Comparison of creatine kinase elevation and outcome of comparison of percutaneous coronary intervention for saphenous vein graft in-stent restenosis versus de novo stenosis

3. Stone GW, Peterson MA, Lansky AJ, Dangas G, Mehran R, Leon MB. Impact of normalized myocardial perfusion after successful angioplasty in acute myocardial infarction. J Am Coll Cardiol 2002;39:591–597. 4. Schroder R, Dissmann R, Bruggemann T, Wegscheider K, Linderer T, Tebbe U, Neuhaus KL. Extent of early ST segment elevation resolution: a simple but strong predictor of outcome in patients with acute myocardial infarction. J Am Coll Cardiol 1994;24:384 –391. 5. van den Merkhof LFM, Zijlstra F, Olsson H, Grip L, Veen G, Bar FW, van den Brand MJ, Simoons M, Verheugt FW. Abciximab in the treatment of acute myocardial infarction eligible for primary percutaneous transluminal coronary angioplasty; results of the Glycoprotein Receptor Antagonist Patency Evaluation (GRAPE) pilot study. J Am Coll Cardiol 1999;33:1528 –1532. 6. Cutlip DE, Cove CJ, Irons D, Kalaria V, Le M, Cronmiller H, Caufield L, Pomerantz RM, Ling FS. Emergency room administration of eptifibatide before primary angioplasty for ST elevation acute myocardial infarction and its effect on baseline coronary flow and procedure outcomes. Am J Cardiol 2001;88:62–64.

7. Gassler J, Topol E. Reperfusion revisited: beyond TIMI 3 flow. Clin Cardiol 1999;22(suppl 8):IV-20 –IV-29. 8. Neumann F, Blasini R, Schmitt C, Alt E, Dirschinger J, Gawaz M, Kastrati A, Schomig A. Effect of glycoprotein IIb/IIIa receptor blockade on recovery of coronary flow and left ventricular function after the placement of coronary-artery stents in acute myocardial infarction. Circulation 1998;98:2695–2701. 9. Stone GW, Grines CL, Cox DA, Garcia E, Tcheng JE, Griffin JJ, Guagliumi G, Stuckey T, Turco M, Carroll JD, Rutherford BD, Lansky AJ. Comparison of angioplasty with stenting, with or without abciximab, in acute myocardial infarction. N Engl J Med 2002;346:957–966. 10. Jennings LK, Jacoski MV, White MM. The pharmacodynamics of parenteral glycoprotein IIb/IIIa inhibitors. J Intervent Cardiol 2002;15:45–60. 11. Batchelor WB, Tolleson TR, Huang Y, Larsen RL, Mantell RM, Dillard P, Davidian M, Zhang D, Cantor WJ, Sketch MH Jr, et al. Randomized comparison of platelet inhibition with abciximab, tirofiban and eptifibatide during percutaneous coronary intervention in acute coronary syndromes: the COMPARE trial. Comparison Of Measurements of Platelet aggregation with Aggrastat, Reopro, and Eptifibatide. Circulation 2002;106:1470 –1476.

Comparison of Creatine Kinase Elevation and Outcome of Comparison of Percutaneous Coronary Intervention for Saphenous Vein Graft In-Stent Restenosis Versus De Novo Stenosis Roswitha Wolfram, MD, Laurent Leborgne, MD, Edouard Cheneau, MD, Augusto Pichard, MD, Lowell Satler, MD, Kenneth Kent, MD, PhD, and Ron Waksman, MD Percutaneous coronary intervention of saphenous vein grafts is associated with distal embolization. We aimed to compare potential differences in patients undergoing percutaneous coronary intervention for in-stent restenosis with de novo saphenous vein graft lesions. Myocardial necrosis was associated with higher mortality regardless of lesion type. 䊚2003 by Excerpta Medica, Inc. (Am J Cardiol 2003;92:980 –983)

pproximately 10 years after coronary artery bypass surgery, up to 67% of saphenous vein grafts A (SVGs) develop either occlusion or severe stenosis. 1

Treatment of graft disease remains challenging because repeat surgery is associated with increases in morbidity and mortality,2 and catheter-based percutaneous interventions carry a substantial risk of periinterventional complications and restenosis.3 Plaque morphology in SVGs is lipid-rich, soft and more prone to rupture than plaque in native coronary arteries.4 Mobilization and distal embolization of plaque debris during SVG interventions is responsible for the high incidence of adverse clinical events.5,6 In-stent restenosis (ISR) lesions are fibrous and have stable plaque formation,4 and prior stenting of SVG lesions may lead to plaque entrapment and to a reduction in debris mobilization at repeat intervention. To elucidate the question of whether prior stenting protects From the Washington Hospital Center, Washington, DC. Dr. Waksman’s address is: Washington Hospital Center, 110 Irving Street, NW, Suite 4B-1, Washington, DC, 20100. E-mail: ron.waksman@ medstar.net. Manuscript received March 18, 2003; revised manuscript received and accepted June 11, 2003.

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©2003 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 92 October 15, 2003

patients from periprocedural myocardial necrosis as reflected by creatine kinase (CK)-MB elevation and its sequelae, we investigated 2,252 patients who underwent percutaneous angioplasty for de novo SVG stenosis, as well as for SVG ISR, for possible differences in procedural complications and outcome. •••

Between January 1990 and June 2002, 2,252 consecutive patients who had undergone prior coronary artery bypass surgery underwent percutaneous angioplasty for SVG stenosis at the Washington Hospital Center. Among this patient population, 278 patients with 342 lesions had ISR and 1,974 patients with 2,555 lesions were treated for de novo SVG stenosis. Patients with acute myocardial infarction were excluded from this investigation. A retrospective analysis was performed in collaboration with the Cardiology Research Institute database. Blood samples were obtained from all patients before and after intervention for assessment of CK-MB enzymes at 6 and 24 hours. Non–Q-wave myocardial infarction was defined as chest pain and/or ST-segment or T-wave abnormalities with CK-MB elevation ⱖ5 times the upper normal values without any new pathologic Q waves; Q-wave myocardial infarction was defined as the appearance of new pathologic Q waves in the coronary distribution of the stented artery and CK-MB elevation ⱖ3 times the upper normal values. Lesions were characterized according to the modified American College of Cardiology/American Heart Association classification.7,8 Hypercholesterolemia was defined as total cholesterol levels ⬎180 mg and/or a patient taking a lipid-lowering agent. 0002-9149/03/$–see front matter doi:10.1016/S0002-9149(03)00984-6

TABLE 1 Baseline Clinical Characteristics of Study Population ISR in SVG ⫹ (n ⫽ 289 patients) Age (yrs) Men Graft age (mo) Diabetes mellitus Systemic hypertension Hypercholesterolemia Smoker at time of procedure Chronic renal insufficiency Unstable angina pectoris Previous myocardial infarction Previous coronary angioplasty Ejection fraction Medications Angiotensin-converting enzyme inhibitor ␤ blocker Angioplasty with an excimer laser Rotational atherectomy No. of stents Maximum stent size (mm) Maximum balloon size (mm) ReoPro periprocedural

66 222 85 103 218 218 30 2 200 174 288 44

0 (n ⫽ 1,895 patients)

⫾ 11 (77.1%) ⫾ 70 (36.0%) (75.7%) (86.1%) (10.4%) (0.7%) (84.7%) (63.3%) (89.4%) ⫾ 14%

69 1,449 96 606 1,292 1,331 315 23 1,326 1,114 1,871 41

⫾ 49 (76.7%) ⫾ 60 (32.3%) (68.5%) (71.0%) (16.6%) (1.7%) (76.8%) (61.4%) (32.9%) ⫾ 13%

p Value 0.01 0.88 0.01 0.20 0.01 ⬍0.001 0.007 0.2 0.006 0.6 ⬍0.001 0.004

113 (41.1%)

479 (36.5%)

0.2

42 (87.5%) 138 (49.5%)

90 (70.9%) 450 (18.9%)

0.02 ⬍0.001

20 1.9 3.9 3.9 114

0.2 ⬍0.001 ⬍0.001 ⬍0.001 0.002

5 1.6 3.7 3.7 11

(1.8%) ⫾ 0.9 ⫾ 0.6 ⫾ 0.7 (2.9%)

(0.8%) ⫾ 1.1 ⫾ 0.6 ⫾ 0.9 (6.0%)

Continuous variables are presented as mean ⫾ SD. ⫹ ⫽ present; 0 ⫽ absent.

TABLE 2 Qualitative and Quantitative Angiographic Characteristics at Baseline ISR in SVG ⫹ 0 (n ⫽ 342 lesions) (n ⫽ 2,555 lesions) p Value Lesion location Ostial Proximal Mid Distal Lesion characteristics Lesion length (mm) Thrombus Eccentricity Quantitative measurements Minimum luminal diameter Before angioplasty (mm) Immediately after angioplasty (mm)

61 136 69 55

(17.8%) (39.8%) (20.2%) (16.1%)

477 742 606 477

17 ⫾ 9.6 10 (7.8%) 28 (21.9%) 0.8 ⫾ 0.5 2.7 ⫾ 0.7

(16.9%) (29.0%) (23.7%) (18.7%)

0.7 ⬍0.001 0.2 0.3

9.9 ⫾ 8.1 213 (18.4%) 588 (50.8%)

⬍0.001 0.003 0.001

1.0 ⫾ 0.7 2.8 ⫾ 0.9

0.011 0.145

See Table 1 for explanation of ⫹ and 0.

TABLE 3 Procedural Results and In-hospital Events ISR in SVG Event

⫹ (n ⫽ 289 patients)

Death Q-wave myocardial infarction Coronary bypass Repeated coronary angioplasty Non–Q-wave myocardial infarction CK- MB ⱖ3 times the upper normal values CK-MB ⱖ4 times the upper normal values Troponin I abnormal See Table 1 for explanation of ⫹ and 0.

0 1 1 0 28

(0.0%) (0.4%) (0.0%) (0%) (10.1%)

0 (n ⫽ 1,895 patients) 37 17 7 0 294

(2.0%) (0.9%) (0.3%) (0%) (16.6%)

p Value 0.007 0.35 0.97 0.006

49 (17.8%)

411 (23.3%)

0.04

35 (12.7%)

335 (19.0%)

0.01

22 (10.9%)

95 (17.3%)

0.03

Revascularization was performed with the use of balloon dilation, an excimer laser, rotational atherectomy, additional stenting, or a combination of these interventions. Coronary angioplasty and stent implantation were performed by standard percutaneous techniques. During the procedure, all patients received intravenous heparin to maintain an activated clotting time of ⬎300 seconds. All patients were pretreated with aspirin and received ticlopidine (500 mg) or clopidogrel (300 mg) at the time of angioplasty. Ticlopidine (500 mg/day) or clopidogrel (75 mg/day) were maintained for 4 weeks. Abciximab (a bolus of 0.25 mg/kg followed by a 12-hour infusion of 10 ␮g/mn) or eptifibatide (Integrilin; Millennium Pharmaceuticals, Cambridge, Massachusetts) (2 bolus doses of 180 ␮g/kg followed by an 18- to 24-hour infusion of 2 ␮g/kg/mn) was administered at the discretion of the clinician. Intracoronary vascular ultrasound was performed at the discretion of the operator to optimize stent deployment. Quantitative angiographic analysis was performed using previously reported methods.9 Statistical analysis was done with the SAS statistical software (SAS Institute Inc., Cary, North Carolina). Continuous variables are presented as mean ⫾ SD and categoric variables as percentages. Comparisons between the 2 groups were obtained using chisquare or Fisher’s exact tests to analyze differences between categoric variables; we used Student’s t test to compare continuous variables. Independent factors associated with follow-up events were identified with Cox regression analysis. Survival curves were constructed by the Kaplan-Meier method and displayed using the SAS LIFETEST procedure. Wilcoxon’s log-rank test was used for survival comparison between groups. A p value ⱕ0.05 was considered statistically significant. Clinical characteristics of the patients are listed in Table 1. Lesions and procedural characteristics are listed in Table 2. Procedural results and in-hospital events are listed in Table 3 and clinical follow-up data in Table 4. The differences in CK-MB release between the 2 groups are depicted in Figure 1. The actuarial death-free survival curve BRIEF REPORTS

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TABLE 4 One-year Clinical Follow-up ISR in SVG ⫹ 0 (n ⫽ 289 patients) (n ⫽ 1,895 patients) p Value

Event Death Q-wave myocardial infarction Non–Q-wave myocardial infarction Coronary bypass Target lesion revascularization Target lesion revascularizationmajor adverse cardiac events

13 30 39 5 42 67

(6.2%) (14.6%) (18.4%) (2.5%) (20.6%) (31.5%)

189 111 395 60 246 476

(11.9%) (7.7%) (26.0%) (4.2%) (16.8%) (29.5%)

See Table 1 for explanation for ⫹ and 0.

•••

FIGURE 1. CK-MB elevation in the ISR group compared with the de novo group. xN ⴝ times normal.

FIGURE 2. Death-free survival curve for major adverse clinical events (including target lesion revascularization) at 12-month follow-up.

TABLE 5 Cox Proportional-hazards Model for Death-censored Graft Survival

Diabetes mellitus Hypercholesterolemia Age 70–79 yrs Age ⱖ80 yrs Unstable angina pectoris CK-MB ⬎5 times the upper normal values

0.01 ⬍0.001 0.02 0.26 0.19 0.57

for major adverse clinical events (including target lesion revascularization) at 12-month follow-up is shown in Figure 2. Covariates for the Cox proportional-hazards model for death-censored survival are listed in Table 5. History of diabetes, unstable angina, age ⱖ70 years, and CK-MB release ⱖ5 times the upper normal value were significant predictors of death. ISR was not an independent predictor of survival.

Hazard Ratio

95% CI

p Value

2.00 0.63 2.09 1.92 1.66 1.51

1.48–2.72 0.46–0.87 1.50–2.93 1.19–3.10 1.09–2.54 1.05–2.17

⬍0.001 0.004 ⬍0.001 0.007 0.018 0.026

CI ⫽ confidence interval.

982 THE AMERICAN JOURNAL OF CARDIOLOGY姞

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The results of our study reveal that perinterventional myocardial necrosis, as reflected by CK-MB elevation and consequently mortality, occurs in SVG ISR lesions in patients who undergo percutaneous coronary intervention. Although CK-MB elevation occurs less frequently and is less pronounced (maximum CK-MB 137.8 ⫾ 216.5 vs 193.2 ⫾ 507.9; p ⫽ 0.008) in SVG ISR than in SVG de novo lesions, myocardial necrosis has an impact on mortality in ISR and de novo lesions. Within 10 years of coronary artery bypass grafting, 50% of all patients with SVGs present with severe atherosclerotic disease and significantly compromised lumen.10 –12 Percutaneous coronary intervention including stent implantation has become a common procedure in graft failure. Stent implantation has shown a potential benefit over angioplasty alone in reducing restenosis, death, and overall cardiac events.13,14 Myocardial ischemia has been observed as a major complication in the percutaneous treatment of SVGs,15 and mortality after percutaneous coronary intervention has been linked to the extent of myocardial necrosis and consequently to the extent of CK-MB elevations. In our investigation, we observed that myocardial necrosis was a common phenomenon after percutaneous coronary intervention in ISR. Patients in the ISR group with CK-MB ⱖ5 times the upper normal values were 6.2 times more likely to die than ISR patients with normal CK-MB levels. After adjusting for independent predictors of death, CK-MB 5 times the upper normal values is an important prognostic factor of death, whereas ISR or de novo lesions have not been found to be independent predictors of the latter. Morphologic differences in ISR and de novo lesions4,16 suggest that debris mobilization into small coronary arteries leading to myocardial necrosis may be less of an issue in ISR. However, our study demonstrates that the problem of myocardial necrosis itself persists in ISR. A possible explanation could be that the injured segment in ISR treatment usually exceeds the previously stented part of the vessel, thus including segments that actually share the morphologic characteristics of de novo lesions. Strategies applied to ISR usually are more aggressive, such as the use of debulking devices and bulky brachytherapy sources, which may traumatize the graft. Furthermore, restenting of ISR SVG lesions again may include vessel segments outside the area of initial stent placeOCTOBER 15, 2003

ment. These hypotheses are confirmed by our data, which show that CK-MB elevation in SVG ISR occurred more often and was relatively higher in patients who underwent additional stenting (52.2%) and in those who were treated with debulking devices (60.4%). Brachytherapy has shown substantial efficacy and feasibility in reducing restenosis in SVG ISR.17 Focus should now be placed on enzyme release as a result of myocardial infarction, which has a tremendous impact on mortality and cardiac events. A number of distal protective devices have proved feasible and efficient in reducing CK-MB release in SVG de novo lesions.18 –20 These devices and new antithrombotic regimens should be tested in the setting of ISR SVG, and eventually in combination with endovascular radiation therapy, to establish new strategies in preventing recurrence of disease and peri-interventional ischemic events. 1. Bourassa MG, Fisher LD, Campeau L, Gillespie MJ, McConney M, Lesperance J. Long-term fate of bypass grafts: the Coronary Artery Surgery Study (CASS) and Montreal Heart Institute Experiences. Circulation 1985;72(suppl V):V-71–V-78. 2. Foster ED, Fisher LD, Kaiser GC, Myers WO, Carpenter J, Abele S, Ells R. Comparison of operative mortality and morbidity for initial and repeat coronary artery bypass grafting: The Coronary Artery Surgery Study (CASS) registry experience. Ann Thorac Surg 1984;38:563–570. 3. Cameron A, Kemp HG, Green GE. Reoperation for coronary artery disease: 10 years of clinical follow-up. Circulation 1988;78:1158 –1162. 4. Webb JG, Carere RG, Virmani R, Baim D, Teirstein PS, Whitlow P, McQueen C, Kolodgie FD, Buller E, Dodek A, Mancini GB, Oesterle S. Retrieval and analysis of particulate debris following saphenous vein graft intervention. J Am Coll Cardiol 1999;34:461–467. 5. Piana RN, Paik GY, Moscucci M, Cohen DJ, Gibson GM, Kugelmass AD, Carrozza JP Jr, Kuntz RE, Baim DS. Incidence and treatment of “no-reflow” after percutaneous coronary intervention. Circulation 1994;89:2514 –2518. 6. Hong MK, Mehran R, Dangas G, Mintz GS, Lansky AJ, Pichard AD, Kent KM, Satler LF, Stone GW, Leon MB. Creatine kinase-MB enzyme elevation following successful saphenous vein graft intervention is associated with late mortality. Circulation 1999;100:2400 –2405. 7. Herz I, Assali A, Adler Y, Solodky A, Shor N, Ben-Gal T, Sclarovsky S, Pardes A. Coronary stent deployment without predilation: prevention of complications of venous graft angioplasty. Angiology 1998;49:613–617.

8. Ryan TJ, Faxon DP, Gunnar RM, Kennedy JW, King SB III, Loop FD, Peterson KL, Reeves TJ, Williams DO, Winters WL Jr. Guidelines for percutaneous transluminal coronary angioplasty. A report of the American College of Cardiology/American Heart Association Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures (Subcommittee on Percutaneous Transluminal Coronary Angioplasty). Circulation 1988;78:486 –502. 9. Lansky A, Popma J. Qualitative and quantitative angiography. In: Topol E, ed. Textbook of Interventional Cardiology. Philadelphia: WB Saunders, 1999:725– 747. 10. Lawrie GM, Lie JT, Morris GC Jr, Beazley HL. Vein graft patency and intimal proliferation after aortocoronary bypass: early and long-term angiopathologic correlations. Am J Cardiol 1976;38:856 –862. 11. Hamby RI, Aintablian A, Handler M, Voleti C, Weisz D, Garvey JW, Wisoff G. Aortocoronary saphenous vein bypass grafts: long-term patency, morphology and blood flow in patients with patent grafts early after surgery. Circulation 1979;60:901–909. 12. Bourassa MG, Enjalbert M, Campeau L, Lesperance J. Progression of atherosclerosis in coronary arteries and bypass grafts: ten years later. Am J Cardiol 1984;53(suppl):102C–107C. 13. de Feyter PJ, van Suylen RJ, de Jaegere PP, Topol EJ, Serruys PW. Balloon angioplasty for the treatment of lesions in saphenous vein bypass grafts. J Am Coll Cardiol 1993;21:1539 –1549. 14. Wong SC, Baim DS, Schatz RA, Teirstein PS, King SB III, Curry RC Jr, Heuser RR, Ellis SG, Cleman MW, Overlie P. Immediate results and late outcomes after stent implantation in saphenous vein graft lesions: the multicenter U.S. Palmaz-Schatz stent experience. The Palmaz-Schatz Stent Study Group. J Am Coll Cardiol 1995;26:704 –712. 15. Abdelmeguid AE, Topol EJ, Whitlow PL, Sapp SK, Ellis SG. Significance of mild transient release of creatine kinase-MB fraction after percutaneous coronary interventions. Circulation 1996;94:1528 –1536. 16. Depre C, Havaux X, Wijns W. Pathology of restenosis in saphenous bypass grafts after long-term stent implantation. Am J Clin Pathol 1998;110:378 –384. 17. Waksman R, Ajani AE, White RL, Chan RC, Satler LF, Kent KM, Pichard AD, Pinnow EE, Bui AB, Ramee S, Teirstein P, Lindsay J. Intravascular gamma radiation for in-stent restenosis in saphenous-vein bypass grafts. N Engl J Med 2002;346:1194 –1199. 18. Baim DS, Wahr D, George B, Leon MB, Greenberg J, Cutlip DE, Kaya U, Popma JJ, Ho KK, Kuntz RE, Saphenous Vein Graft Angioplasty Free of Emboli Randomized (SAFER) Trial Investigators. Randomized trial of a distal embolic protection device during percutaneous intervention of saphenous vein aortocoronary bypass grafts. Circulation 2002;105:1285–1290. 19. Carlino M, De Gregorio J, Di Mario C, Anzuini A, Airoldi F, Albiero R, Briguori C, Dharmadhikari A, Sheiban I, Colombo A. Prevention of distal embolization during saphenous vein graft lesion angioplasty. Experience with a new temporary occlusion and aspiration system. Circulation 1999;99:3221–3223. 20. Grube E, Schofer JJ, Webb J, Schuler G, Colombo A, Sievert H, Gerckens U, Stone GW, for the Saphenous Vein Graft Angioplasty Free of Emboli (SAFE) Trial Study Group. Evaluation of a balloon occlusion and aspiration system for protection from distal embolization during stenting in saphenous vein grafts. Am J Cardiol 2002;89:941–945.

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