Accepted Manuscript Five-Year Follow-Up of the Plaque Sealing with Paclitaxel-Eluting Stents versus Medical Therapy for the Treatment of Intermediate Non-Obstructive Saphenous Vein Graft Lesions (VELETI) Trial Josep Rodés-Cabau, MD Olivier F. Bertrand, MD, PhD Eric Larose, MD Jean-Pierre Déry, MD Stéphane Rinfret, MD Marina Urena, MD Miguel Jerez, MD Luis NombelaFranco, MD Henrique B. Ribeiro, MD Ricardo Allende, MD Guy Proulx, MD Can M. Nguyen, MD Jean-Rock Boudreault, MD Jacques Rouleau, MD Louis Roy, MD Onil Gleeton, MD Gérald Barbeau, MD Bernard Noël, MD Mélanie Côté, MSc Jean-Pierre Després, PhD Gilles R. Dagenais, MD Robert DeLarochellière, MD PII:
S0828-282X(13)01632-2
DOI:
10.1016/j.cjca.2013.11.002
Reference:
CJCA 1025
To appear in:
Canadian Journal of Cardiology
Received Date: 9 October 2013 Revised Date:
5 November 2013
Accepted Date: 5 November 2013
Please cite this article as: Rodés-Cabau J, Bertrand OF, Larose E, Déry J-P, Rinfret S, Urena M, Jerez M, Nombela-Franco L, Ribeiro HB, Allende R, Proulx G, Nguyen CM, Boudreault J-R, Rouleau J, Roy L, Gleeton O, Barbeau G, Noël B, Côté M, Després J-P, Dagenais GR, DeLarochellière R, Five-Year Follow-Up of the Plaque Sealing with Paclitaxel-Eluting Stents versus Medical Therapy for the Treatment of Intermediate Non-Obstructive Saphenous Vein Graft Lesions (VELETI) Trial, Canadian Journal of Cardiology (2013), doi: 10.1016/j.cjca.2013.11.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Five-Year Follow-Up of the Plaque Sealing with Paclitaxel-Eluting Stents versus Medical Therapy for the Treatment of Intermediate Non-Obstructive
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Saphenous Vein Graft Lesions (VELETI) Trial
Josep Rodés-Cabau, MD, Olivier F. Bertrand, MD, PhD, Eric Larose, MD, Jean-Pierre Déry,
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MD, Stéphane Rinfret, MD, Marina Urena, MD, Miguel Jerez, MD, Luis Nombela-Franco, MD, Henrique B. Ribeiro, MD, Ricardo Allende, MD, Guy Proulx, MD, Can M. Nguyen, MD, Jean-
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Rock Boudreault, MD, Jacques Rouleau, MD, Louis Roy, MD, Onil Gleeton, MD, Gérald Barbeau, MD, Bernard Noël, MD, Mélanie Côté, MSc, Jean-Pierre Després, PhD, Gilles R Dagenais, MD, Robert DeLarochellière, MD
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Quebec Heart and Lung Institute, Quebec City, Quebec, Canada Key words: stents; saphenous vein graft; atherosclerosis; angiography Short title: Plaque Sealing and SVGs
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Word count: 4493
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Address for correspondence :
Josep Rodés-Cabau, MD Quebec Heart and Lung Institute 2725, chemin Sainte-Foy Québec (Québec) G1V 4G5 Canada E-mail: [email protected]
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BRIEF SUMMARY In the VELETI trial, patients with ≥1 intermediate SVG lesion were randomized to either stenting the SVG lesion with a paclitaxel-eluting stent (n=30, PES group) or to medical treatment
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alone (n=27). At 5-year follow-up, major adverse cardiac events (MACE) related to the target SVG lesion tended to be lower in the PES group due to a lower lesion revascularization rate (P=0.07). However, MACE related to target SVG and global MACE were similar between
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groups.
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ABSTRACT Background: Very few data exists on the long-term follow-up of the patients with intermediate non-obstructive saphenous vein graft (SVG) lesions. The purpose of this study was to evaluate
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the 5-year clinical outcomes of the patients enrolled in the VELETI trial and the factors associated with SVG disease progression and outcomes.
Methods and Results: Patients with ≥1 intermediate SVG lesion (30% to 60% diameter
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stenosis) were randomized to either stenting the SVG lesion with a paclitaxel-eluting stent (n=30, PES group) or to medical treatment alone (n=27, MT group). All patients were followed yearly
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up to 5 years. Major adverse cardiac events (MACE; cardiac death, myocardial infarction [MI], revascularization) related to the target SVG lesion tended to be lower in the PES group (17% vs. 33%, P=0.147) due to a lower lesion revascularization rate (13% vs. 33%, P=0.072), with no difference in cardiac death or MI between groups. MACE related to target SVG and global
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MACE were similar between groups (P>0.20 for both). A higher cholesterol level at baseline was the only independent predictive factor of MACE related to the target SVG (P=0.016). Conclusions: Over a 5-year period, one third of intermediate lesions in old SVGs progressed
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leading to a cardiac event. Stenting these lesions with PES tended to improve clinical outcomes by reducing lesion progression, but not SVG failure. Higher cholesterol levels were associated
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with SVG disease progression and clinical events. This pilot study provides the basis for a larger trial to determine the efficacy of intermediate SVG lesion plaque sealing.
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INTRODUCTION The appearance and progression of saphenous vein graft (SVG) atherosclerosis remains the first cause of graft failure, and about half of the SVGs are already occluded 10 years after
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coronary artery bypass grafting1. Several studies have identified the presence of intermediate non-obstructive SVG lesions as the most important predictor of SVG atherosclerosis progression and cardiac events 2-9. The VELETI (Moderate VEin Graft LEsion Stenting With the Taxus Stent
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and Intravascular Ultrasound) trial was a randomized, prospective, pilot trial assessing the effects of stenting intermediate non-obstructive SVG lesions on the prevention of atherosclerosis
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progression as evaluated by angiography and intravascular ultrasound at 1-year follow-up8. The study showed the efficacy and safety of sealing moderate non-obstructive SVG lesions with a drug-eluting stent to prevent SVG atherosclerosis progression. The VELETI trial also confirmed the high rate of rapid progression and clinical events related to intermediate non-obstructive
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SVG lesions at 1-year follow-up. The purpose of our study was to evaluate the 5-year outcomes of the patients enrolled in the VELETI trial and to determine the factors associated with cardiac
METHODS
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events in these patients.
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Study design and patients. Details of the VELETI study design have been previously provided.8 Briefly, patients with previous CABG involving SVG implantation who required coronary and SVG angiography by clinical indication were screened, and those with at least one intermediate SVG lesion (30% to 60% diameter stenosis) which was not the culprit lesion responsible for the clinical syndrome of the patient were eligible. A total of 57 patients were included in the study and patients were randomized to either stenting the moderate SVG lesion
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with a paclitaxel-eluting stent [PES] (Taxus Express stent, Boston Scientific Corp., Natick, Massachussets, USA; 30 patients) or to medical treatment alone (27 patients). Informed consent was obtained from each patient and the study protocol conforms to the
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ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution’s human research committee.
Clinical follow-up and outcomes. Patients had clinical visits at 1-, 6- and 12-month follow-up,
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and yearly thereafter up to 5 years. The follow-up was complete in 100% of the patients. In each clinical visit, the occurrence of clinical events was systematically evaluated; this included the
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occurrence of coronary or SVG revascularization, myocardial infarction and death. Any death was considered of cardiac origin unless proven otherwise. Stent thrombosis occurrence was defined and classified according to the Academic Research Consortium criteria 10. In the case of repeat coronary/SVG angiography (with or without revascularization) during the follow-up
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period, the angiography was systematically reviewed and compared to baseline angiography. Quantitative coronary angiography measurements of SVG lesion were obtained in all cases as previously described.8 All major adverse cardiovascular events (MACE; cardiac death, MI,
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revascularization) were classified as either related or unrelated to the target SVG lesion and to the target SVG independently by 2 investigators. In case of disagreement, a third investigator
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also evaluated the case for final assignment. The occurrence of SVG obstruction was considered to be related to the intermediate SVG lesion unless proven otherwise. Statistical methods. Comparison of numerical variables was performed using the student’s t test or Wilcoxon rank-sum test depending on variable distribution. The chi-square (if >5 events) or Fisher’s exact tests (if ≤5 events) were used to compare qualitative variables. Differences in clinical events between groups were evaluated using the Cox proportional hazard model. Univariate and multivariate Cox proportional hazard models were used to determine both
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differences in clinical events between groups and the predictive factors of MACE at 5-year follow-up. The variables exhibiting a p value 1 year) restenosis of the PES in 4 patients (57%) and to progression of the disease in other segments of the SVG in 3 patients (43%). The mean percent diameter stenosis in patients with restenosis was 76±16%, and 77±14% in patients with SVG disease progression in non-stented
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segments. In the PES group, stent restenosis or disease progression led to an acute coronary syndrome in all cases (MI in 29%). The cumulative incidence of MACE related to the target SVG lesion, target SVG and global over time according to randomization group are shown in
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Figures 1, 2, and 3, respectively.
A total of 7 patients died during the follow-up period, 6 of them of non-cardiovascular
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causes (2 cancers, 2 bleeding complications, 1 pneumonia and 1 car accident). The only cardiac death occurred in a patient of the PES group. The patient had an episode of unstable angina due to in-stent restenosis 59 months after initial PES implantation. The patient had successful revascularization with implantation of an everolimus-eluting stent and died suddenly 3 weeks after this intervention. This event was considered as a probable stent thrombosis of the everolimus-eluting stent.
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Predictors of MACE at 5-year follow-up. Clinical and angiographic characteristics of the study population grouped according to the occurrence of MACE related to the target SVG are shown in Supplemental Table S2. In the multivariate analysis, a higher cholesterol value at baseline was
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the only factor determining a higher risk for target SVG disease progression leading to clinical events at follow-up (HR: 1.20 for each increase of 10 mg/dL [95%CI:1.04-1.40], P=0.016). The independent predictors of global MACE (related or unrelated to the target SVG) were female sex
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(HR: 4.51 [95%CI: 1.61-11.03], P=0.002) and higher cholesterol levels at baseline [HR: 1.24 for
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each increase of 10 mg/dl [95%CI: 1.61-11.03], P50% in lesion revascularization as compared to the MT group. Interestingly, no cases of stent restenosis were observed within the first year following PES-PCI, and all cases were late, at >2 years of follow-up. This late restenosis phenomenon has also been observed in other studies using DES for the treatment of SVG
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lesions. In the RRISC trial most cases of restenosis at 3-year follow-up occurred >1 year after sirolimus-eluting stent implantation15, and in the SOS trial half of the cases of stent restenosis after a mean follow-up of 3 years following PES implantation occurred after the first year 14.
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This late restenosis phenomenon contributed to reduce the efficacy of the plaque sealing strategy and it was probably secondary to delayed healing and/or late neoatherosclerosis associated with DES16. About half of the events related to SVG failure in the PES group were due to SVG
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disease progression in non-stented SVG segments. Although the SVG failure rate was still 30% lower than in the MT group, this pilot study had a limited sample size and was not powered for
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clinical endpoints, and between-group differences in clinical events secondary to SVG failure were non-significant. The importance of SVG disease progression in non-stented segments for late clinical events following SVG-PCI has been well established in prior studies 14,17. SVG intervention trials using DES have shown that 30 to 50% of the clinical events occurring within
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the first year following SVG-DES implantation are related to non-stented SVG segments, and this rate increases to >50% of the events at 3 year follow-up 11-15. This rapid progression of SVG disease in non-stented segments highlights the importance of additional (medical) measures to
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prevent SVG disease progression in such patients. Despite the relatively high MI rate (11%) related to SVG lesion progression in the MT
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group, no differences in the rate of MI were observed between the PES and MT groups. Although no cases of stent thrombosis related to the PES were observed, one patient suffered a periprocedural MI secondary to transient no-reflow phenomenon following PCI of the intermediate SVG lesion, and half of the patients with PES restenosis presented with a non-ST elevation, leading to an MI rate of 10% at 5-year follow-up. The post-CABG trial showed that intensive lipid-lowering therapy was associated with a significant reduction in SVG disease progression18 and this translated into a lower rate of cardiac
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events at long-term follow-up 5. The mean cholesterol and LDL levels in the post-CABG trial were of ~170 mg/dL and 93 mg/dL, respectively. The vast majority of patients included in the VELETI trial were on lipid-lowering therapy, and mean cholesterol and LDL levels were much
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lower (mean: 143 mg/dL and 74 mg/dL, respectively) than those reported in the post-CABG trial. However, higher cholesterol levels were associated with a higher rate of MACE globally and particularly with those associated with SVG disease progression, suggesting that further
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lowering of cholesterol levels might be associated with a reduction in cardiac events in such patients.
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Study limitations. This was a one-center pilot study. The number of patients included was small and the study was not powered for clinical endpoints. A larger randomized study is needed to determine the efficacy of stenting intermediate SVG lesions. This is the purpose of the ongoing VELETI II trial (NCT01223443), a prospective multicenter randomized trial to evaluate the
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efficacy of plaque sealing with DES in a larger study population. While most patients included in the study had repeated coronary angiography at 1-year follow-up, no further systematic imaging studies were performed up to 5-year follow-up. Some cases of late silent SVG obstruction may
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have been missed, and the rate of SVG failure may have been underestimated.
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Conclusions. Intermediate non-obstructive lesions in old (mean of 12 years) SVGs were associated with a high rate of rapid progression and clinical events at 5-year follow-up. While stenting these SVG lesions with PES was safe and associated with a tendency towards a lower incidence of events related to lesion progression, it failed to significantly reduce SVG failure, due to both late stent restenosis phenomena and SVG disease progression in non-stented segments. Larger and adequately powered studies will be needed to definitely address the efficacy of stenting intermediate SVG lesions. Finally, despite low mean total and LDL
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cholesterol levels, a higher cholesterol level remained the main factor determining SVG disease progression and clinical events at follow-up, strongly suggesting that further reductions in cholesterol levels will probably be needed to optimize clinical outcomes in the high-risk
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population of post-CABG patients with old SVGs.
ACCEPTED MANUSCRIPT Rodés-Cabau et al. FUNDING SOURCES The VELETI trial (ClinicalTrials.gov number: NCT00289835) was an investigator initiated study supported by an unrestricted grant from Boston Scientific Inc. Canada (Toronto, Canada) and
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from the Fondation de l’Institut de Cardiologie de Québec, Québec, Canada.
CONFLICT OF INTEREST DISCLOSURE
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This trial was partially supported by a grant from Boston Scientific Inc. Canada
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REFERENCES
1. Goldman S, Zadina K, Moritz T, et al. Long-term patency of saphenous vein and left internal mammary artery grafts after coronary artery bypass surgery: results from a Department of
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Veterans Affairs Cooperative Study. J Am Coll Cardiol. 2004;44:2149-56
2. Domanski MJ, Borkowf CB, Campeau L, et al. Prognostic factors for atherosclerosis progression in saphenous vein grafts. J Am Coll Cardiol. 2000;36:1877-83.
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3. Ellis SG, Brener SJ, DeLuca S, et al. Late myocardial ischemic events after saphenous vein graft intervention: importance of initially "nonsignificant" vein graft lesions. Am J Cardiol.
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1997;79:1460-64.
4. Rodés-Cabau J, Facta A, Larose E, et al. Predictors of aorto-saphenous vein bypass narrowing late after coronary artery bypass grafting. Am J Cardiol. 2007;100:640-5. 5. Knatterud GL, White C, Geller NL, et al. Angiographic changes in saphenous vein grafts are
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predictors of clinical outcomes. Am Heart J. 2003;145:262-9.
6. Le May MR, Labinaz M, Marquis JF, et al. Predictors of long-term outcome after stent implantation in a saphenous vein graft. Am J Cardiol. 1999;83:681-6.
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7. Lytle BW, Loop FD, Taylor PC, et al. Vein graft disease: the clinical impact of stenoses in saphenous vein grafts to coronary arteries. J Thorac Cardiovasc Surg. 1992;103:831-40.
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8. Rodés-Cabau J, Bertrand OF, Larose E, et al. Comparison of plaque sealing with paclitaxeleluting stents versus medical therapy for the treatment of moderate nonsignificant saphenous vein graft lesions: the moderate vein graft lesion stenting with the taxus stent and intravascular ultrasound (VELETI) pilot trial. Circulation. 2009;120:1978-86. 9. Abdel-Karim AR, Da Silva M, Lichtenwalter C, et al. Prevalence and outcomes of intermediate saphenous vein graft lesions: Findings from the stenting of saphenous vein grafts
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randomized-controlled trial. Int J Cardiol. 2013 doi:pii: S0167-5273(13)00424-5. 10.1016/j.ijcard.2013.03.006. [Epub ahead of print].
for standardized definitions. Circulation. 2007;115:2344-51.
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10. Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials. A case
11. Mehilli J, Pache J, Abdel-Wahab M, et al. Drug-eluting versus bare-metal stents in saphenous vein graft lesions (ISAR-CABG): a randomised controlled superiority trial. Lancet.
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2011;378:1071-78.
12. Brilakis ES, Lichtenwalter C, de Lemos JA, et al. A randomized controlled trial of a
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paclitaxel-eluting stent versus a similar bare-metal stent in saphenous vein graft lesions the SOS (Stenting of Saphenous Vein Grafts) trial. J Am Coll Cardiol. 2009;53:919-28. 13. Vermeersch P, Agostoni P, Verheye S, et al. Randomized double-blind comparison of sirolimus-eluting stent versus bare-metal stent implantation in diseased saphenous vein grafts:
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six-month angiographic, intravascular ultrasound, and clinical follow-up of the RRISC Trial. J Am Coll Cardiol. 2006;48:2423-31.
14. Brilakis ES, Lichtenwalter C, Abdel-karim AR, et al. Continued benefit from paclitaxel-
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eluting compared with bare-metal stent implantation in saphenous vein graft lesions during longterm follow-up of the SOS (Stenting of Saphenous Vein Grafts) trial. JACC Cardiovasc Interv.
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2011;4:176-82.
15. Vermeersch P, Agostoni P, Verheye S, et al. Increased late mortality after sirolimus-eluting stents versus bare-metal stents in diseased saphenous vein grafts: results from the randomized DELAYED RRISC Trial. J Am Coll Cardiol. 2007;50:261-7. 16. Habara M, Terashima M, Nasu K, et al. Morphological differences of tissue characteristics between early, late, and very late restenosis lesions after first generation drug-eluting stent
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implantation : an optical coherence tomography study. Eur Heart J Cardiovasc Imaging 2013;14:276-84. 17. Keeley EC, Velez CA, O'Neill WW, Safian RD. Long-term clinical outcome and predictors
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of major adverse cardiac events after percutaneous interventions on saphenous vein grafts. J Am Coll Cardiol. 2001;38:659-65.
18. The Post Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering
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of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive
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changes in saphenous vein coronary-artery bypass grafts. N Engl J Med 1997;336:153–62.
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Table 1. Baseline Characteristics of the Study Population, According to Randomization Group
P value
69 ± 9
0.726
25 (83)
0.197
1 (3)
0.180
16 (53)
1.00
29 (97)
0.336
10 (33)
0.788
15 (56)
20 (67)
0.425
59 ± 13
54 ± 12
0.084
7 (25)
5 (17)
0.519
17 (63)
24 (80)
0.238
13 (76)
17 (79)
3 (18)
5 (21)
1 (6)
0 (0)
3 (11)
1 (3)
0.336
11 ± 6
11 ± 6
0.540
Number of grafts per patient
3.8 ± 1.0
3.6 ± 1.4
0.579
Number of SVGs per patient
2.7 ± 1.0
2.4 ± 1.3
0.474
Internal mammary artery to LAD
23 (85)
24 (80)
0.734
PCI of a culprit lesion
12 (44)
15 (50)
0.464
Total cholesterol (mg/dL)
143 ± 31
142 ± 39
0.977
LDL cholesterol (mg/dL)
74 ± 28
73 ± 34
0.911
HDL cholesterol (mg/dL)
42 ± 11
45 ± 10
0.299
Triglycerides (mg/dL)
136 ± 53
124 ± 50
0.380
C-reactive protein (mg/L)
6.4 ± 17.1
4.0 ± 5.8
0.497
27 (100)
30 (100)
1.00
Baseline clinical characteristics 69 ± 7 26 (96)
Current smoking
4 (15)
Hypertension
15 (56)
Dyslipidemia
24 (89)
Diabetes mellitus
10 (37)
Prior myocardial infarction Ejection fraction (%) Clinical indication for angiography Stable angina pectoris Acute coronary syndrome
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Unstable angina
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Male sex
Non-STEMI STEMI Other
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Time from CABG (years)
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Age (years)
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Paclitaxel-eluting stenting (n=30)
Medical Treatment (n=27)
Baseline Biological markers
Treatment Aspirin
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Clopidogrel
19 (70)
26 (87)
0.200
Statins
24 (89)
27 (90)
1.00
30
40
0.310
1.1 ± 0.3
1.3 ± 0.6
0.086
3.53 ± 0.51
0.555
2.15 ± 0.37
0.700
39 ± 6
0.826
9.95 ± 4.23
0.544
Number of moderate SVG lesions Number of lesions per patient Reference diameter (mm)
3.65 ± 0.91
Minimal lumen diameter (mm)
2.20 ± 0.57
Percent diameter stenosis
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Baseline angiographic characteristics
40 ± 7 9.24 ± 3.29
Values are reported as n (%) or mean ± standard deviation
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Lesion length (mm)
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STEMI:ST-Elevation Myocardial Infarction; CABG :coronary artery bypass grafting; SVG: saphenous vein graft; LAD: left anterior descending artery; PCI: percutaneous coronary intervention; LDL: low density
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lipoprotein; HDL: high density lipoprotein
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Table 2. Cumulative Rates of Major Adverse Cardiac Events, According to Randomization Group Paclitaxel-eluting stent
27
30
0
1 (3)
Cardiac death
0
0
Myocardial infarction
0
n
Revascularization
Cardiac death
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Cumulative
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Myocardial infarction
Cardiac death
Myocardial infarction
P value
-
1.00
-
-
-
1.00
0
0
-
-
9 (33)
4 (13)
2.84 (0.88-9.23)
0.082
0
1 (3)
-
1.00
3 (11)
2 (7)
1.54 (0.26-9.26)
0.635
9 (33)
4 (13)
2.95 (0.91-9.60)
0.072
9 (33)
5 (17)
2.25 (0.75-6.73)
0.146
0
1 (3)
-
1.00
3 (11)
3 (10)
1.04 (0.21-5.17)
0.960
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Follow-up
Revascularization
1 (3)
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In hospital
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Patients with MACE related to the target SVG lesion
HR (95% CI)
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Medical Treatment
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Revascularization
9 (33)
4 (13)
0
1 (3)
Cardiac death
0
0
Myocardial infarction
0
Revascularization
0
2.95 (0.91-9.60)
20
0.072
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Patients with MACE related to the target SVG
1.00
-
-
1 (3)
-
1.00
0
-
-
9 (33)
6 (20)
1.84 (0.65-5.17)
0.248
0
1 (3)
-
1.00
Myocardial infarction
3 (11)
2 (7)
1.54 (0.26-9.26)
0.635
Revascularization
9 (33)
7 (23)
1.63 (0.61-4.38)
0.333
9 (33)
7 (23)
1.57 (0.58-4.21)
0.374
0
1 (3)
-
1.00
3 (11)
3 (10)
1.04 (0.21-5.17)
0.960
9 (33)
7 (23)
1.63 (0.61-4.38)
0.333
0
1 (3)
-
1.00
Cardiac death
0
0
-
-
Myocardial infarction
0
1 (3)
-
1.00
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Follow-up Cardiac death
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Cumulative Cardiac death
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Myocardial infarction Revascularization
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-
In hospital
In hospital
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Patients with MACE related or unrelated to the target SVG
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1 (3)
-
1.00
13 (48)
12 (40)
1.27 (0.58-2.78)
0.555
0
1 (3)
-
1.00
Myocardial infarction
3 (11)
5 (17)
0.68 (0.16-2.85)
0.592
Revascularization
13 (48)
12 (40)
1.27 (0.58-2.79)
0.545
13 (43)
1.17 (0.55-2.55)
0.675
1 (3)
-
1.00
Cardiac death
13 (48)
Cumulative
0
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Cardiac death
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Follow-up
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0
Revascularization
Myocardial infarction
3 (11)
6 (20)
0.56 (0.14-2.26)
0.415
Revascularization
13 (48)
13 (43)
0.18 (0.55-2.55)
0.675
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MACE: major adverse cardiac events
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Values are reported as n (%)
ACCEPTED MANUSCRIPT 22 FIGURE LEGENDS
Figure 1
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Kaplan-Meier cumulative event curves for major adverse cardiac events related to the target saphenous vein graft lesion throughout 5-year follow-up, according to randomization group. Death (A), myocardial infarction (B), revascularization (C), major adverse cardiac events –
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cardiac death, myocardial infarction, revascularization- (D).
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Figure 2
Kaplan-Meier cumulative event curves for major adverse cardiac events related to the target saphenous vein graft throughout 5-year follow-up, according to the randomization group. Death (A), myocardial infarction (B), revascularization (C), major adverse cardiac events –cardiac
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death, myocardial infarction, revascularization- (D).
Figure 3
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Kaplan-Meier cumulative event curves for death and global (related and unrelated to the target saphenous vein graft) major adverse cardiac events up to 5-year follow-up, according to
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randomization group. Death (A), myocardial infarction (B), revascularizaton (C), major adverse cardiac events –cardiac death, myocardial infarction, revascularization- (D).
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Supplemental Table S1. Clinical and Angiographic Features of the Patients who Suffered a MACE Related to the Target SVG During the 5-Year Follow-Up
SVG progression location
Treatment
13
62
Target lesion
Angioplasty
Non-STEMI
38
91
Target lesion
Angioplasty
Medical treatment
Unstable angina
8
72
Target lesion
Angioplasty
48
Medical treatment
Unstable angina
11
75
Target lesion
Angioplasty
12
46
Medical treatment
Stable angina + positive functional test
13
100
Target lesion
Angioplasty
66
13
40
Medical treatment
Unstable angina
28
61
Target lesion
Angioplasty
7
80
18
31
Medical treatment
Non-STEMI
6
66
Target lesion
Angioplasty
8
61
12
38
Medical treatment
Unstable angina
60
62
Target lesion
Angioplasty
9
62
5
58
Medical treatment
Non-STEMI
60
85
Target lesion
Angioplasty
10
61
6
42
Stenting
Non-STEMI
30
59
Target lesion (restenosis)
Angioplasty
Target lesion stenosis (QCA, %)
Treatment allocation
Clinical presentation
1
53
11
45
Medical treatment
Stable angina + positive functional test
2
79
20
36
Medical treatment
3
76
9
43
4
66
9
5
72
6
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Time from initial coronary angiography (months)
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SVG age (years)
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Target SVG maximal stenosis (QCA, %)
Patient age (years)
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Target SVG, new lesion
Angioplasty
51
72
Target lesion (restenosis)
Angioplasty
43
90
Target lesion (restenosis)
Angioplasty
26
85
Target lesion (restenosis)
Angioplasty
52
62
Target SVG, new lesion
Angioplasty
45
65
Target SVG, new lesion
Angioplasty
31 ± 19
75 ± 14
83
17
45
Stenting
Unstable angina
20
12
73
5
33
Stenting
Unstable angina
13
51
5
46
Stenting
Unstable angina
14
62
18
31
Stenting
Non-STEMI
15
48
14
44
Stenting
Unstable angina
16
74
8
51
Stenting
Unstable angina
Mean
67 ± 11
11 ± 5
42 ± 7
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Non-STEMI: non-ST segment elevation myocardial infarction, QCA: quantitative coronary angiography
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Supplemental Table S2. Univariate and Multivariate Predictors of MACE Related to the Target SVG Multivariate Model
HR (95% CI)
P value
Age
0.95 (0.89-1.02)
0.144
Female sex
2.13 (0.61-7.48)
0.238
Current smoking
0.84 (0.24-2.93)
0.779
Hypertension
1.53 (0.55-4.20)
0.413
Dyslipidemia
-
-
Diabetes mellitus
0.91 (0.31-2.61)
0.853
Prior myocardial infarction
1.02 (0.37-2.82)
0.965
Ejection fraction Clinical indication for angiography Stable angina pectoris
1.00 (0.96-1.05)
0.844
1.80 (0.60-5.39)
0.293
0.79 90.23-2.77)
0.711
Acute coronary syndrome
0.79 (0.28-2.28)
0.666
Other
3.78 (0.81-17.70)
0.091
Time from CABG (years)
0.99 (0.99-1.01)
0.719
Number of grafts
0.96 (0.63-1.47)
0.862
HR (95% CI)
Total cholesterol *
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0.932
1.55 (0.35-6.82)
0.563
0.08 (0.01-0.85)
0.036
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Baseline Biological markers
1.22 (1.07-1.40)
0.003
1.22 (1.06-1.05)
0.007
1.18 (0.75-1.82)
0.495
Triglycerides *
1.08 (0.98-1.19)
0.104
C-reactive protein
0.93 (0.80-1.08)
0.313
-
-
0.47 (0.16-1.35)
0.159
Statins Baseline angiographic characteristics Number of lesions per patient
0.90 (0.20-3.96)
0.888
2.02 (1.01-4.07)
0.049
Reference diameter
0.95 (0.48-1.88)
0.891
LDL cholesterol *
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HDL cholesterol *
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Variables
Number of SVGs Internal mammary artery to LAD PCI of a culprit lesion
P value
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Univariate
1.20 (1.04-1.40)
0.016
1.29 (0.62-2.67)
0.493
Baseline treatment Aspirin
Clopidogrel
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Minimal lumen diameter Percent diameter stenosis
0.58 90.20-1.72)
0.326
1.07 (0.99-1.14)
0.059
Lesion length
0.98 (0.86-1.12)
0.772
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*For each increase of 10 mg/dL.
S0828-282X(13)01632-2
DOI:
10.1016/j.cjca.2013.11.002
Reference:
CJCA 1025
To appear in:
Canadian Journal of Cardiology
Received Date: 9 October 2013 Revised Date:
5 November 2013
Accepted Date: 5 November 2013
Please cite this article as: Rodés-Cabau J, Bertrand OF, Larose E, Déry J-P, Rinfret S, Urena M, Jerez M, Nombela-Franco L, Ribeiro HB, Allende R, Proulx G, Nguyen CM, Boudreault J-R, Rouleau J, Roy L, Gleeton O, Barbeau G, Noël B, Côté M, Després J-P, Dagenais GR, DeLarochellière R, Five-Year Follow-Up of the Plaque Sealing with Paclitaxel-Eluting Stents versus Medical Therapy for the Treatment of Intermediate Non-Obstructive Saphenous Vein Graft Lesions (VELETI) Trial, Canadian Journal of Cardiology (2013), doi: 10.1016/j.cjca.2013.11.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Five-Year Follow-Up of the Plaque Sealing with Paclitaxel-Eluting Stents versus Medical Therapy for the Treatment of Intermediate Non-Obstructive
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Saphenous Vein Graft Lesions (VELETI) Trial
Josep Rodés-Cabau, MD, Olivier F. Bertrand, MD, PhD, Eric Larose, MD, Jean-Pierre Déry,
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MD, Stéphane Rinfret, MD, Marina Urena, MD, Miguel Jerez, MD, Luis Nombela-Franco, MD, Henrique B. Ribeiro, MD, Ricardo Allende, MD, Guy Proulx, MD, Can M. Nguyen, MD, Jean-
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Rock Boudreault, MD, Jacques Rouleau, MD, Louis Roy, MD, Onil Gleeton, MD, Gérald Barbeau, MD, Bernard Noël, MD, Mélanie Côté, MSc, Jean-Pierre Després, PhD, Gilles R Dagenais, MD, Robert DeLarochellière, MD
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Quebec Heart and Lung Institute, Quebec City, Quebec, Canada Key words: stents; saphenous vein graft; atherosclerosis; angiography Short title: Plaque Sealing and SVGs
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Word count: 4493
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Address for correspondence :
Josep Rodés-Cabau, MD Quebec Heart and Lung Institute 2725, chemin Sainte-Foy Québec (Québec) G1V 4G5 Canada E-mail: [email protected]
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BRIEF SUMMARY In the VELETI trial, patients with ≥1 intermediate SVG lesion were randomized to either stenting the SVG lesion with a paclitaxel-eluting stent (n=30, PES group) or to medical treatment
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alone (n=27). At 5-year follow-up, major adverse cardiac events (MACE) related to the target SVG lesion tended to be lower in the PES group due to a lower lesion revascularization rate (P=0.07). However, MACE related to target SVG and global MACE were similar between
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groups.
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ABSTRACT Background: Very few data exists on the long-term follow-up of the patients with intermediate non-obstructive saphenous vein graft (SVG) lesions. The purpose of this study was to evaluate
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the 5-year clinical outcomes of the patients enrolled in the VELETI trial and the factors associated with SVG disease progression and outcomes.
Methods and Results: Patients with ≥1 intermediate SVG lesion (30% to 60% diameter
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stenosis) were randomized to either stenting the SVG lesion with a paclitaxel-eluting stent (n=30, PES group) or to medical treatment alone (n=27, MT group). All patients were followed yearly
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up to 5 years. Major adverse cardiac events (MACE; cardiac death, myocardial infarction [MI], revascularization) related to the target SVG lesion tended to be lower in the PES group (17% vs. 33%, P=0.147) due to a lower lesion revascularization rate (13% vs. 33%, P=0.072), with no difference in cardiac death or MI between groups. MACE related to target SVG and global
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MACE were similar between groups (P>0.20 for both). A higher cholesterol level at baseline was the only independent predictive factor of MACE related to the target SVG (P=0.016). Conclusions: Over a 5-year period, one third of intermediate lesions in old SVGs progressed
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leading to a cardiac event. Stenting these lesions with PES tended to improve clinical outcomes by reducing lesion progression, but not SVG failure. Higher cholesterol levels were associated
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with SVG disease progression and clinical events. This pilot study provides the basis for a larger trial to determine the efficacy of intermediate SVG lesion plaque sealing.
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INTRODUCTION The appearance and progression of saphenous vein graft (SVG) atherosclerosis remains the first cause of graft failure, and about half of the SVGs are already occluded 10 years after
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coronary artery bypass grafting1. Several studies have identified the presence of intermediate non-obstructive SVG lesions as the most important predictor of SVG atherosclerosis progression and cardiac events 2-9. The VELETI (Moderate VEin Graft LEsion Stenting With the Taxus Stent
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and Intravascular Ultrasound) trial was a randomized, prospective, pilot trial assessing the effects of stenting intermediate non-obstructive SVG lesions on the prevention of atherosclerosis
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progression as evaluated by angiography and intravascular ultrasound at 1-year follow-up8. The study showed the efficacy and safety of sealing moderate non-obstructive SVG lesions with a drug-eluting stent to prevent SVG atherosclerosis progression. The VELETI trial also confirmed the high rate of rapid progression and clinical events related to intermediate non-obstructive
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SVG lesions at 1-year follow-up. The purpose of our study was to evaluate the 5-year outcomes of the patients enrolled in the VELETI trial and to determine the factors associated with cardiac
METHODS
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events in these patients.
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Study design and patients. Details of the VELETI study design have been previously provided.8 Briefly, patients with previous CABG involving SVG implantation who required coronary and SVG angiography by clinical indication were screened, and those with at least one intermediate SVG lesion (30% to 60% diameter stenosis) which was not the culprit lesion responsible for the clinical syndrome of the patient were eligible. A total of 57 patients were included in the study and patients were randomized to either stenting the moderate SVG lesion
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with a paclitaxel-eluting stent [PES] (Taxus Express stent, Boston Scientific Corp., Natick, Massachussets, USA; 30 patients) or to medical treatment alone (27 patients). Informed consent was obtained from each patient and the study protocol conforms to the
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ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution’s human research committee.
Clinical follow-up and outcomes. Patients had clinical visits at 1-, 6- and 12-month follow-up,
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and yearly thereafter up to 5 years. The follow-up was complete in 100% of the patients. In each clinical visit, the occurrence of clinical events was systematically evaluated; this included the
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occurrence of coronary or SVG revascularization, myocardial infarction and death. Any death was considered of cardiac origin unless proven otherwise. Stent thrombosis occurrence was defined and classified according to the Academic Research Consortium criteria 10. In the case of repeat coronary/SVG angiography (with or without revascularization) during the follow-up
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period, the angiography was systematically reviewed and compared to baseline angiography. Quantitative coronary angiography measurements of SVG lesion were obtained in all cases as previously described.8 All major adverse cardiovascular events (MACE; cardiac death, MI,
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revascularization) were classified as either related or unrelated to the target SVG lesion and to the target SVG independently by 2 investigators. In case of disagreement, a third investigator
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also evaluated the case for final assignment. The occurrence of SVG obstruction was considered to be related to the intermediate SVG lesion unless proven otherwise. Statistical methods. Comparison of numerical variables was performed using the student’s t test or Wilcoxon rank-sum test depending on variable distribution. The chi-square (if >5 events) or Fisher’s exact tests (if ≤5 events) were used to compare qualitative variables. Differences in clinical events between groups were evaluated using the Cox proportional hazard model. Univariate and multivariate Cox proportional hazard models were used to determine both
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differences in clinical events between groups and the predictive factors of MACE at 5-year follow-up. The variables exhibiting a p value 1 year) restenosis of the PES in 4 patients (57%) and to progression of the disease in other segments of the SVG in 3 patients (43%). The mean percent diameter stenosis in patients with restenosis was 76±16%, and 77±14% in patients with SVG disease progression in non-stented
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segments. In the PES group, stent restenosis or disease progression led to an acute coronary syndrome in all cases (MI in 29%). The cumulative incidence of MACE related to the target SVG lesion, target SVG and global over time according to randomization group are shown in
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Figures 1, 2, and 3, respectively.
A total of 7 patients died during the follow-up period, 6 of them of non-cardiovascular
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causes (2 cancers, 2 bleeding complications, 1 pneumonia and 1 car accident). The only cardiac death occurred in a patient of the PES group. The patient had an episode of unstable angina due to in-stent restenosis 59 months after initial PES implantation. The patient had successful revascularization with implantation of an everolimus-eluting stent and died suddenly 3 weeks after this intervention. This event was considered as a probable stent thrombosis of the everolimus-eluting stent.
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Predictors of MACE at 5-year follow-up. Clinical and angiographic characteristics of the study population grouped according to the occurrence of MACE related to the target SVG are shown in Supplemental Table S2. In the multivariate analysis, a higher cholesterol value at baseline was
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the only factor determining a higher risk for target SVG disease progression leading to clinical events at follow-up (HR: 1.20 for each increase of 10 mg/dL [95%CI:1.04-1.40], P=0.016). The independent predictors of global MACE (related or unrelated to the target SVG) were female sex
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(HR: 4.51 [95%CI: 1.61-11.03], P=0.002) and higher cholesterol levels at baseline [HR: 1.24 for
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each increase of 10 mg/dl [95%CI: 1.61-11.03], P50% in lesion revascularization as compared to the MT group. Interestingly, no cases of stent restenosis were observed within the first year following PES-PCI, and all cases were late, at >2 years of follow-up. This late restenosis phenomenon has also been observed in other studies using DES for the treatment of SVG
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lesions. In the RRISC trial most cases of restenosis at 3-year follow-up occurred >1 year after sirolimus-eluting stent implantation15, and in the SOS trial half of the cases of stent restenosis after a mean follow-up of 3 years following PES implantation occurred after the first year 14.
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This late restenosis phenomenon contributed to reduce the efficacy of the plaque sealing strategy and it was probably secondary to delayed healing and/or late neoatherosclerosis associated with DES16. About half of the events related to SVG failure in the PES group were due to SVG
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disease progression in non-stented SVG segments. Although the SVG failure rate was still 30% lower than in the MT group, this pilot study had a limited sample size and was not powered for
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clinical endpoints, and between-group differences in clinical events secondary to SVG failure were non-significant. The importance of SVG disease progression in non-stented segments for late clinical events following SVG-PCI has been well established in prior studies 14,17. SVG intervention trials using DES have shown that 30 to 50% of the clinical events occurring within
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the first year following SVG-DES implantation are related to non-stented SVG segments, and this rate increases to >50% of the events at 3 year follow-up 11-15. This rapid progression of SVG disease in non-stented segments highlights the importance of additional (medical) measures to
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prevent SVG disease progression in such patients. Despite the relatively high MI rate (11%) related to SVG lesion progression in the MT
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group, no differences in the rate of MI were observed between the PES and MT groups. Although no cases of stent thrombosis related to the PES were observed, one patient suffered a periprocedural MI secondary to transient no-reflow phenomenon following PCI of the intermediate SVG lesion, and half of the patients with PES restenosis presented with a non-ST elevation, leading to an MI rate of 10% at 5-year follow-up. The post-CABG trial showed that intensive lipid-lowering therapy was associated with a significant reduction in SVG disease progression18 and this translated into a lower rate of cardiac
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events at long-term follow-up 5. The mean cholesterol and LDL levels in the post-CABG trial were of ~170 mg/dL and 93 mg/dL, respectively. The vast majority of patients included in the VELETI trial were on lipid-lowering therapy, and mean cholesterol and LDL levels were much
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lower (mean: 143 mg/dL and 74 mg/dL, respectively) than those reported in the post-CABG trial. However, higher cholesterol levels were associated with a higher rate of MACE globally and particularly with those associated with SVG disease progression, suggesting that further
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lowering of cholesterol levels might be associated with a reduction in cardiac events in such patients.
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Study limitations. This was a one-center pilot study. The number of patients included was small and the study was not powered for clinical endpoints. A larger randomized study is needed to determine the efficacy of stenting intermediate SVG lesions. This is the purpose of the ongoing VELETI II trial (NCT01223443), a prospective multicenter randomized trial to evaluate the
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efficacy of plaque sealing with DES in a larger study population. While most patients included in the study had repeated coronary angiography at 1-year follow-up, no further systematic imaging studies were performed up to 5-year follow-up. Some cases of late silent SVG obstruction may
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have been missed, and the rate of SVG failure may have been underestimated.
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Conclusions. Intermediate non-obstructive lesions in old (mean of 12 years) SVGs were associated with a high rate of rapid progression and clinical events at 5-year follow-up. While stenting these SVG lesions with PES was safe and associated with a tendency towards a lower incidence of events related to lesion progression, it failed to significantly reduce SVG failure, due to both late stent restenosis phenomena and SVG disease progression in non-stented segments. Larger and adequately powered studies will be needed to definitely address the efficacy of stenting intermediate SVG lesions. Finally, despite low mean total and LDL
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cholesterol levels, a higher cholesterol level remained the main factor determining SVG disease progression and clinical events at follow-up, strongly suggesting that further reductions in cholesterol levels will probably be needed to optimize clinical outcomes in the high-risk
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population of post-CABG patients with old SVGs.
ACCEPTED MANUSCRIPT Rodés-Cabau et al. FUNDING SOURCES The VELETI trial (ClinicalTrials.gov number: NCT00289835) was an investigator initiated study supported by an unrestricted grant from Boston Scientific Inc. Canada (Toronto, Canada) and
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from the Fondation de l’Institut de Cardiologie de Québec, Québec, Canada.
CONFLICT OF INTEREST DISCLOSURE
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This trial was partially supported by a grant from Boston Scientific Inc. Canada
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REFERENCES
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2. Domanski MJ, Borkowf CB, Campeau L, et al. Prognostic factors for atherosclerosis progression in saphenous vein grafts. J Am Coll Cardiol. 2000;36:1877-83.
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3. Ellis SG, Brener SJ, DeLuca S, et al. Late myocardial ischemic events after saphenous vein graft intervention: importance of initially "nonsignificant" vein graft lesions. Am J Cardiol.
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4. Rodés-Cabau J, Facta A, Larose E, et al. Predictors of aorto-saphenous vein bypass narrowing late after coronary artery bypass grafting. Am J Cardiol. 2007;100:640-5. 5. Knatterud GL, White C, Geller NL, et al. Angiographic changes in saphenous vein grafts are
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7. Lytle BW, Loop FD, Taylor PC, et al. Vein graft disease: the clinical impact of stenoses in saphenous vein grafts to coronary arteries. J Thorac Cardiovasc Surg. 1992;103:831-40.
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8. Rodés-Cabau J, Bertrand OF, Larose E, et al. Comparison of plaque sealing with paclitaxeleluting stents versus medical therapy for the treatment of moderate nonsignificant saphenous vein graft lesions: the moderate vein graft lesion stenting with the taxus stent and intravascular ultrasound (VELETI) pilot trial. Circulation. 2009;120:1978-86. 9. Abdel-Karim AR, Da Silva M, Lichtenwalter C, et al. Prevalence and outcomes of intermediate saphenous vein graft lesions: Findings from the stenting of saphenous vein grafts
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randomized-controlled trial. Int J Cardiol. 2013 doi:pii: S0167-5273(13)00424-5. 10.1016/j.ijcard.2013.03.006. [Epub ahead of print].
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10. Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials. A case
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six-month angiographic, intravascular ultrasound, and clinical follow-up of the RRISC Trial. J Am Coll Cardiol. 2006;48:2423-31.
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eluting compared with bare-metal stent implantation in saphenous vein graft lesions during longterm follow-up of the SOS (Stenting of Saphenous Vein Grafts) trial. JACC Cardiovasc Interv.
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implantation : an optical coherence tomography study. Eur Heart J Cardiovasc Imaging 2013;14:276-84. 17. Keeley EC, Velez CA, O'Neill WW, Safian RD. Long-term clinical outcome and predictors
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Table 1. Baseline Characteristics of the Study Population, According to Randomization Group
P value
69 ± 9
0.726
25 (83)
0.197
1 (3)
0.180
16 (53)
1.00
29 (97)
0.336
10 (33)
0.788
15 (56)
20 (67)
0.425
59 ± 13
54 ± 12
0.084
7 (25)
5 (17)
0.519
17 (63)
24 (80)
0.238
13 (76)
17 (79)
3 (18)
5 (21)
1 (6)
0 (0)
3 (11)
1 (3)
0.336
11 ± 6
11 ± 6
0.540
Number of grafts per patient
3.8 ± 1.0
3.6 ± 1.4
0.579
Number of SVGs per patient
2.7 ± 1.0
2.4 ± 1.3
0.474
Internal mammary artery to LAD
23 (85)
24 (80)
0.734
PCI of a culprit lesion
12 (44)
15 (50)
0.464
Total cholesterol (mg/dL)
143 ± 31
142 ± 39
0.977
LDL cholesterol (mg/dL)
74 ± 28
73 ± 34
0.911
HDL cholesterol (mg/dL)
42 ± 11
45 ± 10
0.299
Triglycerides (mg/dL)
136 ± 53
124 ± 50
0.380
C-reactive protein (mg/L)
6.4 ± 17.1
4.0 ± 5.8
0.497
27 (100)
30 (100)
1.00
Baseline clinical characteristics 69 ± 7 26 (96)
Current smoking
4 (15)
Hypertension
15 (56)
Dyslipidemia
24 (89)
Diabetes mellitus
10 (37)
Prior myocardial infarction Ejection fraction (%) Clinical indication for angiography Stable angina pectoris Acute coronary syndrome
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Unstable angina
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Male sex
Non-STEMI STEMI Other
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Time from CABG (years)
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Age (years)
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Paclitaxel-eluting stenting (n=30)
Medical Treatment (n=27)
Baseline Biological markers
Treatment Aspirin
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Clopidogrel
19 (70)
26 (87)
0.200
Statins
24 (89)
27 (90)
1.00
30
40
0.310
1.1 ± 0.3
1.3 ± 0.6
0.086
3.53 ± 0.51
0.555
2.15 ± 0.37
0.700
39 ± 6
0.826
9.95 ± 4.23
0.544
Number of moderate SVG lesions Number of lesions per patient Reference diameter (mm)
3.65 ± 0.91
Minimal lumen diameter (mm)
2.20 ± 0.57
Percent diameter stenosis
RI PT
Baseline angiographic characteristics
40 ± 7 9.24 ± 3.29
Values are reported as n (%) or mean ± standard deviation
SC
Lesion length (mm)
M AN U
STEMI:ST-Elevation Myocardial Infarction; CABG :coronary artery bypass grafting; SVG: saphenous vein graft; LAD: left anterior descending artery; PCI: percutaneous coronary intervention; LDL: low density
AC C
EP
TE D
lipoprotein; HDL: high density lipoprotein
ACCEPTED MANUSCRIPT Rodés-Cabau et al.
19
Table 2. Cumulative Rates of Major Adverse Cardiac Events, According to Randomization Group Paclitaxel-eluting stent
27
30
0
1 (3)
Cardiac death
0
0
Myocardial infarction
0
n
Revascularization
Cardiac death
AC C
Cumulative
EP
Myocardial infarction
Cardiac death
Myocardial infarction
P value
-
1.00
-
-
-
1.00
0
0
-
-
9 (33)
4 (13)
2.84 (0.88-9.23)
0.082
0
1 (3)
-
1.00
3 (11)
2 (7)
1.54 (0.26-9.26)
0.635
9 (33)
4 (13)
2.95 (0.91-9.60)
0.072
9 (33)
5 (17)
2.25 (0.75-6.73)
0.146
0
1 (3)
-
1.00
3 (11)
3 (10)
1.04 (0.21-5.17)
0.960
TE D
Follow-up
Revascularization
1 (3)
M AN U
In hospital
SC
Patients with MACE related to the target SVG lesion
HR (95% CI)
RI PT
Medical Treatment
ACCEPTED MANUSCRIPT Rodés-Cabau et al.
Revascularization
9 (33)
4 (13)
0
1 (3)
Cardiac death
0
0
Myocardial infarction
0
Revascularization
0
2.95 (0.91-9.60)
20
0.072
RI PT
Patients with MACE related to the target SVG
1.00
-
-
1 (3)
-
1.00
0
-
-
9 (33)
6 (20)
1.84 (0.65-5.17)
0.248
0
1 (3)
-
1.00
Myocardial infarction
3 (11)
2 (7)
1.54 (0.26-9.26)
0.635
Revascularization
9 (33)
7 (23)
1.63 (0.61-4.38)
0.333
9 (33)
7 (23)
1.57 (0.58-4.21)
0.374
0
1 (3)
-
1.00
3 (11)
3 (10)
1.04 (0.21-5.17)
0.960
9 (33)
7 (23)
1.63 (0.61-4.38)
0.333
0
1 (3)
-
1.00
Cardiac death
0
0
-
-
Myocardial infarction
0
1 (3)
-
1.00
M AN U
Follow-up Cardiac death
TE D
Cumulative Cardiac death
EP
Myocardial infarction Revascularization
SC
-
In hospital
In hospital
AC C
Patients with MACE related or unrelated to the target SVG
ACCEPTED MANUSCRIPT Rodés-Cabau et al.
21
1 (3)
-
1.00
13 (48)
12 (40)
1.27 (0.58-2.78)
0.555
0
1 (3)
-
1.00
Myocardial infarction
3 (11)
5 (17)
0.68 (0.16-2.85)
0.592
Revascularization
13 (48)
12 (40)
1.27 (0.58-2.79)
0.545
13 (43)
1.17 (0.55-2.55)
0.675
1 (3)
-
1.00
Cardiac death
13 (48)
Cumulative
0
M AN U
Cardiac death
SC
Follow-up
RI PT
0
Revascularization
Myocardial infarction
3 (11)
6 (20)
0.56 (0.14-2.26)
0.415
Revascularization
13 (48)
13 (43)
0.18 (0.55-2.55)
0.675
AC C
EP
MACE: major adverse cardiac events
TE D
Values are reported as n (%)
ACCEPTED MANUSCRIPT 22 FIGURE LEGENDS
Figure 1
RI PT
Kaplan-Meier cumulative event curves for major adverse cardiac events related to the target saphenous vein graft lesion throughout 5-year follow-up, according to randomization group. Death (A), myocardial infarction (B), revascularization (C), major adverse cardiac events –
SC
cardiac death, myocardial infarction, revascularization- (D).
M AN U
Figure 2
Kaplan-Meier cumulative event curves for major adverse cardiac events related to the target saphenous vein graft throughout 5-year follow-up, according to the randomization group. Death (A), myocardial infarction (B), revascularization (C), major adverse cardiac events –cardiac
TE D
death, myocardial infarction, revascularization- (D).
Figure 3
EP
Kaplan-Meier cumulative event curves for death and global (related and unrelated to the target saphenous vein graft) major adverse cardiac events up to 5-year follow-up, according to
AC C
randomization group. Death (A), myocardial infarction (B), revascularizaton (C), major adverse cardiac events –cardiac death, myocardial infarction, revascularization- (D).
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT
RI PT
Supplemental Table S1. Clinical and Angiographic Features of the Patients who Suffered a MACE Related to the Target SVG During the 5-Year Follow-Up
SVG progression location
Treatment
13
62
Target lesion
Angioplasty
Non-STEMI
38
91
Target lesion
Angioplasty
Medical treatment
Unstable angina
8
72
Target lesion
Angioplasty
48
Medical treatment
Unstable angina
11
75
Target lesion
Angioplasty
12
46
Medical treatment
Stable angina + positive functional test
13
100
Target lesion
Angioplasty
66
13
40
Medical treatment
Unstable angina
28
61
Target lesion
Angioplasty
7
80
18
31
Medical treatment
Non-STEMI
6
66
Target lesion
Angioplasty
8
61
12
38
Medical treatment
Unstable angina
60
62
Target lesion
Angioplasty
9
62
5
58
Medical treatment
Non-STEMI
60
85
Target lesion
Angioplasty
10
61
6
42
Stenting
Non-STEMI
30
59
Target lesion (restenosis)
Angioplasty
Target lesion stenosis (QCA, %)
Treatment allocation
Clinical presentation
1
53
11
45
Medical treatment
Stable angina + positive functional test
2
79
20
36
Medical treatment
3
76
9
43
4
66
9
5
72
6
TE D
EP
AC C
Time from initial coronary angiography (months)
M AN U
Patient
SVG age (years)
SC
Target SVG maximal stenosis (QCA, %)
Patient age (years)
ACCEPTED MANUSCRIPT
95
Target SVG, new lesion
Angioplasty
51
72
Target lesion (restenosis)
Angioplasty
43
90
Target lesion (restenosis)
Angioplasty
26
85
Target lesion (restenosis)
Angioplasty
52
62
Target SVG, new lesion
Angioplasty
45
65
Target SVG, new lesion
Angioplasty
31 ± 19
75 ± 14
83
17
45
Stenting
Unstable angina
20
12
73
5
33
Stenting
Unstable angina
13
51
5
46
Stenting
Unstable angina
14
62
18
31
Stenting
Non-STEMI
15
48
14
44
Stenting
Unstable angina
16
74
8
51
Stenting
Unstable angina
Mean
67 ± 11
11 ± 5
42 ± 7
M AN U
SC
RI PT
11
AC C
EP
TE D
Non-STEMI: non-ST segment elevation myocardial infarction, QCA: quantitative coronary angiography
ACCEPTED MANUSCRIPT
Supplemental Table S2. Univariate and Multivariate Predictors of MACE Related to the Target SVG Multivariate Model
HR (95% CI)
P value
Age
0.95 (0.89-1.02)
0.144
Female sex
2.13 (0.61-7.48)
0.238
Current smoking
0.84 (0.24-2.93)
0.779
Hypertension
1.53 (0.55-4.20)
0.413
Dyslipidemia
-
-
Diabetes mellitus
0.91 (0.31-2.61)
0.853
Prior myocardial infarction
1.02 (0.37-2.82)
0.965
Ejection fraction Clinical indication for angiography Stable angina pectoris
1.00 (0.96-1.05)
0.844
1.80 (0.60-5.39)
0.293
0.79 90.23-2.77)
0.711
Acute coronary syndrome
0.79 (0.28-2.28)
0.666
Other
3.78 (0.81-17.70)
0.091
Time from CABG (years)
0.99 (0.99-1.01)
0.719
Number of grafts
0.96 (0.63-1.47)
0.862
HR (95% CI)
Total cholesterol *
M AN U
TE D 0.98 (0.63-1.54)
0.932
1.55 (0.35-6.82)
0.563
0.08 (0.01-0.85)
0.036
EP
Baseline Biological markers
1.22 (1.07-1.40)
0.003
1.22 (1.06-1.05)
0.007
1.18 (0.75-1.82)
0.495
Triglycerides *
1.08 (0.98-1.19)
0.104
C-reactive protein
0.93 (0.80-1.08)
0.313
-
-
0.47 (0.16-1.35)
0.159
Statins Baseline angiographic characteristics Number of lesions per patient
0.90 (0.20-3.96)
0.888
2.02 (1.01-4.07)
0.049
Reference diameter
0.95 (0.48-1.88)
0.891
LDL cholesterol *
AC C
HDL cholesterol *
SC
Variables
Number of SVGs Internal mammary artery to LAD PCI of a culprit lesion
P value
RI PT
Univariate
1.20 (1.04-1.40)
0.016
1.29 (0.62-2.67)
0.493
Baseline treatment Aspirin
Clopidogrel
ACCEPTED MANUSCRIPT
Minimal lumen diameter Percent diameter stenosis
0.58 90.20-1.72)
0.326
1.07 (0.99-1.14)
0.059
Lesion length
0.98 (0.86-1.12)
0.772
AC C
EP
TE D
M AN U
SC
RI PT
*For each increase of 10 mg/dL.
