Mini-Focus: Stent Strut Coverage |
Heterogeneous Arterial Healing in Patients Following Paclitaxel-Eluting Stent ImplantationComparison With Sirolimus-Eluting Stents
Masaki Awata, MD*,
Shinsuke Nanto, MD, PhD ,*,
Masaaki Uematsu, MD, PhD*,
Takakazu Morozumi, MD, PhD*,
Tetsuya Watanabe, MD, PhD*,
Toshinari Onishi, MD*,
Osamu Iida, MD*,
Fusako Sera, MD*,
Hitoshi Minamiguchi, MD*,
Jun-ichi Kotani, MD, PhD,
Seiki Nagata, MD, PhD*
* Cardiovascular Division, Kansai Rosai Hospital, Amagasaki, Japan
Advanced Cardiovascular Therapeutics, Osaka University Graduate School of Medicine, Suita, Japan
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Abstract
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Objectives: We angioscopically compared paclitaxel-eluting stents (PES) and sirolimus-eluting stents (SES) to explore differences in arterial healing.
Background: Drug-eluting stents may demonstrate different arterial healing processes.
Methods: Angioscopy was performed 9 ± 2 months after 30 PES and 36 SES were implanted initially in the native coronary artery. Heterogeneity of the neointimal coverage (NIC) as well as the dominant grade was examined. Neointimal coverage was defined as follows: grade 0 = fully visible struts; grade 1 = struts bulged into the lumen, but covered; grade 2 = embedded, but translucent struts; grade 3 = invisible struts. Heterogeneity was judged when the NIC grade variation  1. Thrombi and yellow plaques (YP) were also explored.
Results: In-stent late loss (0.44 ± 0.44 mm vs. 0.13 ± 0.33 mm; p < 0.0001) and dominant NIC grade (1.8 ± 1.1 vs. 1.3 ± 0.7; p = 0.02) were greater in PES than in SES. Of PES, 48% showed the heterogeneity of 1 grade; 26% showed that of 2 grades. Of SES, 53% showed homogeneous coverage; the remaining SES showed the heterogeneity of 1 grade; and 72% showed dominant grade 1. Thrombi were more common in PES than in SES (43% vs. 19%; p = 0.04). Both stents commonly revealed YP (83% vs. 78%; p = 0.76).
Conclusions: NIC was more heterogeneous in PES, associated with a higher incidence of thrombi. Homogeneous NIC may be an important factor for competent arterial healing.
Key Words: angioscope • imaging • neointima • stent
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Abbreviations and Acronyms
| | BMS = bare-metal stent(s) | | DES = drug-eluting stent(s) | | LL = late loss | | LST = late stent thrombosis | | NIC = neointimal coverage | | PES = paclitaxel-eluting stent(s) | | SES = sirolimus-eluting stent(s) | | YP = yellow plaques |
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Drug-eluting stents (DES) have significantly reduced restenosis through an inhibitory effect on neointimal hyperplasia (1,2). Currently, concerns have been raised about late stent thrombosis (LST) and very LST after DES implantation as a negative aspect of the strong inhibition of neointimal proliferation (3–6). Pathological studies showed that incomplete neointimal coverage (NIC) following stenting contributes to LST (7,8). Using angioscopy, we have previously reported (9) that the NIC was not complete even 2 years after sirolimus-eluting stent (SES) implantation, associated with yellow plaques (YP) and subclinical thrombi, whereas bare-metal stents (BMS) showed complete NIC. The paclitaxel-eluting stent (PES) is also a first-generation DES that has been widely used in the real world. Although clarifying the differences in arterial healing between PES and SES is important to discuss clinical managements following DES, arterial healing following PES has not been angioscopically defined. Hence, using angioscopy, we sought to investigate the lumen/stent surfaces following PES and SES implantation for new lesions of the native coronary arteries.
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Methods
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Patients.
This study was a nonrandomized, historical control study that included 40 patients with stable angina pectoris in whom 66 DES were implanted (35 men, age 35 to 85 years). The patients agreed to receive follow-up angioscopy as well as angiography 8 months after stenting. Among them, 19 patients were treated with SES alone (27 stents) (Cypher, Cordis, Miami Lakes, Florida); 14 patients were treated with PES alone (18 stents) (TAXUS Express 2, Boston Scientific, Natick, Massachusetts); 7 patients were treated with both SES (9 stents) and PES (12 stents). All patients received ticlopidine (200 mg/day) in addition to aspirin (100 to 200 mg/day) during the follow-up, except for 2 patients. Neither a glycoprotein IIb/IIIa inhibitor nor clopidogrel was used because they were not approved for stable angina pectoris in Japan.
Angiographic and angioscopic follow-up.
Coronary angiography was performed after the administration of heparin (5,000 IU) into the femoral artery via the inserted sheath, and isosorbide dinitrate (2.5 mg) into the coronary artery. Subsequently, angioscopy was performed using Vecmova NEO (FiberTech, Tokyo, Japan). The detailed specifications and the procedures of the angioscope have been described elsewhere (10,11). Briefly, the optical fiber was placed at the distal segment of the coronary artery and was manually pulled back from the distal edge of the stent to the proximal edge under careful angioscopic and angiographic guidance. Angioscopic images consisted of 3,000 pixels with full color and were stored on digital videotapes for off-line analysis.
Quantitative coronary angiography.
Coronary angiography was performed in at least 10 projections, and the view showing the most severe stenosis was selected for quantitative coronary angiography (12). Quantitative coronary angiography was performed using the CASS system (Pie Medical BV, Maastricht, the Netherlands) before stenting, immediately after stenting, and also at follow-up with the same angle of projection.
Angioscopic analysis.
Angioscopic images were analyzed as follows: 1) the dominant degree of NIC over the stent; 2) heterogeneity of NIC; 3) existence of thrombus; and 4) existence of YP underneath the stent. Neointimal coverage over the stent was classified into 4 grades as previously described (9,13,14). In brief, grade 0 = stent struts were fully visible, similar to immediately after implantation; grade 1 = stent struts bulged into the lumen and, although covered, were still transparently visible; grade 2 = stent struts were embedded by the neointima, but were translucently seen; grade 3 = stent struts were fully embedded and were invisible by angioscopy. Neointimal coverage was evaluated in the entire stented segments, and if different NIC grades of more than or equal to 1 grade were present, the NIC was judged as heterogeneous. Struts that crossed the side branch were excluded from grading because they all showed grade 0 regardless of the stent types. The stent edges were also excluded from the heterogeneity analysis. Stent overlapped segments were also evaluated separately. Thrombus was defined based on the criteria adopted by the European Working Group on Coronary Angioscopy (15). The angioscopic definition of YP was adopted from the earlier reports (10,11,16), and the existence of YP underneath the stent was evaluated.
Statistical analysis.
All results are expressed as mean ± SD [median] unless otherwise stated. Comparisons between the 2 groups were done with the Wilcoxon rank sum test. Categorical variables were analyzed with Fisher exact test for 2 x 2 comparisons; for more than 2 x 2 comparisons, the chi-square test was used. Analyses for quantitative coronary angiography and angioscopic findings were performed per stent, but not per patient. Statistical significance was defined as p < 0.05. All calculations were performed using JMP 7.0.1 (SAS Institute, Cary, North Carolina).
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Results
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Patients.
Patient, lesion, and procedure characteristics were equally distributed between the PES and the SES groups (Tables 1 and 2), except that the duration from the stent implantation to the follow-up angiography and angioscopy were slightly longer in SES (9.2 ± 1.5 [9.2] months) than in PES (8.4 ± 1.7 [8.0] months; p = 0.01).
Quantitative coronary angiography.
Quantitative coronary angiographic findings in the PES and the SES groups are shown in Table 2. Although there were no statistical differences between them, baseline lesion length tended to be longer in SES than in PES; reference diameter tended to be larger in SES than in PES. Although a post-interventional angiogram as well as procedural characteristics were similar between PES and SES, in-stent late loss (LL) from the post-intervention to follow-up was smaller in SES (0.13 ± 0.33 [0.08] mm) than in PES (0.44 ± 0.44 [0.32] mm; p < 0.0001), and resulted in the smaller minimal lumen diameter and a larger percent diameter stenosis at follow-up in PES than in SES. Three PES and a SES showed in-stent restenosis (>50% of diameter stenosis) at follow-up angiography. Among them, all the PES received target lesion revascularization, but the SES did not.
Angioscopic findings.
Dominant NIC grade was significantly different between PES and SES (Fig. 1). The average grade was greater in PES (1.8 ± 1.1 [2] grades) than in SES (1.3 ± 0.7 [1] grades; p = 0.02). Although the majority of SES showed grade 1 (n = 26, 72%), PES showed dispersed NIC grades. Within the stents, NIC was more heterogeneous in PES than in SES (Fig. 2). Of SES, 47% had heterogeneous NIC, but all of them showed heterogeneity of 1 grade. In contrast, PES showed a higher incidence of heterogeneity (74%); the heterogeneity of 1 grade was detected in 48%; the heterogeneity of 2 grades was detected in 26%, which was not observed in SES. A representative case is shown in Figure 3.
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Figure 1 Distribution of Dominant Neointimal Coverage Grades at Follow-Up in PES and in SES
Although 72% of sirolimus-eluting stents (SES) showed the dominant neointimal coverage of grade 1, paclitaxel-eluting stents (PES) showed widely dispersed neointimal coverage. PES versus SES, p = 0.0006 by chi-square test.
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Figure 2 Heterogeneity of NIC Grades in PES and in SES
Forty-seven percent of SES showed the heterogeneity of 1 grade. Fifty-three percent demonstrated homogenous neointimal coverage (NIC). In contrast, 74% of PES showed heterogeneous NIC: 48% showed the heterogeneity of 1 grade; 26% showed the heterogeneity of 2 grades, which was not observed in SES. PES versus SES, p = 0.002 by chi-square test. Abbreviations as in Figure 1.
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Figure 3 Coronary Angiograms and Angioscopic Images 8 Months After the Tandem Implantation of SES and PES
Angiograms at follow-up revealed no restenosis at the segment of SES (3.5 x 23 mm) and PES (3.5 x 24 mm) implanted in tandem. Angioscopic images of SES showed homogeneous NIC of grade 1. In contrast, PES showed the heterogeneity of 2 grades; the dominant degree of NIC was grade 2 in PES; the distal segment showed NIC of grade 0, with mural red thrombi adhered on the yellow plaques and the naked stent struts. Dashed blue line = SES-implanted site; dashed red line = PES-implanted site. GW = guide wire; other abbreviations as in Figures 1 and 2.
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All the thrombi detected were mural and subclinical and were more frequently observed in PES (43%) than in SES (19%; p = 0.04). One of these thrombi was white, which was detected in a SES that showed NIC of grade 1. The remaining 19 thrombi were red thrombi. All the thrombi were present at the site of grade 0/1. Yellow plaques were similarly common in PES (83%) and in SES (78%; p = 0.76). Most of them were detected underneath the neointima of grades 0 to 2 (88%).
A total of 12 segments were overlapped: PES covering PES (n = 1); SES covering SES (n = 4); PES covering SES (n = 3); SES covering PES (n = 4). Five segments were overlapped with the same DES. The PES covering PES showed grade 2, and the nonoverlapped segments revealed grade 3. Three of the SES covering SES showed grade 1 throughout the stent. The other SES covering SES revealed grade 3, which was associated with moderate stenosis (<50% of diameter stenosis). The other 7 segments were overlapped with SES and PES, which in general showed low-grade coverage that was similar to the nonoverlapped segments, except for a SES covering PES, which showed grade 3 with moderate stenosis: SES covering PES showed grade 0 (n = 2) to grade 1 (n = 1); PES covering SES showed grade 1 (n = 2) to grade 2 (n = 1). Exposed struts were only seen in the segments of SES covering PES in this limited observation.
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Discussion
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The present study compared the vascular lumen/stent surfaces in patients following PES implantation with those following SES using angioscopy. Late loss was slightly, but statistically greater in PES than in SES. Although 72% of SES showed the dominant NIC of grade 1, PES showed widely dispersed NIC grades. Within the stents, NIC was more heterogeneous in PES than in SES. Thrombi were more frequently observed in PES (43%) than in SES (19%, p = 0.04). Yellow plaques were commonly detected both in PES (83%) and in SES (78%, p = 0.76).
Late losses in each group of this study were similar to those found in several other clinical studies for these stents (1,2,17). Similar to SES, PES is one of the first generation DES to reduce LL and target lesion revascularization by inhibiting neointimal hyperplasia. It has been pointed out, however, that incidence of LST may be higher following PES or SES placements than following BMS placements (3–6). Since the beginning of the BMS era, pathological studies have indicated that incomplete NIC causes LST (7). Another pathological study also suggested that incomplete NIC over SES and PES causes LST (8). In our previous study, a zotarolimus-eluting stent (Endeavor, Medtronic, Minneapolis, Minnesota), which demonstrated greater LL than SES, appeared to have angioscopically more competent NIC than SES (14). Although PES showed intermediate LL among these DES (17), PES revealed heterogeneous NIC, which did not cover the stent struts as well as the underlying YP completely. Both intra- and interstent heterogeneities of NIC grades were more significant in PES, while PES was associated with a higher frequency of thrombi than SES. Several meta-analyses revealed the higher incidence of LST in PES than in SES, whereas PES had higher LL than SES (18,19). The results of this study may explain the mechanism of the higher incidence of LST in PES in spite of the greater LL in PES than in SES. Angioscopically, thrombus adheres to the sites of incomplete NIC following DES placement (9,13).
In the present study, PES had a similar incidence of YP as did SES. Using angioscopy, Miyamoto et al. (20) demonstrated that intimal wall thickness and percent yellow saturation correlated inversely in vitro; that is, angioscopic color reflected the thickness of the fibrous cap. A clinical study using optical coherence tomography also demonstrated the relationship between the fibrous cap thickness and the yellow saturation of YP in angioscopy (21). Yellow plaque was reduced following BMS or zotarolimus-eluting stent placement, possibly by covering the YP with the neointimal development. Neointima covering the YP may have a "plaque-sealing effect" to stabilize plaques (9,11,14). In fact, although the event rate following BMS implantation was higher in target lesions than in nontarget lesions due to restenosis in year 1, the target lesions (i.e., stented segments) were clinically stable from year 2 through year 5 (target lesion = 1.7% vs. nontarget lesion = 6.3%) (22). This may be due to a lesion stabilization effect of the neointima. Our previous angioscopic studies (9,14) suggested that this plaque-sealing effect may not be expected in SES implantation due to the lack of neointimal development. Paclitaxel-eluting stents may also lack this protective sealing effect because both SES and PES showed a high incidence of YP. Although PES had a higher incidence of grade 3 than did SES, both without restenosis, the heterogeneity of NIC following PES hampered the YP sealing effect as observed in BMS or zotarolimus-eluting stents.
Clinical implications.
The present study demonstrated heterogeneous NIC following PES, which resulted in the higher incidence of thrombus adhesion as well as partially incomplete NIC. These angioscopic results endorse the recommendation of dual antiplatelet therapy for at least 1 year for patients treated with DES including PES (23,24). It is important to recognize from this study the homogeneous NIC following stenting may also be an indispensable factor to developing next-generation stents.
Study limitations.
This study was a single center, nonrandomized, historical control study with a small sample size. The follow-up term in this study was slightly longer in SES than in PES. However, NIC 3 months to 1 year after SES implantation was similar when serially compared using angioscopy (9). The follow-up term may be too short to understand the chronological changes in arterial healing following PES. Long-term, serial angioscopic follow-up study is necessary for this purpose. Although statistically insignificant, PES tended to have more restenosis (n = 3) than SES (n = 1; p = 0.3). This may bias the angioscopic observation. Nonetheless, this may also be clinically relevant because meta-analyses including a large number of patients have indicated higher rates of restenosis and target lesion revascularization rates in PES than in SES (18,19). Although 7 patients were treated with both PES and SES, analyses in the quantitative coronary angiography and angioscopy were performed per stent without correction for correlated observations in the same patients.
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Conclusions
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Neointimal coverage grades were more heterogeneous in PES than in SES and were associated with a higher incidence of thrombi in PES. Homogeneous NIC may be an important factor for competent arterial healing following DES.
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Acknowledgments
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The authors acknowledge the expertise of Drs. Hirokuni Akahori, Masamichi Yano, Kenji Kawamoto, Shin Okamoto, Haruyo Yasui, Kuniyasu Ikeoka, Nobuaki Tanaka, Takayuki Ishihara, and Tomoharu Dohi in performing cardiac catheterization.
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Footnotes
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Supported in part by a research grant to Dr. Awata from the Japan Labor Health and Welfare Organization, Kawasaki, Kanagawa, Japan.
* Reprint requests and correspondence: Prof. Shinsuke Nanto, Advanced Cardiovascular Therapeutics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita 565-0871 Japan (Email: snanto{at}bca.bai.ne.jp).
Manuscript received September 8, 2008;
revised manuscript received February 11, 2009,
accepted March 19, 2009.
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REFERENCES
|
|---|
- Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery N Engl J Med 2003;349:1315-1323.[CrossRef][Web of Science][Medline]
- Stone GW, Ellis SG, Cox DA, et al. One-year clinical results with the slow-release, polymer-based, paclitaxel-eluting TAXUS stent: the TAXUS-IV trial Circulation 2004;109:1942-1947.[Abstract/Free Full Text]
- Pfisterer M, Brunner-La Rocca HP, Buser PT, et al. Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of drug-eluting versus bare-metal stents J Am Coll Cardiol 2006;48:2584-2591.[Abstract/Free Full Text]
- Stone GW, Moses JW, Ellis SG, et al. Safety and efficacy of sirolimus- and paclitaxel-eluting coronary stents N Engl J Med 2007;356:998-1008.[CrossRef][Medline]
- Lagerqvist B, James SK, Stenestrand U, Lindback J, Nilsson T, Wallentin L. Long-term outcomes with drug-eluting stents versus bare-metal stents in Sweden N Engl J Med 2007;356:1009-1019.[CrossRef][Medline]
- Kastrati A, Mehilli J, Pache J, et al. Analysis of 14 trials comparing sirolimus-eluting stents with bare-metal stents N Engl J Med 2007;356:1030-1039.[CrossRef][Medline]
- Farb A, Burke AP, Kolodgie FD, Virmani R. Pathological mechanisms of fatal late coronary stent thrombosis in humans Circulation 2003;108:1701-1706.[Abstract/Free Full Text]
- Finn AV, Joner M, Nakazawa G, et al. Pathological correlates of late drug-eluting stent thrombosis: strut coverage as a marker of endothelialization Circulation 2007;115:2435-2441.[Abstract/Free Full Text]
- Awata M, Kotani J, Uematsu M, et al. Serial angioscopic evidence of incomplete neointimal coverage after sirolimus-eluting stent implantation: comparison with bare-metal stents Circulation 2007;116:910-916.[Abstract/Free Full Text]
- Takano M, Mizuno K, Yokoyama S, et al. Changes in coronary plaque color and morphology by lipid-lowering therapy with atorvastatin: serial evaluation by coronary angioscopy J Am Coll Cardiol 2003;42:680-686.[Abstract/Free Full Text]
- Sakai S, Mizuno K, Yokoyama S, et al. Morphologic changes in infarct-related plaque after coronary stent placement: a serial angioscopy study J Am Coll Cardiol 2003;42:1558-1565.[Abstract/Free Full Text]
- Haase J, Escaned J, van Swijndregt EM, et al. Experimental validation of geometric and densitometric coronary measurements on the new generation Cardiovascular Angiography Analysis System (CAAS II) Cathet Cardiovasc Diagn 1993;30:104-114.[Web of Science][Medline]
- Kotani J, Awata M, Nanto S, et al. Incomplete neointimal coverage of sirolimus-eluting stents: angioscopic findings J Am Coll Cardiol 2006;47:2108-2111.[Abstract/Free Full Text]
- Awata M, Nanto S, Uematsu M, et al. Angioscopic comparison of neointimal coverage between zotarolimus- and sirolimus-eluting stents J Am Coll Cardiol 2008;52:789-790.[Free Full Text]
- den Heijer P, Foley DP, Hillege HL, et al. The "Ermenonville" classification of observations at coronary angioscopy—evaluation of intra- and inter-observer agreement Eur Heart J 1994;15:815-822.[Abstract/Free Full Text]
- Ueda Y, Asakura M, Yamaguchi O, Hirayama A, Hori M, Kodama K. The healing process of infarct-related plaques. Insights from 18 months of serial angioscopic follow-up. J Am Coll Cardiol 2001;38:1916-1922.[Abstract/Free Full Text]
- Mauri L, Orav EJ, Candia SC, Cutlip DE, Kuntz RE. Robustness of late lumen loss in discriminating drug-eluting stents across variable observational and randomized trials Circulation 2005;112:2833-2839.[Abstract/Free Full Text]
- Schomig A, Dibra A, Windecker S, et al. A meta-analysis of 16 randomized trials of sirolimus-eluting stents versus paclitaxel-eluting stents in patients with coronary artery disease J Am Coll Cardiol 2007;50:1373-1380.[Abstract/Free Full Text]
- Stettler C, Wandel S, Allemann S, et al. Outcomes associated with drug-eluting and bare-metal stents: a collaborative network meta-analysis Lancet 2007;370:937-948.[CrossRef][Web of Science][Medline]
- Miyamoto A, Prieto AR, Friedl SE, et al. Atheromatous plaque cap thickness can be determined by quantitative color analysis during angioscopy: implications for identifying the vulnerable plaque Clin Cardiol 2004;27:9-15.[Web of Science][Medline]
- Kubo T, Imanishi T, Takarada S, et al. Implication of plaque color classification for assessing plaque vulnerability J Am Coll Cardiol Intv 2008;1:74-80.[Abstract/Free Full Text]
- Cutlip DE, Chhabra AG, Baim DS, et al. Beyond restenosis: five-year clinical outcomes from second-generation coronary stent trials Circulation 2004;110:1226-1230.[Abstract/Free Full Text]
- Grines CL, Bonow RO, Casey Jr. DE, et al. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians Circulation 2007;115:813-818.[Abstract/Free Full Text]
- King 3rd SB, Smith Jr. SC, Hirshfeld Jr. JW, et al. 2007 focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: 2007 Writing Group to Review New Evidence and Update the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention, Writing on Behalf of the 2005 Writing Committee J Am Coll Cardiol 2008;51:172-209.[Free Full Text]
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Abstract
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