J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S
`
`© 2 0 1 1 B Y T H E A M E R I C A N C O L L E G E O F C A R D I O L O G Y F O U N D A T I O N
`
`P U B L I S H E D B Y E L S E V I E R I N C .
`
`V O L . 4 , N O . 8 , 2 0 1 1
`
`I S S N 1 9 3 6 - 8 7 9 8 / $ 3 6 . 0 0
`
`D O I : 1 0 . 1 0 1 6 / j . j c i n . 2 0 1 1 . 0 5 . 0 1 4
`
`STATE-OF-THE-ART PAPER
`
`Saphenous Vein Graft Intervention
`
`Michael S. Lee, MD,* Seung-Jung Park, MD,‡ David E. Kandzari, MD,§
`Ajay J. Kirtane, MD, SM,储 William F. Fearon, MD,† Emmanouil S. Brilakis, MD, PHD,¶
`Paul Vermeersch, MD,# Young-Hak Kim, MD,‡ Ron Waksman, MD,**
`Julinda Mehilli, MD,†† Laura Mauri, MD,‡‡ Gregg W. Stone, MD储
`Los Angeles and Palo Alto, California; Seoul, South Korea; Atlanta, Georgia; New York, New York;
`Dallas, Texas; Antwerp, Belgium; Washington, DC; Munich, Germany; and Boston, Massachusetts
`
`Saphenous vein grafts are commonly used conduits for surgical revascularization of coronary arteries but
`are associated with poor long-term patency rates. Percutaneous revascularization of saphenous vein grafts
`is associated with worse clinical outcomes including higher rates of in-stent restenosis, target vessel revas-
`cularization, myocardial infarction, and death compared with percutaneous coronary intervention of native
`coronary arteries. Use of embolic protection devices is a Class I indication according to the American College of
`Cardiology/American Heart Association guidelines to decrease the risk of distal embolization, no-reflow, and
`periprocedural myocardial infarction. Nonetheless, these devices are underused in clinical practice. Various phar-
`macological agents are available that may also reduce the risk of or mitigate the consequences of no-reflow.
`Covered stents do not decrease the rates of periprocedural myocardial infarction and restenosis. Most available
`evidence supports treatment with drug-eluting stents in this high-risk lesion subset to reduce angiographic and
`clinical restenosis, although large, randomized trials comparing drug-eluting stents and bare-metal stents are
`needed.
`(J Am Coll Cardiol Intv 2011;4:831–43) © 2011 by the American College of Cardiology Foundation
`
`The long-term success of surgical coronary re-
`vascularization is limited by accelerated athero-
`sclerosis and intimal fibrosis of the saphenous
`vein graft (SVG) after its use as a vascular conduit.
`At 1 year, the incidence of 1 or more total SVG
`occlusions has been reported to be as high as 41%
`after on-pump bypass surgery (Table 1) (1–8). Be-
`
`cause of increased morbidity and mortality with
`repeat coronary artery bypass graft surgery, SVG
`intervention is considered by many to be the
`preferred revascularization modality in patients
`with diseased SVGs and accounts for approxi-
`mately 5% to 10% of all percutaneous coronary
`interventions (PCI) (9–14).
`
`From the *University of California–Los Angeles Medical Center, Los
`Angeles, California; †Stanford University Medical Center, Palo Alto,
`California; ‡University of Ulsan College of Medicine, Asan Medical
`Center, Seoul, South Korea; §Piedmont Heart Institute, Atlanta, Geor-
`gia; 储Columbia University Medical Center and the Cardiovascular
`Research Foundation, New York, New York; ¶Veterans Affairs North
`Texas Healthcare System, and University of Texas Southwestern Med-
`ical Center, Dallas, Texas; #Antwerp Cardiovascular Institute Middel-
`heim, AZ Middelheim, Antwerp, Belgium; **Washington Hospital
`Center, Washington, DC; ††Deutsches Herzzentrum, Technische Uni-
`versität, Munich, Germany; and the ‡‡Brigham and Woman’s Hospital,
`Boston, Massachusetts. Dr. Lee has received honoraria from Boston
`Scientific, St. Jude Medical, Daiichi-Sankyo, Bristol-Myers Squibb, and
`Merck. Dr. Park has received consulting fees from Cordis; lecture fees
`from Cordis, Medtronic, and Boston Scientific; and research grants from
`Cordis and Medtronic. Dr. Kandzari has received research/grant support
`from Abbott Vascular, Cordis, and Medtronic Cardiovascular, and
`consulting honoraria from Abbott Vascular and Medtronic. Dr. Kirtane
`has served as a consultant and speaker for Medtronic Cardiovascular,
`
`Abbott Vascular, and Boston Scientific. Dr. Fearon has received a
`research grant from St. Jude Medical. Dr. Brilakis received speaker
`honoraria from St. Jude Medical and Terumo; received research
`support from Abbott Vascular and InfraReDx; and his spouse is an
`employee of Medtronic. Dr. Kim has received lecture fees from
`Cordis. Dr. Waksman received consulting and speaker fees from
`Biotronik, Medtronic, Boston Scientific, and received research grants
`from Biotronik, Boston Scientific, The Medicines Company, Glaxo-
`SmithKline, Schering-Plough, and Sanofi-Aventis. Dr. Mehilli re-
`ceived lecture fees from Abbott and Terumo. Dr. Mauri received
`research grants from Abbott, Cordis, Boston Scientific, Medtronic,
`Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly, Daiichi Sankyo, and
`consulting fees from Abbott, Cordis, and Medtronic. Dr. Stone is a
`consultant to Abbott Vascular, Boston Scientific, and Medtronic. Dr.
`Vermeersch has reported that he has no relationships relevant to the
`contents of this paper to disclose.
`
`Manuscript received March 11, 2011; revised manuscript received April
`21, 2011, accepted May 14, 2011.
`
`
`Page 1
`
`Teleflex Ex. 2213
`Medtronic v. Teleflex
`
`

`

`832
`
`Lee et al.
`SVG Intervention
`
`J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S , V O L . 4 , N O . 8 , 2 0 1 1
`
`A U G U S T 2 0 1 1 : 8 3 1 – 4 3
`
`In this review, we describe the risk factors for complications
`after SVG intervention and discuss the optimal procedural
`treatment strategies regarding periprocedural anticoagulation,
`choice of stent, and measures to mitigate the risks of distal
`embolization.
`
`Pathobiology of SVG
`
`Abbreviations
`and Acronyms
`
`BMS ⴝ bare-metal stent(s)
`
`CI ⴝ confidence interval
`
`CK-MB ⴝ creatine kinase-
`myocardial band
`
`DES ⴝ drug-eluting stent(s)
`
`FDA ⴝ U.S. Food and Drug
`Administration
`
`SVG intervention remains technically challenging and is asso-
`ciated with higher rates of periprocedural myocardial infarc-
`tion, in-hospital mortality, restenosis, and occlusion compared
`with PCI of native coronary arteries largely because of the
`friable, degenerated atheromatous and thrombotic debris that
`develop when SVGs deteriorate (15). Progression of disease
`outside the stented segment can also lead to high rates of target
`vessel revascularization. Therefore,
`treatment of native coronary artery
`lesions is preferred to treatment of
`degenerated SVG if feasible.
`A recognized consequence of
`SVG intervention is distal emboli-
`zation of atheroembolic debris with
`decreased epicardial and microvas-
`cular perfusion due to capillary
`plugging and vasospasm from the
`release of neurohumoral factors
`such as serotonin. Distal emboliza-
`tion may result in the slow or no-
`reflow phenomenon in approxi-
`mately 10% to 15% of cases and is
`associated with periprocedural an-
`gina and ischemic ST-segment
`changes (16). In such instances,
`subsequent myocardial
`infarction
`occurs in 31% of patients and in-
`hospital mortality increases 10-fold
`(17). However, distal embolization
`remains difficult to predict (18).
`
`FFR ⴝ fractional flow
`reserve
`
`HR ⴝ hazard ratio
`
`MACE ⴝ major adverse
`cardiac event(s)
`
`OR ⴝ odds ratio
`
`PCI ⴝ percutaneous
`coronary intervention
`
`PTFE ⴝ
`polytetrafluorethylene
`
`SVG ⴝ saphenous vein graft
`
`TIMI ⴝ Thrombolysis In
`Myocardial Infarction
`
`Predictors of
`Adverse Clinical Events
`
`Periprocedural creatine kinase-myocardial band (CK-MB)
`elevation after successful SVG intervention was common
`(ranging from 15% to 47%) (19,20). The use of embolic
`protection devices has been systematically associated with
`periprocedural myocardial infarction rates ⬍10% (21,22).
`Differences in myocardial infarction rates between studies
`may also be explained by differences in myocardial infarction
`definitions,
`the sensitivity and frequency of biomarker
`measurement, and the complexity of SVG disease studied.
`Hong et al. (19) reported that 15% of patients experienced
`major CK-MB release exceeding 5⫻ the upper limit of
`normal following SVG PCI. Although the association of
`
`Table 1. Saphenous Vein Graft Occlusion Rates From Selected Studies
`
`Study/First
`Author (Ref. #)
`
`1 Year
`
`5 Years
`
`10 Years
`
`PRAGUE-4 (1)
`
`41 (per patient on-pump)
`
`51 (per patient off-pump)
`
`PREVENT IV (2)
`
`41.7 (per patient)
`
`26.6 (per SVG)
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`Fitzgibbon et al. (3) 19 (per SVG)
`
`25 (per SVG)
`
`40 (per SVG)
`
`RIGOR (4)
`
`31 (per patient)
`
`19 (per SVG)
`
`Halabi et al. (5)
`
`39.3 (per patient)
`
`Khot et al. (6)
`
`30.1 (SVG)
`
`ROOBY (7)
`
`28.7 (per patient on-pump)
`
`36.5 (per patient off-pump)
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`Goldman et al. (8)
`
`20 (per patient)
`
`31 (per patient) 39 (per patient)
`
`Values are %.
`NA ⫽ not available; PREVENT IV ⫽ Project of Ex Vivo Vein Graft Engineering via Transfection;
`RIGOR ⫽ Reduction in Graft Occlusion Rates; ROOBY ⫽ Veterans Affairs Randomized On/Off
`Bypass study.
`
`periprocedural myonecrosis and late clinical outcomes is
`controversial among patients undergoing native vessel PCI,
`even minor elevations of CK-MB (1⫻ to 5⫻ normal) after
`SVG intervention have been associated with increased
`mortality at 1 year (6.5% vs. 4.8%, p ⬍ 0.05), with CK-MB
`release exceeding 5⫻ the upper limit of normal increasing
`1-year mortality by 144%. Multivariate analysis revealed
`that major CK-MB release after SVG intervention was a
`powerful independent predictor of late mortality (odds ratio
`[OR]: 3.3, 95% confidence interval [CI]: 1.7 to 6.2).
`Lesion length, greater angiographic degeneration of
`SVGs, and larger estimated plaque volume have been
`identified as predictors of 30-day major adverse cardiac
`events (MACE) after SVG intervention (23–25). This may
`be explained by the fact that the greater the amount of
`plaque, the greater the likelihood of distal embolization
`after intervention, leading to myocardial infarction.
`Patient sex also appears to be a significant predictor of
`outcomes after SVG intervention. Women had higher 30-day
`cumulative mortality rates (4.4% vs. 1.9%, p ⫽ 0.02) compared
`with men (26). Furthermore, women had a higher incidence of
`vascular complications (12% vs. 7.3%, p ⫽ 0.006) and post-
`procedural acute renal failure (8.1% vs. 4%, p ⫽ 0.02).
`In a 172-patient study of SVG intervention with drug-
`eluting stents (DES), chronic renal
`insufficiency (serum
`creatinine ⱖ1.5 mg/dl) was the only significant predictor of
`1-year MACE (hazard ratio [HR]: 2.2, 95% CI: 1.1 to 4.3,
`p ⫽ 0.03) (27). A trend was also present toward higher rates
`of target vessel revascularization in the renal insufficiency
`group (21.8% vs. 10.3%, HR: 2.42, 95% CI: 0.94 to 6.24,
`p ⫽ 0.059). Similar results were observed with bare-metal
`stents (BMS). Overall mortality rates were significantly
`higher in patients with renal insufficiency (p ⬍ 0.001) (28).
`
`
`Page 2
`
`Teleflex Ex. 2213
`Medtronic v. Teleflex
`
`

`

`J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S , V O L . 4 , N O . 8 , 2 0 1 1
`
`A U G U S T 2 0 1 1 : 8 3 1 – 4 3
`
`Lee et al.
`SVG Intervention
`
`833
`
`Decision to Perform
`SVG Percutaneous Intervention
`
`The decision regarding whether or not to intervene in a
`diseased SVG should be guided by the patient’s symptoms,
`angiographic evidence of a significant stenosis, and nonin-
`vasive evidence of myocardial ischemia in the region sub-
`tended by the SVG. Even though the role of intravascular
`ultrasound or fractional flow reserve (FFR) measurement in
`assessing the significance of SVG disease has not been well
`studied, FFR can be performed in an SVG in a similar
`fashion as in a native coronary vessel. The pressure sensor
`should be positioned in the distal two-thirds of the native
`vessel so the entire conduit can be interrogated. Intravenous
`adenosine should be administered to induce hyperemia and
`a slow pullback of the pressure wire can be performed to
`distinguish focal from diffuse disease. Prospective validation
`of an FFR cutoff value of 0.75 to 0.80 to detect hemody-
`namically significant SVG stenosis has not been performed.
`Nonetheless, this cutoff is generally used in clinical practice.
`Of note, however, SVG disease progresses more rapidly
`than native coronary artery disease, and the safety of
`deferring intervention on a diseased SVG with a nonisch-
`emic FFR has not been studied.
`Adverse clinical events occurring ⬎12 months after initial
`SVG intervention most frequently resulted from disease
`progression at untreated intermediate lesions (29). Because
`SVG disease can progress rapidly, some have advocated
`prophylactically stenting intermediate SVG lesions as op-
`posed to continuing with medical therapy alone. In the
`small (57-patient) randomized VELETI (Treatment of
`Moderate Vein Graft Lesions With Paclitaxel Drug-
`Eluting Stents) trial, the 1- and 3-year MACE rates were
`significantly lower in patients in whom moderate (30% to
`60%) SVG stenoses were treated with paclitaxel-eluting
`stents compared with patients who received medical treat-
`ment (3% vs. 19%, p ⫽ 0.09 at 1 year, and 3% vs. 26%, p ⫽
`0.02 at 3 years), thus supporting a strategy of plaque sealing
`with DES in moderate nonangiographically significant le-
`sions in degenerated SVGs at increased risk for disease
`progression and adverse clinical events (30,31). However,
`this trial was an imaging study that was not powered for
`clinical endpoints. The 450-patient VELETI II (Sealing
`Moderate Coronary Saphenous Vein Graft Lesions With
`Paclitaxel-Eluting Stents) trial (NCT01223443) is currently
`randomizing patients with intermediate SVG lesions to
`either SVG intervention with paclitaxel-eluting stents ver-
`sus medical therapy alone and has a primary clinical rather
`than angiographic endpoint.
`
`Treatment of Occluded SVGs
`
`In a study of 34 patients with chronic total SVG occlusion
`for which percutaneous revascularization was attempted,
`
`successful recanalization with stent implantation was low
`(68%) (32). At a median follow-up of 18 months, the rates
`of in-stent restenosis and target vessel revascularization were
`unacceptably high (68% and 61%, respectively) in patients
`who underwent successful stenting despite a high use of
`DES (95%). Given the poor short- and long-term outcomes
`of percutaneous revascularization in chronic total occlusion
`of SVGs, percutaneous revascularization should rarely be
`considered except for acute occlusion in the setting of
`myocardial infarction. Instead, attempts to recanalize the
`native coronary artery are preferred if feasible.
`
`Antithrombin and Antiplatelet Therapy
`
`The preferred parenteral antithrombotic therapy during
`SVG intervention has not been studied in a dedicated,
`prospective clinical trial. Several studies demonstrated that
`the role of glycoprotein IIb/IIIa antagonists in SVG inter-
`vention is limited given their failure to demonstrate a
`reduction in periprocedural myocardial infarction (33–35).
`However, 1 post hoc analysis demonstrated a trend toward
`improved procedural success when glycoprotein IIb/IIIa
`antagonists were used in conjunction with filter-based
`embolic protection (p ⫽ 0.058) but the MACE was not
`different at 30 days (36). In a single center, retrospective
`observational study, bivalirudin was associated with a sig-
`nificant reduction in major CK-MB elevation and a trend
`toward lower in-hospital non–Q-wave myocardial infarc-
`tion, repeat revascularization, and vascular complications
`compared with unfractionated heparin (37). In the subset of
`329 patients who underwent SVG intervention in ACUITY
`(Acute Catheterization and Urgent Intervention Triage
`Strategy Trial) (38), the rates of ischemic bleeding and net
`clinical endpoints were similar with bivalirudin mono-
`therapy, bivalirudin plus a glycoprotein IIb/IIIa antagonist,
`and heparin plus a glycoprotein IIb/IIIa antagonist. Minor
`bleeding complications were lower with bivalirudin alone
`compared with heparin plus a glycoprotein IIb/IIIa antag-
`onist (26% vs. 38%, p ⫽ 0.05). Thus, bivalirudin may offer
`a safety advantage over other antithrombotic regimens, with
`equal or greater suppression of adverse ischemic events,
`although this conclusion is not definitive in the absence of
`an adequately powered randomized trial.
`
`Stent Type Selection
`
`Bare-metal stents. The SAVED (Saphenous Vein de Novo)
`trial reported that compared with balloon angioplasty, BMS
`were associated with higher procedural success (92% vs.
`69%, p ⬍ 0.001), a trend toward a reduction in angiographic
`restenosis (36% vs. 47%, p ⫽ 0.11), and lower MACE
`through 240 days (26% vs. 38%, p ⫽ 0.04) (39). Since the
`SAVED report, the overwhelming majority of SVG inter-
`vention has been performed with stents, and subsequent
`
`
`Page 3
`
`Teleflex Ex. 2213
`Medtronic v. Teleflex
`
`

`

`834
`
`Lee et al.
`SVG Intervention
`
`J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S , V O L . 4 , N O . 8 , 2 0 1 1
`
`A U G U S T 2 0 1 1 : 8 3 1 – 4 3
`
`randomized trials have compared BMS with covered stents
`or DES (Table 2).
`Covered stents. Stents covered with a mesh, most com-
`monly polytetrafluorethylene (PTFE), have a theoretical
`advantage over conventional stents because they may “trap”
`friable atheroemboli and prevent distal embolization and
`serve as a smooth-muscle cell barrier and therefore decrease
`restenosis. However, 3 prospective randomized trials failed
`to demonstrate benefit with covered stents. SYMBIOT III
`(A Prospective, Randomized Trial of a Self-Expanding
`PTFE Stent Graft During SVG Intervention–Late Results)
`(40) compared the self-expandable PTFE-covered nitinol
`Symbiot stent (Boston Scientific Corp., Natick, Massachu-
`setts) with BMS. At 8 months, the incidence of MACE
`between the Symbiot group and BMS was similar (30.6% vs.,
`26.6%, p ⫽ 0.43). A trend toward increased target lesion
`revascularization with the Symbiot stent was also observed
`(23.5% vs. 15.6%, p ⫽ 0.055). The RECOVERS (Randomized
`Evaluation of Polytetrafluoroethylene-Covered Stent in Sa-
`phenous Vein Grafts) trial (41) randomized 301 patients to
`treatment with either the PTFE-covered JoStent balloon-
`expandable stent (Jomed International AB, Helsingborg, Swe-
`den) or BMS. The PTFE group had a higher incidence of
`30-day MACE (10.9% vs. 4.1%, p ⫽ 0.047), mainly attributed
`to increased incidence of myocardial infarction (10.3% vs.
`3.4%, p ⫽ 0.037). At 6 months, the restenosis rate was similar
`between the 2 groups (24.2% vs. 24.8%, p ⫽ 0.237), and the
`MACE rate was not different (23.1% vs. 15.9%, p ⫽ 0.153).
`
`The BARRICADE (Barrier Approach to Restenosis: Restrict
`Intima to Curtail Adverse Events) trial (42) also randomized
`243 patients to treatment with either the PTFE-covered
`JoStent balloon-expandable stent (Jomed) or BMS. At 5-year
`follow-up, target vessel failure was higher in the JoStent group
`than in the BMS group (68.3% vs. 51.8%, p ⫽ 0.007),
`emphasizing the dismal long-term prognosis of SVG treat-
`ment with either BMS or covered stents.
`Two other covered stents have shown promise in the
`treatment of degenerated SVGs although long-term head-
`to-head comparison data with BMS are lacking. In the
`SESAME first
`in human trial (43), 20 patients who
`underwent SVG intervention with a novel nanosynthesized,
`membrane-covered self-expanding superelastic all-metal
`endoprosthesis stent (SESAME stent, Advanced Biopros-
`thetic Surfaces, Ltd., San Antonio, Texas) had a 0% rate of
`MACE at 30 days. At 9 months, the MACE rate was 14%
`(3 patients underwent repeat intervention: 1 underwent
`target lesion revascularization for restenosis at the overlap of
`2 stents and 2 underwent target vessel revascularization for
`lesions outside the stented segment). Preliminary results
`with the MGuard stent (InspireMD, Tel Aviv, Israel), a
`BMS with a polymeric net attached to its surface, demon-
`strated favorable early performance in a study that included
`16 patients who underwent SVG intervention with no
`angiographic/procedural complications, and no adverse
`events up to 30 days (44).
`
`Table 2. Clinical Outcomes of Randomized Stent Trials in Saphenous Vein Grafts
`
`SYMBIOT III
`
`BARRICADE
`
`RECOVERS
`
`SOS
`
`RRISC
`
`ISAR-CABG
`
`PTFE BMS
`
`p Value
`
`PTFE
`
`BMS
`
`p Value
`
`PTFE
`
`BMS
`
`p Value
`
`PES
`
`BMS
`
`p Value
`
`SES
`
`BMS
`
`p Value
`
`DES
`
`BMS
`
`p Value
`
`MACE
`
`1 yr
`
`30.6
`
`26.6
`
`0.43
`
`NA
`
`39.2*
`
`28.0*
`
`60.2
`
`37.0
`
`0.07
`
`0.001
`
`23.1†
`
`15.9†
`
`NA
`
`NA
`
`0.15
`
`NA
`
`37
`
`54
`
`49
`
`77
`
`0.20
`
`0.49
`
`15.8†
`
`29.7†
`
`58
`
`41
`
`0.15
`
`0.13
`
`15.4
`
`NA
`
`22.1
`
`NA
`
`0.03
`
`NA
`
`3 yrs
`
`5 yrs
`
`Death
`
`1 yr
`
`3 yrs
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`68.3
`
`51.8
`
`0.007
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`2.6‡
`
`NA
`
`4.7‡
`
`NA
`
`0.29
`
`NA
`
`7.0
`
`18.8
`
`5.0
`
`11.2
`
`0.51
`
`0.13
`
`2.6†
`
`NA
`
`2.8†
`
`NA
`
`0.92
`
`NA
`
`12
`
`24
`
`5
`
`13
`
`0.27
`
`0.19
`
`2.6†
`
`29
`
`0†
`
`0
`
`NA
`
`0.99
`⬍0.001
`
`NA
`
`5.2
`
`NA
`
`NA
`
`4.7
`
`NA
`
`NA
`
`0.82
`
`NA
`
`NA
`
`5 yrs
`
`NA
`
`NA
`
`NA
`
`29.8
`
`22.3
`
`0.20
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`MI
`
`1 yr
`
`3 yrs
`
`9.2
`
`NA
`
`10.9
`
`NA
`
`0.61
`
`NA
`
`14.2
`
`21.0
`
`11.3
`
`14.1
`
`0.53
`
`0.21
`
`0.16
`
`14.1†
`
`5.5†
`
`NA
`
`NA
`
`NA
`
`NA
`
`0.02
`
`NA
`
`NA
`
`15
`
`17
`
`NA
`
`31
`
`46
`
`NA
`
`0.10
`
`0.01
`
`NA
`
`2.6†
`
`18
`
`NA
`
`0†
`
`5
`
`NA
`
`0.99
`
`0.15
`
`NA
`
`4.2
`
`NA
`
`NA
`
`6.0
`
`NA
`
`NA
`
`0.27
`
`NA
`
`NA
`
`5 yrs
`
`NA
`
`NA
`
`NA
`
`26.2
`
`17.4
`
`TLR
`
`1 yr
`
`3 yrs
`
`5 yrs
`
`23.5
`
`15.6
`
`NA
`
`NA
`
`NA
`
`NA
`
`0.06
`
`NA
`
`NA
`
`28.2
`
`37.4
`
`43.9
`
`21.1
`
`21.8
`
`29.6
`
`0.46
`
`0.02
`
`0.04
`
`9.6†
`
`8.3†
`
`NA
`
`NA
`
`NA
`
`NA
`
`0.84
`
`NA
`
`NA
`
`5
`
`10
`
`NA
`
`28
`
`41
`
`NA
`
`0.003
`
`0.004
`
`NA
`
`5.3†
`
`21.6†
`
`24
`
`NA
`
`30
`
`NA
`
`0.05
`
`0.55
`
`NA
`
`7.2
`
`NA
`
`NA
`
`13.1
`
`NA
`
`NA
`
`0.02
`
`NA
`
`NA
`
`*Target vessel failure (composite of all-cause death, MI, or clinically driven target vessel revascularization). †6 months. ‡Cardiac death.
`BARRICADE ⫽ Barrier Approach to Restenosis: Restrict Intima to Curtail Adverse Events study; BMS ⫽ bare-metal stent(s); DES ⫽ drug-eluting stent(s); ISAR-CABG ⫽ Prospective, Randomized Trial of
`Drug-Eluting Stents Versus Bare Metal Stents for the Reduction of Restenosis in Bypass Grafts; MACE ⫽ major adverse cardiac event(s); MI ⫽ myocardial infarction; NA ⫽ not available; PTFE ⫽
`polytetrafluorethylene; RECOVERS ⫽ Randomized Evaluation of Polytetrafluoroethylene-Covered Stent in Saphenous Vein Grafts; RRISC ⫽ Reduction of Restenosis in Saphenous Vein Grafts With
`Cypher Sirolimus-Eluting Stent; SOS ⫽ Stenting of Saphenous Vein Grafts; SYMBIOT III ⫽ A Prospective, Randomized Trial of a Self-Expanding PTFE Stent Graft During SVG Intervention–Late Results;
`TLR ⫽ target lesion revascularization.
`
`
`Page 4
`
`Teleflex Ex. 2213
`Medtronic v. Teleflex
`
`

`

`J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S , V O L . 4 , N O . 8 , 2 0 1 1
`
`A U G U S T 2 0 1 1 : 8 3 1 – 4 3
`
`Lee et al.
`SVG Intervention
`
`835
`
`Drug-eluting stents. The RRISC (Reduction of Restenosis
`in Saphenous Vein Grafts With Cypher Sirolimus-Eluting
`Stent) trial (21), which included 75 patients, reported that
`sirolimus-eluting stents (Cordis, Warren, New Jersey) re-
`duced late loss, the binary restenosis rate, and target lesion
`and vessel
`revascularization compared with BMS at
`6-month follow-up. However, the DELAYED RRISC
`(Death and Events at Long-Term Follow-Up Analysis:
`Extended Duration of the Reduction of Restenosis in
`Saphenous Vein Grafts With Cypher Stent) study (45),
`which was a post hoc analysis of RRISC trial at 3 years,
`reported similar rates of target vessel revascularization.
`Although statistically underpowered for clinical outcomes,
`significantly higher all-cause mortality at 3 years was re-
`ported with sirolimus-eluting stents compared with BMS.
`The SOS (Stenting of Saphenous Vein Grafts) trial (22),
`which included 80 patients randomized to either paclitaxel-
`eluting stents (Taxus, Boston Scientific Corp., Maple
`Grove, Minnesota) or BMS, demonstrated a significant
`reduction in MACE driven by lower target lesion revascu-
`larization rates with paclitaxel-eluting stents without in-
`creased death or myocardial infarction through nearly 3-year
`follow-up (46). The primary endpoint of these 2 small trials
`was angiographic restenosis, and the results showed similar
`angiographic restenosis rates at 6- (RRISC) and 12-month
`(SOS)
`follow-up but higher mortality at
`long-term
`follow-up in the RRISC trial. ISAR-CABG (Prospective,
`Randomized Trial of Drug-Eluting Stents Versus Bare
`Metal Stents for the Reduction of Restenosis in Bypass
`Grafts), which randomized 610 patients with diseased SVGs
`to DES and BMS, the primary endpoint of MACE at 1-year
`post index PCI was lower in the DES group than in the BMS
`group (15.4% vs. 22.1%, p ⫽ 0.03) and was mainly driven by
`a nearly 50% relative reduction in the risk of target lesion
`revascularization (7.2% vs. 13.1%, p ⫽ 0.02), with nonsignif-
`icant differences in mortality (47).
`A meta-analysis comparing DES with BMS in SVG
`intervention (which also included nonrandomized studies)
`has also reported lower mortality, MACE, target lesion
`revascularization, and target vessel revascularization without
`increased risk of myocardial infarction or stent thrombosis
`(48). Eight other meta-analyses comparing DES with BMS
`in SVG intervention have demonstrated consistent results of
`improved efficacy with DES and no significant safety hazard
`(48–55).
`Two ongoing trials are comparing DES with BMS in
`SVGs: 1) BASKETSAVAGE (Basel Stent Kosten Effek-
`tivitäts Trial–Saphenous Venous Graft Angioplasty Using
`Glycoprotein IIb/IIIa Receptor Inhibitors and Drug-
`Eluting Stents) (NCT00595647); and 2) the Veterans’
`Affairs Cooperative Study #571, DIVA (Drug Eluting
`Stents Versus Bare-Metal Stents in Saphenous Vein Graft
`Angioplasty) trials (NCT01121224).
`
`Choice of DES in SVG. In a multicenter analysis of 172
`real-world patients comparing first-generation DES, SVG
`intervention with sirolimus- and paclitaxel-eluting stents
`resulted in nonsignificant differences in survival (HR: 1.28,
`95% CI: 0.39 to 4.25, p ⫽ 0.69) and target vessel revascu-
`larization (HR: 2.54, 95% CI: 0.84 to 7.72, p ⫽ 0.09) (56).
`Outcomes comparing second-generation stents in SVG
`intervention are not yet available; the SOS-Xience V (Pro-
`spective Evaluation of the Xience V Everolimus-Eluting
`Stent in Saphenous Vein Graft Atherosclerosis: The Stent-
`ing of Saphenous Vein Grafts Xience V Angiographic
`Study) (NCT00911976) will provide initial results with the
`everolimus-eluting stent in 2011.
`
`SVG Intervention Technique
`
`Pre-dilation versus direct stenting. As opposed to pre-
`dilation with balloon angioplasty, direct stenting has the
`potential benefit of trapping debris and decreasing distal
`embolization that may occur from repeated balloon infla-
`tions. In a registry of unselected patients who underwent
`SVG intervention, direct stenting was associated with a
`nearly 50% reduction in CK-MB elevations greater than 4⫻
`normal (13.6% vs. 23%, p ⬍ 0.12), overall lower maximum
`CK-MB release (9.5 vs. 19.6, p ⬍ 0.001), and fewer
`non–Q-wave myocardial infarctions (10.7% vs. 18.4%, p ⬍
`0.02) (57). A prospective randomized trial is needed to
`determine whether pre-dilation versus direct stenting is
`effective in reducing distal embolization.
`Small stent diameter. In a study of 209 SVG lesions treated
`with DES, Hong et al. (58) examined the outcomes of 3
`groups according to the ratio of the stent diameter to the
`average intravascular ultrasound reference lumen diameter
`(group I: ⬍0.89, group II: 0.9 to 1.0, and group III: ⬎1.0).
`Plaque intrusion volume as defined as the amount of tissue
`extrusion through the stent struts after SVG intervention
`was smallest in group I (group I: 0.25 ⫾ 0.68 mm3, group II:
`0.40 ⫾ 0.68 mm3, and group III: 0.75 ⫾ 1.34 mm3; p⫽ 0.007).
`The incidence of CK-MB elevation ⬎3⫻ normal was 6% in
`group I, 9% in group II, and 19% in group III (p ⫽ 0.03)
`without an increase in clinical events at 1 year. The
`incidence of 1-year target lesion revascularization (group I:
`13%, group II: 9%, and group III: 15%; p ⫽ 0.5) and target
`vessel revascularization (group I: 13%, group II: 13%, and
`group III: 15%; p ⫽ 0.9) was similar. While the concept of
`undersized stent selection to reduce distal embolization is
`intriguing, such a method must be balanced by theoretically
`possibly higher rates of restenosis and stent thrombosis.
`Therefore, a prospective, randomized study is required to
`confirm the theoretical benefits of this technique.
`Embolic protection devices. Distal embolization is common
`in SVG interventions. Particulate debris has been retrieved
`from as many as 91% of distal embolic protection devices
`(59). Despite the class I American College of Cardiology/
`
`
`Page 5
`
`Teleflex Ex. 2213
`Medtronic v. Teleflex
`
`

`

`836
`
`Lee et al.
`SVG Intervention
`
`J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S , V O L . 4 , N O . 8 , 2 0 1 1
`
`A U G U S T 2 0 1 1 : 8 3 1 – 4 3
`
`Table 3. Comparison of Different Embolic Protection Devices
`
`Distal
`Balloon
`Occlusion
`
`Proximal
`Balloon
`Occlusion
`
`Distal Filter
`
`Complete occlusion
`
`Allows perfusion
`
`Ischemia
`
`Maintenance of antegrade blood flow
`during intervention
`
`Protects before crossing lesion
`
`No
`
`Yes
`
`No
`
`Yes
`
`No
`
`Yes
`
`No
`
`Yes
`
`No
`
`No
`
`Crossing profile
`
`Maneuverability
`
`Ease of use
`
`High (3.2-F)*
`
`Low (2.7)†
`
`Reduced
`
`Simple
`
`Good
`
`Good
`
`Complex
`
`Complex
`
`Yes
`
`No
`
`Yes
`
`No
`
`Yes
`
`NA
`
`loon deflation and restoration of antegrade blood flow.
`Several advantages are the low crossing profile and
`entrapment of debris of all sizes as well as neurohumoral
`mediators such as serotonin and thromboxane that may
`have an adverse effect on the distal microvasculature. Its
`disadvantages are: 1) the need to cross the lesion before
`adequate protection, possibly liberating friable material
`before balloon occlusion; 2) temporary cessation of blood
`flow leading to ischemia and possible hemodynamic
`instability, as well as limiting visualization making accu-
`rate stent placement difficult; 3) inability to obtain full
`evacuation, especially near the occlusion balloon; and 4)
`possible traumatic injury to the SVG during balloon
`occlusion. Distal
`lesions are not amenable to distal
`balloon occlusion devices because a relatively disease-free
`landing zone of approximately 3 cm distal to the lesion is
`required for placement of the occlusion balloon.
`The Food and Drug Administration (FDA)–approved
`PercuSurge GuardWire (Medtronic, Minneapolis, Min-
`nesota) consists of a 0.014-inch diameter wire with a
`central
`lumen affixed to an inflatable distal occlusion
`balloon (Fig. 2, Table 4). SAFER (Saphenous Vein Graft
`Angioplasty Free of Emboli, Randomized Trial) (20)
`demonstrated that it decreased the incidence of no-reflow
`(3.2% vs. 8.3%, p ⫽ 0.005) and 30-day MACE (9.6% vs.
`16.5%, p ⫽ 0.004).
`The TriActiv embolic protection system (Kensey Nash
`Corporation, Exton, Pennsylvania) differs from the Guard-
`Wire in that it has a flush catheter, which infuses heparin-
`ized saline, attached to the balloon guidewire. The mixture
`of saline, blood, and atheromatous debris is extracted
`through the guiding catheter. PRIDE (A Prospective, Ran-
`domized Controlled Trial of Distal Protection With the
`
`Capture of smaller particles
`
`Capture of neurohormonal substances
`
`No
`
`No
`
`Yes
`
`Yes
`
`Yes
`
`Yes
`
`*FilterWire EZ (Boston Scientific). †PercuSurge GuardWire (Medtronic).
`NA ⫽ not available.
`
`American Heart Association PCI guidelines’ recommenda-
`tion for the use of embolic protection devices in SVG
`intervention, overall adoption remains low (60). In the
`American College of Cardiology National Cardiovascular
`Data CathPCI Registry, embolic protection was only used
`in 23% of patients (10). Currently available embolic protec-
`tion devices include occlusion balloon plus aspiration sys-
`tems, distal filter-based devices, and proximal flow interrup-
`tion catheters (Table 3) (61).
`Distal balloon occlusion devices. Distal balloon occlusion
`of the SVG beyond the lesion creates a stagnant column
`of blood that may prevent plaque embolization into the
`myocardial bed (Fig. 1). Upon the conclusion of the
`intervention, the blood with contained debris can be
`removed by an aspiration catheter before occlusion bal-
`
`Figure 1. Distal Balloon Occlusion Device
`
`(A) The lesion is crossed with the GuardWire. (B) GuardWire balloon inflated and percutaneous coronary intervention performed under distal protection.
`(C) Thereafter, the balloon is inflated until angiography shows no forward flow. Saphenous vein graft (SVG) intervention can be performed with complete
`distal protection. Image provided courtesy of Medtronic. ©2011 Medtronic or its affiliates. All rights reserved.
`
`
`Page 6
`
`Teleflex Ex. 2213
`Medtronic v. Teleflex
`
`

`

`J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S , V O L . 4 , N O . 8 , 2 0 1 1
`
`A U G U S T 2 0 1 1 : 8 3 1 – 4 3
`
`Lee et al.
`SVG Intervention
`
`837
`
`Figure 2. PercuSurge GuardWire Distal Protection System
`
`(A) A Microseal adapter controls a miniature valve within the hypotube and keeps the occlusion balloon inflated while standard interventional devices such as
`balloons and stents are passed over the wire to perform percutaneous coronary intervention. A 0.014-inch nitinol-based hypotube guidewire in