (N=897) (N=903) p=0.0016* 34% Reduction COMPARE’s primary endpoint was MACE (all death, non-fatal MI and TVR). At two years, the significant difference between XIENCE V and TAXUS increased from 2.9% at year one to 4.7% at year 2. Q&A Again in COMPARE, there was no difference in performance between XIENCE and Taxus in Diabetics. - As in SPIRIT IV, XIENCE was numerically, but not significantly better than Taxus for diabetics in the composite endpoint of MACE. Once again, XIENCE showed an advantage over Taxus in every subgroup, including significant advantages in AMI, Small Vessels, and Multi-Vessel patients. *Log-rank test **Primary Endpoint of COMPARE. MACE = All death, non-fatal MI and TVR Source: P. Smits. COMPARE 2-Year Results Presentation. TCT TAXUS Liberté was the control in COMPARE.

Sustained Clinical Advantage Observed at 4 Years in On-Label Patients: Again No “Late Catch-Up”
SPIRIT III: 4-Year MACE p=0.01 p=0.02 (N=669) (N=332) (%) 34% Reduction This was mirrored in SPIRIT III for MACE, which also showed an increase in the significant reduction of MACE from 4.2% at year 1 to 5.1% at year What this slide, and the previous two slides for SPIRIT IV and COMPARE reinforce is that there is no catch-up for TAXUS over XIENCE V in terms of efficacy now out to four years. Source: G. Stone. SPIRIT III 4-Year Results Presentation. TCT TAXUS Express2 was the control in SPIRIT III

SPIRIT IV: 2-Year Stent Thrombosis Rate of Stent Thrombosis
Xience V: Consistently Low Stent Thrombosis Rates at 2 Years in Multiple Prospective Randomized Clinical Trials SPIRIT IV: 2-Year Stent Thrombosis (ARC Def/Prob) Rate of Stent Thrombosis XIENCE V N=2458 TAXUS N=1229 0.42% 1.23% p=0.008 66% COMPARE: 2-Year Stent Thrombosis (ARC Def/Prob) p<0.0001* In Thursday’s Late-Breaking Session, two-year updates were provided for SPIRIT IV and COMPARE. In both trials, XIENCE V went head to head against Taxus. SPIRIT IV, which is the largest RCT to date between two DES. XIENCE V’s superiority in safety continues at 2 years, with a 64% reduction in ST rates for XIENCE. In COMPARE, an independent, single center study from the Netherlands, 1800 patients were randomized 1:1 to receive XIENCE V or Taxus Liberte. COMPARE was a real-world, all-comers trial. There was a 77% reduction in the risk of ST for XIENCE V versus Taxus Liberte which was highly significant. SPIRIT IV Q&A What was the DAPT Utilization for SPIRIT IV at 2 years? The rate for XIENCE V patients on thienopyridines (class of antiplatelet therapy, including products such as Plavix and Ticlid) at 24 months in SPIRIT IV was 71.9%, versus 71.1% for TAXUS. The relatively high rates of aspirin and thienopyridine utilization at one year in SPIRIT IV reflects the current ACC guidelines regarding dual antiplatelet therapy (DAPT). These guidelines came into effect after SPIRIT II and SPIRIT III began, therefore the DAPT rates in SPIRIT IV are considerably higher. With consistent use of DAPT in the first 12 months, the variability of DAPT is removed and a better assessment of DES versus DES is possible. Were there any significant differences in baseline demographics in SPIRIT IV? There were no statistically significant differences in either the baseline angiography or demographics in SPIRIT IV. For procedural results, XIENCE V had statistically longer lesions treated (22.4 mm vs mm; p=<0.0001). Boston Scientific cannot claim that the TAXUS patients were more complex than the XIENCE V patients. COMPARE Q&A Since this is a single center study isn’t it not as credible as a multi-center study? The size of the trial is compelling with over 1800 patients, and the complexity of the patients represents a real-world scenario. Events in COMPARE were adjudicated by an independent core lab and clinical events committee, unique for a single-center study. COMPARE was jointly supported by Abbott Vascular and Boston Scientific, and the superior results of COMPARE were strikingly consistent with the results of the multi-center SPIRIT IV trial. This study was also published in Lancet in 2010, a peer reviewed journal. As a single-center in the Netherlands, aren’t the demographics are not reflective of patients treated world-wide? XIENCE V has proven superiority over TAXUS in a broad range of patient types. The SPIRIT Family of studies were conducted around the world including sites in Asia, Europe and the United States with strikingly consistent results. XIENCE V has demonstrated consistent superiority in clinical and angiographic outcomes across the SPIRIT body of data. Largest RCT between two DES to have presented primary endpoint data 3,690 patients Clinically-driven primary and secondary endpoints Investigator-sponsored, single-center, prospective RCT 1,800 All Comer, real-world patients 11% of XIENCE V patients and 15% of TAXUS patients on DAPT at 2 years Source: G. Stone. SPIRIT IV 2-Year Results Presentation. TCT 2010. Source: P. Smits. COMPARE 2-Year Results Presentation. TCT 2010. *Log-rank test

Most Recent Studies of Note
SORT-OUT IV: 9-month results ISAR-TEST 4: 2-year results LESSON I: 3-year results ESSENCE: Diabetes 1-year results References: ESC 2010 and TCT 2010

SORT-OUT IV: TCT 2010 Independently conducted, prospective, randomized, multi-center non-inferiority study in Denmark 2,676 All-Comers, randomized 1:1 XIENCE V vs. CYPHER Select + Primary Endpoint: Composite cardiac death, MI, and definite ST or TVR at 9 months Source: L. Okkles Jensen, SORT OUT 4 9-Month Results Presentation. TCT 2010.

SORT-OUT IV 9-Month MACE* Clinical Advantages at 9 Months
Primary Non-Inferiority Endpoint Met Sort Out IV also demonstrated Clinical Advantages against CYPHER at 9 months with a Numerically lower rates of MACE, TLR, MI, and TVR. Q&A If the trial is considered All-Comers, why were 60% of the eligible patients excluded from randomization? This was a point of discussion - the same thing was seen in the SORT-OUT III study, which was also heavily criticized by Medtronic. For either study, no explanation has been given for this exclusion. For those 2774 patients who were randomized, there were no differences in patient demographics or lesion characteristics for this complex patient population (12% bifurcations, over 55% B2/C lesions, etc). Why was the Stent Deliverability failure higher for XIENCE than CYPHER? Stent delivery failure was different for XIENCE vs CYPHER (2.9% vs 2.0%, p=0.08). While lesion characteristics were similar between the two arms, there are a number of factors that could contribute to this difference. There was no standardized treatment protocol, and as a result XIENCE had numerically higher rates of direct stenting as well as differences in inflation pressures. Why were the overall clinical event rates so low for both arms? Dr. Stone commented that low event rates have been seen historically in other SORT-OUT studies. This may be a reflection of the methodology for data capture. It is important not to compare across multiple trials. However, within the SORT-OUT IV trial, there was a relative reduction for XIENCE over CYPHER in multiple clinical endpoints. Clinical Advantages at 9 Months *Primary endpoint of SORT OUT IV. MACE = cardiac death, MI, def ST, TVR.

SORT-OUT IV 9-Month The Sort-Out IV study illustrated outstanding results for XIENCE vs Cypher. In this study we saw Statistically Low rates of Stent Thrombosis with the Low rate of Definite Stent Thrombosis of 0.1% at 9m for XIENCE (0.7% for CYPHER, p=0.05) What accounts for the large difference in rates for Definite vs Def/Prob Stent Thrombosis? Definite Stent Thrombosis is defined as Occlusion verified by Angiography or Autopsy. There is no doubt that it was a Thrombosis. These events would absolutely be captured in this trial protocol. Definite / Probable includes unconfirmed, but likely, cases of Stent Thrombosis. These probable events may or may not be captured as Thrombotic events within the database. Source: L. Okkles Jensen, SORT OUT 4 9-Month Results Presentation. TCT 2010.

ISAR-TEST 4 Independently-conducted, prospective randomized controlled trial 1,304 patients randomized 1:1 (XIENCE: n=652, CYPHER: n=652) Primary Endpoint: Composite of Cardiac Death, TV-MI and TLR

AP Rev. A Information contained herein intended for healthcare professionals outside the US only

ISAR-TEST 4: 2-Year EES vs. SES
XIENCE V CYPHER Definite Stent Thrombosis Late (30d-1y) Early (<30d) Very late (>1y) p=0.17 0.6% 1.4% Number of Events While the primary objective of ISAR TEST 4 was to compare the efficacy of the ISAR biodegradable stent versus durable polymers, the secondary objective was to compare the efficacy of XIENCE vs. Cypher, and it was these results that were revealed at the TCT Late Breaker. XIENCE V showed very low ST rates, with 0 very late definite ST events versus 2 for Cypher. EES had no very late stent thrombosis Source: R. Byrne. ISAR Test 4 2-Year Results Presentation. TCT 2010.

LESSON I Late-breaking trial presented at ESC 2010 of XIENCE V vs. CYPHER Investigator-initiated, single center, independent study Propensity-matched, with 1342 patients enrolled in each arm Primary endpoint is a composite of Death, MI and TVR through 3 years

LESSON I: ESC LBCT 2010 Propensity Matched, Single-Center
XIENCE V N=1342 CYPHER p-value Primary Endpoint: Death, MI or TVR 14.9% 18.0% 0.056 Cardiac Death 3.9% 4.4% 0.51 MI 3.3% 5.0% 0.017 NQWMI 2.8% 3.1% 0.43 QWMI 0.5% 1.6% 0.010 TVR 7.0% 9.6% 0.039 Definite ST (Overall) Very Late Definite ST 0% 0.7% 0.007 In the Lesson study, XIENCE also demonstrated statistically significant advantages (p<0.05) over Cypher in stent thrombosis, TVR and MI, with a strong trend towards significance in the primary endpoint of Composite Death, MI, and TVR (p=0.056). Key conclusions from Prof. Windecker were as follows: · "In this observational, propensity-score matched study, the unrestricted use of EES was associated with a lower risk of MI, TVR, and ST compared with SES during long-term follow-up to three years." · "DES Efficacy can be further advanced beyond the level of the previous gold standard of SES without compromising, but even improving their safety profile." Q&A What is a propensity-matched analysis? How does it differ from a randomized controlled trial? A propensity-matched analysis is a statistical process that is used to minimize or eliminate any bias in results due to underlying differences between treatment groups. Put in simpler terms, propensity matching enables comparisons to be made between two treatment arms by controlling for any variables that may bias the results. In a RCT, the randomization process ensures any confounding variable will impact both study arms equally, therefore ensuring differences in results can be directly attributed to the treatment. The data is listed as 3-year follow up, but the median follow up is cited as 1.3 years. How do you explain the difference? LESSON 1 is a consecutive enrollment study. The Cypher arm was enrolled between May 2004 and January 2006, and the XIENCE arm was enrolled between November 2006 and March Given the consecutive enrollment, the patients who were enrolled later have not yet reached the 3-year follow up period. However, 3-year data were included in both arms. The number of patients with clinical follow up in each arm was comparable at each time point. What was the clopidogrel duration? The clopidogrel duration was 12 months for both arms. What do you think accounts for the differences between XIENCE and Cypher? During the discussion around the LESSON 1 results at ESC, the discussants theorized that the lower event rates for XIENCE may possibly be attributed to the polymer, lower drug load and thinner struts. Dr. Windecker also noted that there are "observed hypersensitivity reactions” to Cypher. XIENCE V demonstrates positive outcomes in safety and efficacy out to 3 years Source: S. Windecker. LESSON I 3-Year Results. ESC 2010.

LESSON I Definite Stent Thrombosis to 3 Years
The Lesson I data was presented by Stephan Windecker at the August 2010 ESC meeting. This data clearly demonstrated that not all DES are the same. XIENCE demonstrated statistically significant advantages over Cypher in safety and efficacy out to three years in a more complex patient population. Source: S. Windecker. LESSON I 3-Year Results. ESC 2010.

ESSENCE Diabetes: 1-Year
15-center, Independent, non-inferiority study based in Korea 280 diabetic patients, randomized 1:1 XIENCE (n=149) vs. CYPHER (n=151) Late Loss (mm) XIENCE N=108 CYPHER N=107 Primary Endpoint: Late Loss pnin= psup = 0.020 Clinical Outcomes XIENCE CYPHER Death 2 (1.3%) 5 (3.3%) MI ST 1 (0.7%) ID-TLR 4 (2.6%) Death, MI, ID-TLR 3 (2.0%) 8 (5.3%) The ESSENCE Diabetes study further illustrated outstanding data for XIENCE versus Cypher in diabetics. This study demonstrated a Consistently Low Stent Thrombosis Rate at 1yr in Diabetics for ARC Stent Thrombosis rate (Prob) of 0.7% and a Significantly Lower Angiographic Results in Diabetics with an In-segment Late Loss of 0.2mm for XIENCE vs 0.37mm for Cypher. Low clinical event rates at 1 year in diabetics Source: Y. Kim. ESSENCE-DIABETES 1-Year Results. TCT 2010.

Conclusions Xience V EES and Cypher SES
Preclinical studies show slower endothelial healing for Cypher SES compared to Xience V EES Early head-to-head Cypher vs Taxus prospective RCT’s showed either no significant clinical differences or the early Cypher advantage was lost over time Xience V has repeatedly shown clinical superiority to Taxus in multiple prospective RCT’s (SPIRIT III, IV, COMPARE) and no evidence of late clinical catch-up which Cypher was unable to do in its RCT’s In available head-to-head trials of Xience V and Cypher, although composite clinical endpoints are similar, Xience has shown either significant or numerically lower late loss, binary angiographic restenosis, TLR and ARC definite stent thrombosis rates

Xience V Everolimus-Eluting and Cypher Sirolimus-Eluting Stents: There Are Clinical Differences Chuck Simonton MD, FACC, FSCAI Chief Medical Officer Abbott.

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Xience V Everolimus-Eluting and Cypher Sirolimus-Eluting Stents: There Are Clinical Differences Chuck Simonton MD, FACC, FSCAI Chief Medical Officer Abbott.

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Presentation on theme: "Xience V Everolimus-Eluting and Cypher Sirolimus-Eluting Stents: There Are Clinical Differences Chuck Simonton MD, FACC, FSCAI Chief Medical Officer Abbott."— Presentation transcript:

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