Angiographic and clinical outcomes of late total occlusion versus treatment failure without late total occlusion in patients after intracoronary radiation therapy for in-stent restenosis

Angiographic and Clinical Outcomes of Late Total Occlusion Versus Treatment Failure Without Late Total Occlusion in Patients After Intracoronary Radiation Therapy for In-Stent Restenosis Roswitha Wolfram, MD, Edouard Cheneau, MD, Gary S. Mintz, MD, Augusto D. Pichard, MD, Lowell F. Satler, MD, Kenneth M. Kent, MD, William O. Suddath, MD, Ellen E. Pinnow, MS, and Ron Waksman, MD This study aimed to compare the outcomes of patients with late total occlusion (LTO) versus patients with recurrence in the absence of LTO after intracoronary radiation therapy for in-stent restenosis. LTO, especially in the context of acute myocardial infarction, after intracoronary radiation therapy for in-stent restenosis, is associated with negative clinical outcomes after 6 and 12 months compared with in-stent restenosis without LTO. 䊚2004 by Excerpta Medica Inc. (Am J Cardiol 2004;94:1551–1554)

ntracoronary radiation therapy (IRT) using ␤ and ␥ Irestenosis. emitters is effective in reducing recurrent in-stent However, ⬎20% of patients still have no 1–5

success with radiation and require repeat intervention.6 The introduction of prolonged antiplatelet therapy after IRT, however, has significantly reduced the incidence of thrombotic events.7,8 Late total occlusion (LTO) occurring ⬎30 days after intervention has remained a particularly worrisome complication because it may result in unstable angina and acute myocardial infarction (AMI).9,10 The underlying pathomechanism of LTO is different from the common restenotic process. Recurrence after IRT is due to neointimal formation, whereas LTO is a result of delayed healing and subsequent thrombus formation.11–14 LTO has also been associated with the use of repeat stenting at the time of radiation.15 Patients in whom IRT is unsuccessful are typically treated with repeat percutaneous coronary intervention. The primary objective of this present analysis was to investigate short- and long-term clinical outcomes in patients who develop LTO (with or without AMI) and to compare them with patients with recurrent in-stent restenosis without LTO. •••

We retrospectively analyzed 532 patients in whom radiation therapy failed for in-stent restenosis between July 1997 and November 2002. Failed radiation was either recurrent restenosis without LTO (n ⫽ 283) or LTO (n ⫽ 249) at the radiated segment. LTO was defined angiographically as minimal lumen diameter From the Cardiovascular Research Institute, Division of Cardiology, Washington Hospital Center, and Cardiovascular Research Foundation, Washington, DC. Dr. Waksman’s address is: Washington Hospital Center, 110 Irving Street, NW, Suite 4B-1, Washington, DC 20010. E-mail: [email protected]. Manuscript received June 7, 2004; revised manuscript received and accepted August 5, 2004. ©2004 by Excerpta Medica Inc. All rights reserved. The American Journal of Cardiology Vol. 94 December 15, 2004

of 0 mm in the radiated segment. All patients were initially enrolled in radiation trials for in-stent restenosis using ␥ and ␤ emitters at Washington Hospital Center.1,2,16 Revascularization and brachytherapy procedures have been described previously.1,2 All studies involved an investigational device exemption granted by the Food and Drug Administration and were approved by the institutional review board and the radiation safety committee at Washington Hospital Center. Informed consent was obtained from all patients. The inclusion criteria for the initial IRT index procedure included in-stent restenosis, lesion diameter stenosis ⬎50% in the presence of angina or inducible ischemia on functional testing, reference vessel diameter 2.5 to 5.0 mm, lesion length ⬍80 mm, and successful primary coronary intervention. Exclusion criteria were left ventricular ejection fraction ⬍20%, angiographic visible thrombus, multiple coronary lesions, and previous coronary or chest radiation therapy. Patients were treated with aspirin 325 mg/day and clopidogrel (loading dose 300 mg, followed by 75 mg/day) before the procedure. During intervention, heparin was administered to maintain an activated clotting time between 250 and 300 seconds. Patients were discharged with aspirin 325 mg/day indefinitely and clopidogrel 75 mg/day for at least 1 month according to study protocol. Baseline information and angiographic features of all IRT patients were recorded and entered prospectively in a dedicated computerized database. All IRT patients underwent standard prepercutaneous coronary intervention evaluations including pre- and postintervention 12-lead electrocardiography. Independent chart audit was performed by trained quality assurance nurses who worked exclusively with the database. An external committee independently adjudicated all subsequent clinical events including LTO or recurrence without LTO. Patients with LTO were identified, and their 6- and 12-month clinical outcomes were compared with those in patients with recurrent stenosis without LTO. Patients were contacted 6 and 12 months after failure of percutaneous coronary intervention treatment with radiation to determine their status and whether they had undergone any revascularization procedures during the respective period of time. Mean follow-up was 424 ⫾ 409 days. Procedural success was defined as ⬍50% stenosis without major in-hospital complications (death, AMI, or coronary artery bypass surgery). Lesions were clas0002-9149/04/$–see front matter doi:10.1016/j.amjcard.2004.08.037

1551

revascularization. LTO was defined as angiographically documented total occlusion at the lesion site 31 to Recurrent Restenosis/ 270 days after the index procedure. No Late Total Late Total Continuous data are expressed as Occlusion Occlusion mean ⫾ SD and compared using Variable (n ⫽ 283) (n ⫽ 249) p Value analysis of variance. Categorical data Men 192 (67.8%) 161 (64.7%) 0.438 are expressed as frequencies and Age (yrs) 60.26 ⫾ 10.5 60.78 ⫾ 11.16 0.585 compared using chi-square statistics Diabetes mellitus 113 (40.1%) 100 (40.7%) 0.892 Hyperlipidemia 256 (91.1%) 226 (91.1%) 0.992 or Fisher’s exact tests. A p value Systemic hypertension 214 (75.9%) 197 (79.4%) 0.329 ⱕ0.05 was considered significant. Smokers at time of procedure 33 (11.7%) 28 (11.2%) 0.881 The clinical characteristics of the Ex-smokers at time of procedure 137 (48.4%) 124 (49.8%) 0.749 patients in whom IRT failed at the Previous AMI 149 (52.7%) 156 (62.7%) 0.020 index procedure are depicted in TaPrevious stroke 33 (11.7%) 26 (10.7%) 0.465 Previous coronary artery 137 (48.9%) 149 (60.3%) 0.009 ble 1. The patients represent a typical bypass surgery high-risk cohort undergoing treatStable angina pectoris 43 (15.9%) 32 (13.5%) 0.127 ment for in-stent restenosis. Unstable angina pectoris 227 (84.1%) 205 (86.5%) 0.443 In the LTO group, 203 patients Left ventricular ejection fraction 49 ⫾ 13 48 ⫾ 13 0.199 Coronary arteries or conduits presented with new-onset angina Left anterior descending 86 (30.4%) 49 (19.8%) 0.005 (stable [n ⫽ 56], unstable [n ⫽ Left circumflex 59 (20.8%) 67 (27.0%) 0.096 147]), and 46 patients presented with Saphenous vein graft 53 (18.7%) 58 (23.4%) 0.188 AMI. Treatment included percutaneReference vessel diameter (mm) 2.70 ⫾ 0.41 2.71 ⫾ 0.46 0.96 ous transluminal coronary angioLesion length (mm) 22.7 ⫾ 12.1 25.5 ⫾ 11.9 0.11 Time to failure after index 252 ⫾ 221 381 ⫾ 312 ⬍0.001 plasty (n ⫽ 168, 67.5%), coronary procedure (d) artery bypass surgery (n ⫽ 2, 0.8%), Follow-up after failure (d) 404 ⫾ 443 344 ⫾ 351 ⬍0.001 coronary artery bypass surgery after unsuccessful percutaneous transluminal coronary angioplasty (n ⫽ 3, 1.2%), and medical management (n TABLE 2 Six- and 12-month Outcomes ⫽ 76, 30.5%). Mortality at the time Recurrent Restenosis/ of presentation and treatment in the No Late Total Late Total LTO group was 3.2% (n ⫽ 8). Variable Occlusion Occlusion p Value In the recurrent restenosis/noEligible for 6-mo follow-up (n ⫽ 223) (n ⫽ 193) LTO group, 226 patients presented Target vessel revascularization-major 58 (26%) 80 (41%) 0.001 with new-onset angina (stable [n ⫽ adverse cardiac events 68], unstable [n ⫽ 158]) and 24 with Death 14 (6.3%) 12 (6.2%) 0.91 Q-wave AMI 1 (0.5%) 1 (0.5%) 0.66 AMI. Treatment for IRT failure conNon–Q-wave AMI 9 (4.0%) 6 (3.1%) 0.09 sisted of percutaneous transluminal Target vessel revascularization 55 (24.7%) 74 (38.8%) 0.003 coronary angioplasty (n ⫽ 209; Target lesion revascularization 45 (20.2%) 63 (32.6%) 0.004 73.9%), coronary artery bypass surEligible for 12-mo follow-up (n ⫽ 184) (n ⫽ 159) gery (n ⫽ 70; 24.7%), and coronary Target vessel revascularization-major 67 (36.4%) 86 (54.1%) 0.001 adverse cardiac events artery bypass surgery after unsucDeath 16 (8.7%) 14 (8.8%) 0.97 cessful percutaneous transluminal Q-wave AMI 1 (0.5%) 1 (0.6%) 1.0 coronary angioplasty (n ⫽ 4; 1.4%). Non–Q-wave AMI 10 (5.4%) 6 (3.8%) 0.47 Mortality at the time of presentation Target vessel revascularization 63 (34.2%) 78 (49.1%) 0.005 Target lesion revascularization 51 (27.7%) 66 (41.5%) 0.008 and treatment in the no-LTO group was 2.8% (n ⫽ 8). The clinical events at 6 and 12 sified according the modified American College of months are outlined in Table 2. After treatment of IRT Cardiology/American Heart Association lesion classi- failure in the LTO group, 223 patients (78.8%) were fication score.16 Death was defined as all-cause mor- eligible for 6-month follow-up and 184 (65%) for tality. Q-wave and non–Q-wave AMI were defined as 12-month follow-up. In the recurrent restenosis/noa total creatine kinase elevation ⱖ2 times the normal LTO group, 193 (77.8%) were eligible for 6-month value and/or elevated creatine kinase-MB fraction follow-up and 159 (64.1%) for 12-month follow-up. ⱖ20 ng/ml with or without new pathologic Q waves At 6 months, the target lesion revascularization rate (⬎0.4 ms) in ⱖ2 contiguous leads. Target lesion and was 32.6% in the LTO group versus 20.2% in the target vessel revascularizations were characterized as recurrent restenosis/no-LTO group (p ⫽ 0.004); at 12 repeat percutaneous coronary intervention or coronary months, the target lesion revascularization rate was artery bypass surgery involving the treated vessel 41.5% versus 27.7%, respectively (p ⫽ 0.008). Target driven by clinical signs of ischemia in the presence of vessel revascularization and target vessel revascularangiographic restenosis. Major adverse cardiac events ization major adverse cardiac event rates were also were defined as death, Q-wave AMI, or target vessel higher in the LTO group: 6-month target vessel revasTABLE 1 Baseline Clinical Characteristics of Patients in Whom Intracoronary Radiation Therapy Failed at the Time of Index Procedure

1552 THE AMERICAN JOURNAL OF CARDIOLOGY姞

VOL. 94

DECEMBER 15, 2004

TABLE 3 Subgroup Analysis of Six- and 12-month Outcomes According to Presentation of Late Total Occlusion

Variable Eligible for 6-mo follow-up Target vessel revascularization-major adverse cardiac events Death Q-wave AMI Non–Q-wave AMI Target vessel revascularization Target lesion revascularization Eligible for 12-mo follow-up Target vessel revascularization-major adverse cardiac events Death Q-wave AMI Non–Q-wave AMI Target vessel revascularization Target lesion revascularization

Recurrent Restenosis/No Late Total Occlusion

Late Total Occlusion/No AMI

Late Total Occlusion ⫹ AMI

(n ⫽ 223) 58 (26%)

(n ⫽ 156) 61 (39.1%)

(n ⫽ 37) 19 (51.4%)

14 (6.3%) 1 (0.5%) 9 (4.0%) 55 (24.7%) 45 (20.2%) (n ⫽ 184) 67 (36.4%)

7 (4.5%) 1 (0.6%) 1 (0.6%) 58 (37.2%) 49 (37.4%) (n ⫽ 123) 64 (52.0%)

5 (13.5%) 0 5 (13.5%) 16 (43.2%) 14 (37.4%) (n ⫽ 36) 22 (61.0%)

0.12 0.87 ⬍0.001 0.008 0.01

16 1 10 63 51

8 1 1 60 51

6 (16.7%) 0 5 (13.9%) 18 (50%) 15 (41.7%)

0.16 0.85 0.004 ⬍0.001 0.03

(8.7%) (0.5%) (5.4%) (34.2%) (27.7%)

cularization was 38.3% versus 24.7% (p ⫽ 0.003); 6-month target vessel revascularization-major adverse cardiac events was 41% versus 26% (p ⫽ 0.001); 12-month target vessel revascularization was 49.1% versus 34.2% (p ⫽ 0.005); and 12-month target vessel revascularization-major adverse cardiac events was 54.1% versus 36.4% (p ⫽ 0.001). There was no difference in death or AMI between the 2 groups at 6 and 12 months. Subgroup analysis according to whether LTO resulted in AMI is shown in Table 3. Target vessel revascularization-major adverse cardiac events, non– Q-wave AMI, target vessel revascularization, and target lesion revascularization were all higher in the LTO ⫹ AMI group or in the LTO/no-AMI than in the recurrent restenosis/no-LTO group. Non–Q-wave AMI was also higher in the LTO ⫹ AMI group than in the LTO/no-AMI group. A logistic regression model demonstrated that LTO ⫹ AMI was the only independent predictor of target vessel revascularization-major adverse cardiac events at 6 months (odds ratio 2.23, 95% confidence interval 1.08 to 4.59). History of AMI, history of coronary artery bypass surgery, lesion length, LTO ⫹ AMI, and LTO without AMI were included in the multivariate model. At 12 months, LTO ⫹ AMI and history of AMI were independent predictors of target vessel revascularizationmajor adverse cardiac events (odds ratio 2.97, 95% confidence interval 1.39 to 6.31). •••

The present study shows that the long-term prognosis after percutaneous coronary intervention for radiation failure is worse for patients with LTO than for patients with recurrence of in-stent restenosis in the absence of LTO. Patients who presented with LTO had a higher incidence of subsequent target lesion revascularization and the combined end point of target vessel revascularization-major adverse cardiac events after 6 and 12 months than patients who presented with recurrence alone. This was especially true of

(6.5%) (0.8%) (0.8%) (48.8%) (41.5%)

p Value 0.001

0.003

patients with LTO who presented with AMI. The outcomes of patients who underwent repeat intervention after in-stent restenosis recurrence in the absence of LTO are consistent with previous reports.10 The only currently available data on patients with LTO are immediate outcomes without further intervention.16 Patients who present with LTO after treatment of in-stent restenosis have a poor long-term prognosis despite successful repeat percutaneous coronary intervention. This emphasizes (1) the importance of preventing LTO after radiation therapy by avoiding repeat stenting during IRT and by administering prolonged antiplatelet therapy and (2) the importance of increased surveillance of high-risk patients for LTO. 1. Teirstein PS, Massullo V, Jani S, Popma JJ, Mintz GS, Russo RJ, Schatz RA,

Guarneri EM, Steuterman S, Morris NB, Leon MB, Tripuraneni P. Catheterbased radiotherapy to inhibit restenosis after coronary stenting. N Engl J Med 1997;336:1697–1703. 2. Waksman R, White RL, Chan RC, Bass BG, Geirlach L, Mintz GS, Satler LF, Mehran R, Serruys PW, Lansky AJ, et al. Intracoronary gamma-radiation therapy after angioplasty inhibits recurrence in patients with in-stent restenosis. Circulation 2000;101:2165–2171. 3. Leon MB, Teirstein PS, Moses JW, Tripuraneni P, Lansky AJ, Jani S, Wong SC, Fish D, Ellis S, Holmes DR, Kerieakes D, Kuntz RE. Localized intracoronary gamma-radiation therapy to inhibit the recurrence of restenosis after stenting. N Engl J Med 2001;344:250 –256. 4. 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. 5. Waksman R, Raizner AE, Yeung AC, Lansky AJ, Vandertie L. Use of localised intracoronary beta radiation in treatment of in-stent restenosis: the INHIBIT randomised controlled trial. Lancet 2002;359:551–557. 6. Waksman R, Lew R, Ajani AE, Pichard AD, Satler LF, Kent KM, Chan R, White RL, Suddath WO, Pinnow E, et al. Repeat intracoronary radiation for recurrent in-stent restenosis in patients who failed intracoronary radiation. Circulation 2003;108:654 – 656. 7. Waksman R, Ajani AE, Pinnow E, Cheneau E, Leborgne L, Dieble R, Bui AB, Satler LF, Pichard AD, Kent KK, Lindsay J. Twelve versus six months of clopidogrel to reduce major cardiac events in patients undergoing gammaradiation therapy for in-stent restenosis: Washington Radiation for In-Stent restenosis Trial (WRIST) 12 versus WRIST PLUS. Circulation 2002;106:776 – 778. 8. Teirstein P, Reilly JP. Late stent thrombosis in brachytherapy: the role of long-term antiplatelet therapy. J Invasive Cardiol 2002;14:109 –114.

BRIEF REPORTS

1553

9. Costa MA, Sabat M, van der Giessen WJ, Kay IP, Cervinka P, Ligthart JM,

13. Danenberg HD, Lotan C, Hasin Y, Gotsman MS, Rozenman Y. Acute

Serrano P, Coen VL, Levendag PC, Serruys PW. Late coronary occlusion after intracoronary brachytherapy. Circulation 1999;100:789 –792. 10. Waksman R, Bhargava B, Mintz GS, Mehran R, Lansky AJ, Satler LF, Pichard AD, Kent KM, Leon MB. Late total occlusion after intracoronary brachytherapy for patients with in-stent restenosis. J Am Coll Cardiol 2000;36: 65– 68. 11. Rozenman Y, Gilon D, Welber S, Sapoznikov D, Wexler D, Lotan C, Mosseri M, Weiss AT, Hasin Y, Gotsman MS. Total coronary artery occlusion late after successful coronary angioplasty of moderately severe lesions: incidence and clinical manifestations. Cardiology 1994;85:222–228. 12. Farb A, Burke AP, Kolodgie FD, Virmani R. Pathological mechanisms of fatal late coronary stent thrombosis in humans. Circulation 2003;108:1701–1706.

myocardial infarction—a late complication of intracoronary stent placement. Clin Cardiol 2000;23:376 –378. 14. Heller LI, Shemwell KC, Hug K. Late stent thrombosis in the absence of prior intracoronary brachytherapy. Catheter Cardiovasc Interventions 2001;53:23–28. 15. Cha DH, Malik IA, Cheneau E, Ajani AE, Leborgne L, Wolfram R, Porrazzo M, Satler LF, Kent KM, Pichard AD, et al. Use of restenting should be minimized with intracoronary radiation therapy for in-stent restenosis. Catheter Cardiovasc Interventions 2003;59:1–5. 16. Waksman R, Lew R, Ajani AE, Pichard AD, Satler LF, Kent KM, Chan R, White RL, Suddath WO, Pinnow E, et al. Repeat intracoronary radiation for recurrent in-stent restenosis in patients who failed intracoronary radiation. Circulation 2003;108:654 – 656.

Association Between Metabolic Syndrome and Subclinical Coronary Atherosclerosis in Asymptomatic Adults Iftikhar J. Kullo, MD, Andrea E. Cassidy, MPH, Patricia A. Peyser, PhD, Stephen T. Turner, MD, Patrick F. Sheedy II, MD, and Lawrence F. Bielak, DDS, Metabolic syndrome was associated with the presence and quantity of coronary artery calcium, a marker of subclinical coronary atherosclerosis, in 1,129 asymptomatic adults, ages 20 to 79 years, from a community-based study. The association was independent of 10-year risk of coronary heart disease based on the Framingham risk score. 䊚2004 by Excerpta Medica Inc. (Am J Cardiol 2004;94:1554 –1558)

he complex inter-relations among components of the metabolic syndrome and 10-year risk for corT onary heart disease (CHD) based on the Framingham risk score and their relations to noninvasive measures of subclinical coronary atherosclerosis are not well established. Although several studies1–3 have demonstrated an association of the metabolic syndrome with coronary artery calcium (CAC), none of studies used the strict definition of the metabolic syndrome of the Adult Treatment Panel III (ATP III) of the National Cholesterol Education Panel,4 or the study cohorts were comprised of physician- or self-referred subjects. The goal of the present investigation was to determine whether the metabolic syndrome was independently associated with the presence and quantity of CAC in asymptomatic subjects from a community after conFrom the Division of Cardiovascular Disease, Division of Hypertension, Department of Internal Medicine; and Department of Diagnostic Radiology, Mayo Clinic and Foundation, Rochester, Minnesota; and Department of Epidemiology, University of Michigan, Ann Arbor, Michigan. This study was supported by grants R01 HL46292 and M01 RR00585 from the National Institutes of Health, Bethesda, Maryland; grant T32 HG00040 from the National Human Genome Research Institute; and a Mentored Patient-Oriented Research Award to Dr. Kullo (K23 RR17720-01) from the National Institutes of Health, National Center of Research Resources. Dr. Bielak’s address is: University of Michigan, Department of Epidemiology, 611 Church Street, Ann Arbor, Michigan 48104-3028. E-mail: [email protected]. Manuscript received May 11, 2004; revised manuscript received and accepted August 6, 2004.

1554

©2004 by Excerpta Medica Inc. All rights reserved. The American Journal of Cardiology Vol. 94 December 15, 2004

MPH

sidering (1) conventional CHD risk factors and (2) the estimated 10-year risk for a CHD event. •••

The Epidemiology of Coronary Artery Calcification Study is an ongoing community-based study of the etiology of CAC in Rochester, Minnesota.5,6 Subjects were recruited from the community-based Rochester Family Heart Study, were not self or physician referred, and did not have previous bypass surgery, angioplasty, or other coronary surgery.7,8 Between December 1990 and May 1998, 1,240 subjects were examined for CAC with electron beam computed tomography. We excluded 8 subjects who were ⱖ80 years of age, 23 who had a history of stroke or myocardial infarction, 5 who were nonwhite, 19 who had diabetes mellitus, 37 who had missing data (including 17 who had missing fasting glucose values), and 19 who had outliers for risk factor data. The final study group consisted of 1,129 asymptomatic white subjects (548 men and 581 women). Subjects belonged to 843 sibships (668 singletons, 105 sibships of size 2, 45 sibships of size 3, 3 sibships of size 4, 2 sibships of size 5, and 3 sibships of size 6). Study protocols were approved by the institutional review boards of the Mayo Clinic and the University of Michigan, and subjects gave written informed consent. During an interview, subjects reported current medication use, history of smoking, physician-diagnosed hypertension, myocardial infarction, stroke, or diabetes. Systolic and diastolic blood pressures at rest were measured in the right arm with a random-zero sphygmomanometer (Hawksley and Sons, London, United Kingdom). Three measurements ⱖ2 minutes apart were taken, and the average of the second and third measurements was used. Waist circumference was measured between the lowest rib and the iliac crest. Blood samples were obtained after an overnight fast. Standard enzymatic methods were used to measure plasma glucose, total cholesterol, high-density lipoprotein cholesterol, and triglycerides. Low-density lipoprotein cholesterol was calculated with Friede0002-9149/04/$–see front matter doi:10.1016/j.amjcard.2004.08.038