Late “Catch-Up” in Target Vessel Revascularization with DES vs BMS in SVG Intervention: Two Year Results from the STENT Group Bruce R Brodie, Hadley Wilson, Thomas Stuckey, Marcy Nussbaum, Sherry Laurent, Barbara Bradshaw, Angela Humphrey, Chris Metzger, James Hermiller, Fred Krainin, Stanley Juk, Barry Cheek, Peter Duffy, and Charles A. Simonton TCT 2009

No conflicts

Background and Purpose Drug-eluting stents (DES) have been shown to be safe and more effective than bare metal stents (BMS) with PCI in non- complex lesions. The safety and efficacy of DES for “off-label” use in SVG interventions is controversial. There have been 2 small randomized trials and several small registries evaluating DES with SVG intervention, but they have been limited by small numbers of patients and short follow-up and have yielded conflicting results. The purpose of this study is to test the hypothesis that DES used with SVG intervention are safe and are effective in reducing target vessel revascularization (TVR) compared with BMS.

The STENT Group The STENT Group organized the first US prospective multi-center registry for the evaluation of DES in May Patients undergoing PCI at 8 participating centers were consented for participation, including 9 month and 2 year clinical follow-up. Clinical coordinators entered data into a centralized database, and a central data coordinating center was responsible for quality control and statistical analyses. Physicians adjudicated all major events with audits performed on 10% of the first 4000 procedures with 5% thereafter.

Participating Centers Data Coordinating Center: R. Stuart Dickson Institute for Health Studies, Charlotte, NC Clinical Coordinating Center: Carolinas Heart Institute, Charlotte, NC Participating Centers: Carolinas Heart Institute, Charlotte, NC High Point Regional Hospital, High Point, NC Holston Valley Medical Center, Kingsport, TN Indiana Heart Institute, Indianapolis, IN LeBauer Cardiovascular Research Foundation/ Moses Cone Heart and Vascular Center, Greensboro, NC McLeod Regional Medical Center, Florence, SC Moore Regional Hospital, Pinehurst, NC Sisters of Charity Providence Hospitals, Columbia, SC

Definitions Myocardial Infarction post-PCI: CK > 3x ULN with positive MB Target Vessel Revascularization: PCI or CABG for any lesion in target vessel Stent thrombosis: ARC definite and probable ST 1. Angiographically documented ST 2. MI in distribution of target vessel 3. Sudden cardiac death

Statistical Methods Univariable analysis was conducted using t-tests for continuous variables and Chi-square or Fisher’s Exact test for categorical data depending upon the normality of the distribution. Significance levels were set at <0.05. Propensity scores for selecting DES vs BMS were calculated using logistical regression and these were entered into a Cox Proportional Hazards regression model to provide propensity adjusted outcomes.

SVG PCI N = 1380 All PCI Procedures N = 26,941 DES Only N = 820 BMS Only N = 348 Study Population Consented Procedures N = 24,384 (90.5%) Completed 9 mo F/U N = 785 (95.7%) Completed 9 mo F/U N = 343 (98.6%) Completed 2 year F/U N = 407 (94.9% of eligible) Completed 2 year F/U N = 252 (98.1% of eligible) Index (First) Procedures N = 20,905 May 2003 through June 2006

Baseline Clinical Variables BMS DES (n = 343) (n = 785) p value Age, yrs (mean) Male 79.6%77.6%0.48 Diabetes37.3%38.1%0.84 Prior MI42.3%44.2%0.79 Hypertension79.9%85.2%0.03 Smoker (ever)57.7%60.4%0.43 Prior PCI42.9%46.6%0.27 Clinical Presentation STEMI 9.3% 4.1% <0.001 Acute CHF 9.6% 6.6%0.09 Cardiogenic Shock 0.3% 0.8%0.68

Angiographic and Procedural Variables BMSDESp value (n=343)(n=785) Procedure Indication Elective28.1%32.9%0.005 Urgent60.5%61.2% Emergent11.4% 6.0% Ejection Fraction (mean)46.1%46.2%0.11 Multi-vessel CAD74.8%78.9%0.36 Multi-vessel PCI 8.2%11.6%0.09 Multi-lesion PCI24.2%28.0%0.18 Multiple Stents/Procedure37.0%41.8%0.15 GP IIb/IIIa Use48.1%46.5%0.65

Angiographic Variables Lesion Level BMS DESp value (n=451) (n=1047) RVD mm (mean) <0.001 Reference Vessel <3.5mm 25.8% 41.7%<0.001 Reference Vessel >4.5mm 23.4% 4.0%<0.001 Lesion length mm (mean) Lesion length > 28 mm 9.6% 13.1% Ostial Lesion 10.0% 10.3% 0.93 TIMI 2-3 Flow pre-PCI 88.2% 91.8% 0.58

Procedural Variables Lesion Level BMS DES p value (n=451)(n=1047) Stent Length/Lesion22.0 mm25.0 mm <0.001 Distal Protection Device 33.7% 37.3% 0.20 No Reflow 6.9% 3.3%0.002 TIMI 3 Flow post-PCI 93.6% 98.2% <0.001 Angiographic Success 97.6% 99.3%0.008

Death or Myocardial Infarction Number at risk BMS DES Months 22.3% 17.0% BMS DES

Target Vessel Revascularization BMS DES TVR % Number at risk BMS DES Months Log Rank p value = 0.86 Adjusted HR = 0.70 ( ) p = DES BMS 18.3% 16.9% 10.0% 7.2%

Stent Thrombosis Months Number at risk BMS DES % 2.5% 9 Months 2.1% p = % 9 Mos – 2 Yrs DES 2.0% BMS 0.4% p = 0.11

TVR with DES vs BMS Subgroup Analyses p = p = Month TVR % SVG Reference Vessel Diameter < 3.5 mm DES did not provide statistically significant benefit in any other subgroup including diabetics and patients with long lesions. 8.0% 17.2% 6.0% 6.6%

Conclusions This registry is the largest reported experience with DES in SVG intervention with 785 patients treated with DES and followed for at least 9 months. BMS were more often selected for patients at high clinical risk – more emergent procedures and more STEMI patients. DES were more often selected for lesions at high risk for TVR – smaller diameter grafts and longer lesions.

Conclusions (cont) DES used with SVG intervention were associated with a lower incidence of death or MI but after propensity adjustments there were no significant differences between DES and BMS. DES and BMS has similar frequency of stent thrombosis. DES had a lower incidence of TVR at 9 months, but by 2 years the frequency of TVR was similar between DES and BMS. DES were beneficial in reducing TVR at 9 months in SVG with reference vessel diameter < 3.5 mm but not with reference vessel diameter > 3.5 mm.

Limitations Our study has the limitations of an observational database. There may be hidden biases to select BMS for sicker pts with more co-morbidities and pts who are less compliant with anti-platelet therapy and other therapies. Thus our data may overestimate the safety of DES with regard to death, MI and stent thrombosis. Conversely, there may be hidden biases to select DES for pts more likely to develop TVR. Consequently, our data could underestimate the benefit of DES in reducing TVR.

Limitations (cont) Our registry does not have a core lab for angiographic analysis. Consequently, we are not able to distinguish between TLR and TVR at sites other than the target lesion. This hinders our ability to distinguish the mechanisms for the late “catch-up” TVR with DES. We do not have data regarding compliance with dual anti-platelet therapy which is a major determinant of stent thrombosis and adverse events.

Clinical Implications DES appear to be safe with SVG intervention with similar or lower rates of death or MI and stent thrombosis. DES appear to provide short term benefit in reducing TVR, especially with RVD < 3.5 mm, but there is a “catch up” phenomenom such that at 2 years most of the benefit is lost. The mechanisms are not clear and could be related to either progression of disease at non-target sites or greater late loss after 9 months with DES vs BMS in SVG.

Recommendations Based on our data, DES appear safe and appear to offer short term advantages over BMS in reducing TVR in SVG < 3.5 mm in diameter.