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Six-month outcome after excimer laser coronary angioplasty for diffuse in-stent restenosis in native coronary arteries
Six-Month Outcome After Excimer Laser Coronary Angioplasty for Diffuse In-Stent Restenosis in Native Coronary Arteries Jaap N. Hamburger, MD, PhD, David P. Foley, MB, MRCPI, PhD, Pim J. de Feyter, Alexander J. Wardeh, MD, and Patrick W. Serruys, MD, PhD
MD, PhD,
This study evaluated the intermediate-term follow-up after excimer laser coronary angioplasty (ELCA) and adjunctive percutaneous transluminal coronary angioplasty (PTCA) in patients with diffuse in-stent restenosis (lesion length >10 mm). Clinical and angiographic follow-up were performed at 6 months. Quantitative coronary angiography performed at 3 stages— during stent implantation, before and after ELCA ⴙ PTCA, and at follow-up—included measurements of the minimum lumen diameter (MLD) and percent diameter stenosis (DS). Sixteen consecutive patients were included. The (median ⴙ range) stent length was 36 mm (range 15 to 105), with a restenotic lesion length of 32 mm (range 10 to 90). After ELCA ⴙ PTCA, the MLD increased from 0.60 ⴞ 0.41 to 2.28 ⴞ 0.50 mm, whereas the DS decreased from 76 ⴞ 16% to 22 ⴞ 8%. Despite adjunc-
tive high-pressure PTCA, the MLD after ELCA ⴙ PTCA remained smaller than the MLD after initial stent implantation, (2.28 ⴞ 0.50 mm vs 2.67 ⴞ 0.32 mm, p ⴝ 0.014). Adverse events included ELCA-related acute coronary occlusion in 4 patients and a per-procedural intracerebral hematoma in 1. At 6 months, there was recurrence of angina in all patients. Angiographic follow-up was completed in 13 patients (87%), showing a reocclusion in 6 (46%), a >50% DS in 6 (MLD 1.03 ⴞ 0.87 mm, DS 68 ⴞ 24%), and a distal de novo lesion in 1. Despite satisfactory acute angiographic results, the recurrence of significant restenosis in all patients suggests that ELCA ⴙ PTCA is not a suitable stand-alone therapy for diffuse in-stent restenosis of long stented segments. 䊚2000 by Excerpta Medica, Inc. (Am J Cardiol 2000;86:390 –394)
mproved techniques for stent deployment and the introduction of many new stent designs have made Iintracoronary stenting a procedure with a relatively
bearing on the late outcome after repeat percutaneous treatment, it has been suggested that in-stent restenosis should be subclassified as focal (⬍10 mm), marginal (on the proximal and/or distal rim of the stent), or diffuse restenosis (⬎10 mm in-stent lesion, or stent reocclusion).4,5,10,11 Thus far, no experience has been reported on catheter-based treatment of patients with in-stent restenosis in long stented segments. Therefore, this study evaluates the place of ELCA in the treatment of this patient subset.
1
predictable, high procedural success rate. As a consequence of the increasing rates of coronary stenting in the past 5 years (including in patients with lesions potentially less favorable for stenting), a new iatrogenic disease “in-stent restenosis” has been generated. Initial studies on the intermediate-term results of balloon angioplasty as a treatment for in-stent restenosis have reported recurrence rates ranging from 20% to as high as 83%.2– 4 It has been shown that in-stent restenosis is primarily based on intimal hyperplasia rather than stent recoil.5,6 Also, it has been demonstrated that extruded restenotic material recoiled toward the lumen within minutes after balloon dilatation.7 Therefore, atheroablation of neointima rather than mere repeat dilatation seems a reasonable therapeutic approach. Excimer laser coronary angioplasty (ELCA), given its capacity to ablate soft coronary plaque, is potentially an adequate technique to treat in-stent restenosis.8 –11 Because the type of restenosis appears to have a From the Department of Interventional Cardiology, Thoraxcenter, University Hospital Rotterdam, Rotterdam, The Netherlands. Manuscript received April 16, 1999; revised manuscript received and accepted March 6, 2000 Address for reprints: Jaap N. Hamburger, MD, PhD, Department of Interventional Cardiology, Room Bd 408, Thoraxcenter, University Hospital Rotterdam, PO Box 1738, 3000 DR Rotterdam, The Netherlands.
390
©2000 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 86 August 15, 2000
METHODS
Patient and lesion groups: Between November 1995 and November 1997, 16 consecutive patients (10 men, aged 59 ⫾ 13 years) with diffuse in-stent restenosis (stented lesion length ⬎10 mm) after initial stent implantation were treated with ELCA and adjunctive percutaneous transluminal coronary angioplasty (ELCA ⫹ PTCA). The indications for initial stent placement were a suboptimal balloon result (n ⫽ 7), recanalization of a chronic total occlusion (n ⫽ 4), and elective (n ⫽ 4) or acute myocardial infarction (n ⫽ 1). Vessels treated were the right coronary artery (n ⫽ 8), left anterior descending artery (n ⫽ 7), and left circumflex artery (n ⫽ 1). Seven patients had been treated with a single stent, 9 patients with multiple stents. The stents used and their specific lengths are listed in Table I. Risk factors for coronary artery disease included diabetes in 3 patients (19%), a positive family history in 14 (88%), hypercholesterolemia (defined as a total cholesterol of ⬎5.0 mmol/L) in 9 0002-9149/00/$–see front matter PII S0002-9149(00)00952-8
TABLE I Stents Used
Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Stent Type NIR NIR NIR NIR beStent Wallstent Palmaz-Schatz Microstent II Wallstent Palmaz-Schatz NIR NIR Wallstent Palmaz-Schatz Multilink Palmaz-Schatz Wallstent NIR Wallstent
Stent Length (mm) 2 3 2 2 1 1 1 1 1 1 2 1 1 1 1 1 1 3 1
⫻ ⫻ ⫻ ⫻ ⫻ ⫻ ⫻ ⫻ ⫻ ⫻ ⫻ ⫻ ⫻ ⫻ ⫻ ⫻ ⫻ ⫻ ⫻
32, 32 32 16 35 35 20 18 22 15 32, 32, 32 20 15 15 20 16, 35
2 ⫻ 16, 1 ⫻ 9
2 ⫻ 16 1 ⫻ 16
1⫻9
†
Manufacturer Medinol Medinol Medinol Medinol Medtronic Schneider JJIS AVE Schneider JJIS Medinol Medinol Schneider JJIS ACS JJIS Schneider Medinol Schneider
Serum Creatinine*
Coronary Artery
CK
CK-MB
Right Right Right Right Right Right Right
64 105 249 117 ⫺ 397 36
16 12 20 9 28 8
Right
221
25
LAD LAD LAD LAD LAD LAD LAD
99 182 889 82 69 164 ⫺
17 28 ⫺ 13 9 18
LCx
219
22
*After coronary intervention. Normal upper values: CK 110 U/L, CK-MB 14 U/L. † Medinol, Jerusalem, Israel; Medtronic, Minneapolis, Minnesota; Schneider, Maple Grove, Minnesota; JJIS, Warren, New Jersey; AVE, Santa Rosa, California; ACS, Temecula, California. CK ⫽ creatinine; LAD ⫽ left anterior descending artery; LCx ⫽ left circumflex artery.
(56%), systemic hypertension in 7 (44%), and cigarette smoking in 4 (25%). The initial stent implantation was performed in a standard procedure, using high-pressure postdilatation (ⱖ14 atm) and a balloonartery ratio of 1.1 ⫾ 0.10 as determined by on-line quantitative coronary angiography (QCA). Procedures were performed with the patients taking intravenous heparin and aspirin, and all patients were treated afterward with ticlopidine 250 mg twice daily for 4 weeks. ELCA ⴙ PTCA protocol: A repeat angioplasty was performed in case of recurrence of angina and/or objective signs of ischemia in patients with a ⬎50% diameter stenosis (DS) on diagnostic angiography. Patients were treated with ELCA only if the in-stent stenosed segment had a minimum length of 10 mm as assessed by on-line QCA. The laser was a CVX 300 xenon-chloride excimer laser (Spectranetics, Colorado Springs, Colorado). The fluence used ranged from 45 to 60 mJ/mm2 (mean 51 ⫾ 7), with a pulse repetition rate of 25 to 40 Hz (mean 29 ⫾ 7). To ensure maximum debulking, we consequently used the largest diameter catheter available. At the onset of this study, this would be the 1.7-mm concentric catheter (n ⫽ 2). However, during the study, the 2-mm concentric (n ⫽ 8), and the 1.7-mm (n ⫽ 2) and 2-mm (n ⫽ 4) eccentric laser catheters became available. During activation of the laser, the laser catheter was moved forward at a speed of approximately 0.5 mm/s. To optimize the procedure, a saline flush was used as described elsewhere.12 The median number of pulses applied was 2,625 (range 725 to 16,000) in 3.7 ⫾ 2.7 passes. High-pressure postdilatation was performed in all cases (maximum balloon pressure of 15 ⫾ 3 atm) to achieve an optimal acute result (⬍20% DS). The nominal balloon diameter size ranged from 2.5 to 4.5
mm (mean 3.4 ⫾ 0.4, balloon-artery ratio 1.3 ⫾ 0.2), with a balloon length of 29 ⫾ 10 mm. Procedural success was defined as an average DS of ⬍50% in 2 orthogonal views by on-line QCA. Clinical success was defined as procedural success without death, Qwave myocardial infarction, coronary bypass surgery, or repeat angioplasty during the index hospital stay. A non–Q-wave myocardial infarction was defined as a postprocedure maximum serum creatinine of ⬎200 U/L in the absence of new Q-wave formation on the electrocardiogram. QCA analysis: Serial off-line QCA measurements were obtained at the initial stent implantation, before and after treatment of in-stent restenosis, and at intermediate-term follow-up, using an automated edgedetection algorithm (CAAS II system, PIE Medical, Maastricht, The Netherlands). The non– contrast-filled guiding catheter was used as the calibration standard.13 The reference diameter, minimal lumen diameter (MLD), and percent DS were calculated in multiple views and are given as the resultant average (Table II). The lesion length was measured in the view with the least amount of foreshortening. Patient follow-up: All patients had a 30-day and 6-month clinical follow-up. Angiographic follow-up was scheduled at 6 months after ELCA, or performed earlier if clinically indicated. Statistical analysis: Categorical data were presented as frequencies. Continuous data were presented as mean ⫾ SD, or in case of a non-normal distribution of values as median with range. Comparisons of continuous variables were performed using unpaired t tests. A p value ⱕ0.05 was considered statistically significant. Written informed consent was obtained from all patients.
CORONARY ARTERY DISEASE/FOLLOW–UP OF ELCA FOR STENT RESTENOSIS
391
TABLE II Serial Quantitative Coronary Angiographic Measurements
I
Initial procedure (n ⫽ 16) After stent deployment Reference diameter Minimal lumen diameter Percent diameter stenosis
3.26 ⫾ 0.37 2.67 ⫾ 0.32 15 ⫾ 6
II
First follow-up (n ⫽ 16) Before ELCA Reference diameter Minimal lumen diameter Percent diameter stenosis Absolute loss Relative loss
2.71 0.60 76 2.06 0.78
⫾ ⫾ ⫾ ⫾ ⫾
0.44 0.41 16 0.59 0.27
III
After ELCA ⫹ PTCA (n ⫽ 16) Reference diameter Minimal lumen diameter Percent diameter stenosis Absolute gain Relative gain
2.97 2.28 22 1.68 0.57
⫾ ⫾ ⫾ ⫾ ⫾
0.45 0.50 8 0.67 0.21
IV
Second follow-up (n ⫽ 13) Reference diameter Minimal lumen diameter Percent diameter stenosis Absolute loss Relative loss Loss index
2.94 0.63 80 1.68 0.56 0.99
⫾ ⫾ ⫾ ⫾ ⫾ ⫾
0.43 0.84 25 0.94 0.35 0.61
RESULTS
Procedural results: ELCA ⫹ PTCA was performed in 16 patients with diffuse in-stent restenosis 6.6 ⫾ 3 months after the initial stent implantation. The median stent length was 36 mm (range 15 to 105), with a restenotic lesion length of 32 mm (range 10 to 90). Due to in-stent restenosis, the MLD had decreased from 2.67 ⫾ 0.32 mm (after stenting) to 0.60 ⫾ 0.41 mm (absolute loss 2.06 ⫾ 0.59 mm, p ⬍0.0001). In 4 patients the stent was totally occluded. After ELCA ⫹ PTCA the MLD increased to 2.28 ⫾ 0.50 mm (absolute gain 1.68 ⫾ 0.67 mm, p ⬍0.0001), whereas the DS was reduced from 76 ⫾ 16% to 22 ⫾ 8%. Despite this improvement, the MLD after ELCA ⫹ PTCA remained significantly smaller than the original MLD after stenting (2.28 ⫾ 0.50 vs 2.67 ⫾ 0.32, p ⬍0.011; Figure 1). Procedural complications: In 4 cases (25%), the ELCA procedure was complicated by intracoronary thrombus formation. After intravenous administration of abciximab and additional stenting, normal flow was restored. Because this involved left main stenting in 1 patient, this patient was referred for elective coronary artery bypass surgery during the same hospital stay. Adjunctive high-pressure balloon dilatation caused edge dissections in 2 patients, necessitating additional stent implantation. In 2 patients, the ELCA procedure was complicated by side branch occlusion, which resulted in a non–Q-wave myocardial infarction in 1. Postprocedural serum creatinine values were elevated in 7 patients (Table I). Finally, in 1 patient, the ELCA catheter did not cross the lesion, owing to an initial underdeployment of the stent (“pseudo in-stent restenosis”). This could be confirmed with intravascular ultrasound, after which the stent was redilated (Figure 392 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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2). Unfortunately, after the procedure, this 68-year-old female patient developed an intracerebral bleeding possibly related to the combined use of heparin, aspirin, and abciximab. Despite adequate neurosurgical drainage, her condition deteriorated and she died postoperatively from pulmonary complications. As a result, procedural success was achieved in all cases but clinical success in only 14 patients (88%). Clinical and angiographic follow-up: After an interval of 7.8 ⫾ 4 months, clinical follow-up was completed in all 15 remaining patients. All patients had a recurrence of angina (Canadian Cardiac Society classification): class II in 6, class III in 6, and class IV in 3 patients. Two symptomatic patients refused a repeat coronary angiography. Therefore, repeat coronary angiography was performed in 13 patients (87%). Of these, 6 segments were totally occluded, whereas an additional 6 segments showed a significant recurrence of in-stent restenosis (MLD 0.63 ⫾ 0.84 mm, absolute loss 1.68 ⫾ 0.94, loss index 0.99). In patients with stent reocclusion, the initial indication for stent implantation had been recanalization of a chronic total occlusion in 2, and optimization of a suboptimal balloon angioplasty result in 4. The recurrence of angina in the patient electively referred to coronary artery bypass surgery was explained by a combination of reocclusion in the ELCA-treated segment and a de novo stenosis at the site of the anastomosis of the left internal mammary artery with the left anterior descending artery. In 1 patient, a de novo lesion just distal to the segment previously treated with ELCA was held responsible for the recurrence of ischemia and subsequently treated with additional stenting.
DISCUSSION In-stent restenosis is typically the result of neointima formation within a stent.5,6 The mechanism of lumen enlargement after PTCA is probably a combination of tissue extrusion out of the stent and additional stent expansion.14 Given the possibility of tissue recoil into the stent after initial dilatation,7 a combined use of an atheroablative technique and balloon angioplasty appears to be a more logic approach. Recently, it became apparent that the extent of in-stent restenosis (diffuse or stent occlusion as opposed to focal intima hyperplasia) had a direct bearing on the recurrence rate, regardless of the type of ablative technology used.4 The patients reported in this study had a median stented segment length of 36 mm (range 15 to 105) with a lesion length of 32 mm (range 10 to 90). This patient cohort could very well represent a “worst case scenario”: despite aggressive laser debulking and high-pressure postdilatation with relatively oversized balloons, no more than 85% of the original MLD after stenting could be regained. Moreover, the number of procedural complications and the high percentage of target vessel failure at 6-month follow-up (46% reocclusion, 46% repeat restenosis, and 8% de novo distal disease) suggests that ELCA ⫹ PTCA—at least using the current methods—is not a suitable treatment for diffuse in-stent restenosis. The use of multiple and long stents has seriously broadened the scope of perAUGUST 15, 2000
FIGURE 1. Serial quantitative MLD measurements. I ⴝ post stent implantation; II ⴝ before ELCA; III ⴝ after ELCA ⴙ PTCA, IV ⴝ 6-month angiographic follow-up after ELCA ⴙ PTCA. Values are given as mean ⴞ SD.
nosis, the initial use of long stents, especially in the left anterior descending artery, should be reconsidered. An alternative concept of “spot-stenting” has been suggested within this context.16 Intracoronary brachytherapy with gamma irradiation has been shown to be potentially beneficial in the treatment of in-stent restenosis in a small patient cohort.17 Whether this finding will prove to be true for  irradiation in longer stents and in longer lesions remains to be seen. To preserve the acute improvement achieved with debulking, brachytherapy could be usefully combined with ELCA as a potential treatment for diffuse in-stent restenosis. The combination of aggressive laser debulking followed by  irradiation and balloon dilatation is currently under investigation in our department. Meanwhile, for patients with particularly diffuse in-stent restenosis, coronary artery bypass surgery must be considered as an alternative to the “intraluminal mechanistic approach.”18 The limitations of this study are (1) evolving catheter technology during the study: catheter diameters ranged from 1.7-mm concentric to 2-mm eccentric. Therefore, the ablation therapy efficacy might not have been uniform throughout the study. (2) The number of patients in this single-center study was limited. 1. Colombo A, Hall P, Nakamura S, Almagor Y, Maiello L, Martini G, Gaglione
FIGURE 2. Intravascular ultrasound image of “pseudo in-stent restenosis” due to stent collapse. A, in the stent, proximal to the stenosis; B, in the stent, at the site of the stenosis.
cutaneous revascularization, as a result of which multivessel disease is no longer the exclusive domain of the cardiac surgeon.15 However, if proved to be associated with an increased risk of diffuse in-stent reste-
A, Goldberg SL., Tobis JM. Intracoronary stenting without anticoagulation accomplished with intravascular ultrasound guidance. Circulation 1995;91:1676 –1688. 2. Reimers B, Moussa I, Akiyama T, Tucci G, Ferraro M, Martini G, Blengino S, Di Mario C, Colombo A. Long-term clinical follow-up after successful repeat percutaneous intervention for stent restenosis. J Am Coll Cardiol 1997;30:186 – 192. 3. Bauters Ch, Banos JL, van Belle E, McFadden EP, Lablanche JM, Bertrand ME. Six-month angiographic outcome after successful repeat percutaneous intervention for in-stent restenosis. Circulation 1998;97:318 –321. 4. Mehran R, Dangas G, Abizaid AS, Mintz GS, Lansky AJ, Satler LF, Pichard AD, Kent KM, Stone GW, Leon MB. Angiographic patterns of in-stent restenosis –Classifications and implications for long-term outcome. Circulation 1999;100: 1872–1878. 5. Hoffmann R, Mintz G, Dussaillant GR, Popma JJ, Pichard AD, Satler LF, Kent
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KM, Grifin J, Leon MB. Patterns and mechanisms of in-stent restenosis: a serial intravascular ultrasound study. Circulation 1996;94:1247–1254. 6. Mudra H, Regar E, Klauss V, Werner F, Henneke K-H, Sbarouni E, Theised K. Serial follow-up after optimized ultrasound-guided deployment of PalmazSchatz stents. In-stent neointimal proliferation without significant reference segment response. Circulation 1997;95:363–370. 7. Shiran A, Mintz GS, Waksman R, Mehran R, Abizaid A, Kent KM, Pichard AD, Satler LF, Popma JJ, Leon MB. Early lumen loss after treatment of in-stent restenosis. An intravascular ultrasound study. Circulation 1998;98:200 –203. 8. Hamburger JN, Verhoofstad GGAM, van Marle J, van den Broecke D, Hanekamp CEE, Serruys PW, van Gemert MJC. Excimer laser coronary angioplasty: A physical perspective to clinical results. In: Topol E, Serruys PW, eds. Current Review of Interventional Cardiology. 2nd ed. Philadelphia: Current Medicine, 1995:159 –172. 9. Appelman YEA, Piek JJ, de Feyter PJ, Tijssen JGP, Strikwerda S, David GK, Serruys PW, Margolis JR, Koelemay MJ, van Swijndregt E, Koolen JJ. Excimer laser coronary angioplasty versus balloon angioplasty in the treatment of obstructive coronary artery disease: a randomized clinical trial. Lancet 1996;347:79 – 84. 10. Mehran R, Mintz GS, Satler LF, Pichard AD, Kent KM, Bucher TA, Popma JJ, Leon MB. Treatment of in-stent restenosis with excimer laser coronary angioplasty. mechanisms and results compared with PTCA alone. Circulation 1997;96:2183–2189. 11. Mintz G, Hoffmann R, Mehran R, Pichard AD, Kent KM, Satler LF, Popma JJ, Leon MB. In-stent restenosis: The Washington Hospital Center Experience. Am J Cardiol 1998;81(7A):7E–13E.
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12. Deckelbaum LI, Strauss BH, Bittl JA, Rohlfs K, Scott J. Effect of intracoronary saline infusion on dissection during excimer laser coronary angioplasty: a randomized trial. J Am Coll Cardiol 1995;26:1264 –1269. 13. Di Mario C, Haase J, den Boer A, Reiber JH, Serruys PW. Edge detection versus video densitometry in the quantitative assessment of stenosis phantoms: an in vivo comparison in porcine coronary arteries. Am Heart J 1992;124:1181– 1189. 14. Mehran R, Mintz GS, Popma JJ, Pichard AD, Satler LF, Kent KM, Griffin J, Leon MB. Mechanisms and results of balloon angioplasty for the treatment of in-stent restenosis. Am J Cardiol 1996;78:618 – 622. 15. Moussa I, Reimers B, Moses J, Di Mario C, Di Francesco L, Ferraro M, Colombo A. Long-term angiographic and clinical outcome of patients undergoing multivessel coronary stenting. Circulation 1997;96:3873–3879. 16. Moussa I, De Gregorio J, Di Mario C, Colombo A. The use of intravascular ultrasound and spot stenting for the treatment of long lesions and small vessels. J Invasive Cardiol 1999;11:47–54. 17. Teirstein PS, Massulo 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 stenosis after coronary stenting. N Engl J Med 1997;336:1697–1703. 18. Bergsma TM, Grandjean JG, Voors AA, Boonstra PW, den Heyer P, Ebels T. Low recurrence of angina pectoris after coronary artery bypass graft surgerywith bilateral internal thoracic and right gastroepiploic arteries. Circulation 1998;97:2402–2405.
AUGUST 15, 2000
MD, PhD,
This study evaluated the intermediate-term follow-up after excimer laser coronary angioplasty (ELCA) and adjunctive percutaneous transluminal coronary angioplasty (PTCA) in patients with diffuse in-stent restenosis (lesion length >10 mm). Clinical and angiographic follow-up were performed at 6 months. Quantitative coronary angiography performed at 3 stages— during stent implantation, before and after ELCA ⴙ PTCA, and at follow-up—included measurements of the minimum lumen diameter (MLD) and percent diameter stenosis (DS). Sixteen consecutive patients were included. The (median ⴙ range) stent length was 36 mm (range 15 to 105), with a restenotic lesion length of 32 mm (range 10 to 90). After ELCA ⴙ PTCA, the MLD increased from 0.60 ⴞ 0.41 to 2.28 ⴞ 0.50 mm, whereas the DS decreased from 76 ⴞ 16% to 22 ⴞ 8%. Despite adjunc-
tive high-pressure PTCA, the MLD after ELCA ⴙ PTCA remained smaller than the MLD after initial stent implantation, (2.28 ⴞ 0.50 mm vs 2.67 ⴞ 0.32 mm, p ⴝ 0.014). Adverse events included ELCA-related acute coronary occlusion in 4 patients and a per-procedural intracerebral hematoma in 1. At 6 months, there was recurrence of angina in all patients. Angiographic follow-up was completed in 13 patients (87%), showing a reocclusion in 6 (46%), a >50% DS in 6 (MLD 1.03 ⴞ 0.87 mm, DS 68 ⴞ 24%), and a distal de novo lesion in 1. Despite satisfactory acute angiographic results, the recurrence of significant restenosis in all patients suggests that ELCA ⴙ PTCA is not a suitable stand-alone therapy for diffuse in-stent restenosis of long stented segments. 䊚2000 by Excerpta Medica, Inc. (Am J Cardiol 2000;86:390 –394)
mproved techniques for stent deployment and the introduction of many new stent designs have made Iintracoronary stenting a procedure with a relatively
bearing on the late outcome after repeat percutaneous treatment, it has been suggested that in-stent restenosis should be subclassified as focal (⬍10 mm), marginal (on the proximal and/or distal rim of the stent), or diffuse restenosis (⬎10 mm in-stent lesion, or stent reocclusion).4,5,10,11 Thus far, no experience has been reported on catheter-based treatment of patients with in-stent restenosis in long stented segments. Therefore, this study evaluates the place of ELCA in the treatment of this patient subset.
1
predictable, high procedural success rate. As a consequence of the increasing rates of coronary stenting in the past 5 years (including in patients with lesions potentially less favorable for stenting), a new iatrogenic disease “in-stent restenosis” has been generated. Initial studies on the intermediate-term results of balloon angioplasty as a treatment for in-stent restenosis have reported recurrence rates ranging from 20% to as high as 83%.2– 4 It has been shown that in-stent restenosis is primarily based on intimal hyperplasia rather than stent recoil.5,6 Also, it has been demonstrated that extruded restenotic material recoiled toward the lumen within minutes after balloon dilatation.7 Therefore, atheroablation of neointima rather than mere repeat dilatation seems a reasonable therapeutic approach. Excimer laser coronary angioplasty (ELCA), given its capacity to ablate soft coronary plaque, is potentially an adequate technique to treat in-stent restenosis.8 –11 Because the type of restenosis appears to have a From the Department of Interventional Cardiology, Thoraxcenter, University Hospital Rotterdam, Rotterdam, The Netherlands. Manuscript received April 16, 1999; revised manuscript received and accepted March 6, 2000 Address for reprints: Jaap N. Hamburger, MD, PhD, Department of Interventional Cardiology, Room Bd 408, Thoraxcenter, University Hospital Rotterdam, PO Box 1738, 3000 DR Rotterdam, The Netherlands.
390
©2000 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 86 August 15, 2000
METHODS
Patient and lesion groups: Between November 1995 and November 1997, 16 consecutive patients (10 men, aged 59 ⫾ 13 years) with diffuse in-stent restenosis (stented lesion length ⬎10 mm) after initial stent implantation were treated with ELCA and adjunctive percutaneous transluminal coronary angioplasty (ELCA ⫹ PTCA). The indications for initial stent placement were a suboptimal balloon result (n ⫽ 7), recanalization of a chronic total occlusion (n ⫽ 4), and elective (n ⫽ 4) or acute myocardial infarction (n ⫽ 1). Vessels treated were the right coronary artery (n ⫽ 8), left anterior descending artery (n ⫽ 7), and left circumflex artery (n ⫽ 1). Seven patients had been treated with a single stent, 9 patients with multiple stents. The stents used and their specific lengths are listed in Table I. Risk factors for coronary artery disease included diabetes in 3 patients (19%), a positive family history in 14 (88%), hypercholesterolemia (defined as a total cholesterol of ⬎5.0 mmol/L) in 9 0002-9149/00/$–see front matter PII S0002-9149(00)00952-8
TABLE I Stents Used
Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Stent Type NIR NIR NIR NIR beStent Wallstent Palmaz-Schatz Microstent II Wallstent Palmaz-Schatz NIR NIR Wallstent Palmaz-Schatz Multilink Palmaz-Schatz Wallstent NIR Wallstent
Stent Length (mm) 2 3 2 2 1 1 1 1 1 1 2 1 1 1 1 1 1 3 1
⫻ ⫻ ⫻ ⫻ ⫻ ⫻ ⫻ ⫻ ⫻ ⫻ ⫻ ⫻ ⫻ ⫻ ⫻ ⫻ ⫻ ⫻ ⫻
32, 32 32 16 35 35 20 18 22 15 32, 32, 32 20 15 15 20 16, 35
2 ⫻ 16, 1 ⫻ 9
2 ⫻ 16 1 ⫻ 16
1⫻9
†
Manufacturer Medinol Medinol Medinol Medinol Medtronic Schneider JJIS AVE Schneider JJIS Medinol Medinol Schneider JJIS ACS JJIS Schneider Medinol Schneider
Serum Creatinine*
Coronary Artery
CK
CK-MB
Right Right Right Right Right Right Right
64 105 249 117 ⫺ 397 36
16 12 20 9 28 8
Right
221
25
LAD LAD LAD LAD LAD LAD LAD
99 182 889 82 69 164 ⫺
17 28 ⫺ 13 9 18
LCx
219
22
*After coronary intervention. Normal upper values: CK 110 U/L, CK-MB 14 U/L. † Medinol, Jerusalem, Israel; Medtronic, Minneapolis, Minnesota; Schneider, Maple Grove, Minnesota; JJIS, Warren, New Jersey; AVE, Santa Rosa, California; ACS, Temecula, California. CK ⫽ creatinine; LAD ⫽ left anterior descending artery; LCx ⫽ left circumflex artery.
(56%), systemic hypertension in 7 (44%), and cigarette smoking in 4 (25%). The initial stent implantation was performed in a standard procedure, using high-pressure postdilatation (ⱖ14 atm) and a balloonartery ratio of 1.1 ⫾ 0.10 as determined by on-line quantitative coronary angiography (QCA). Procedures were performed with the patients taking intravenous heparin and aspirin, and all patients were treated afterward with ticlopidine 250 mg twice daily for 4 weeks. ELCA ⴙ PTCA protocol: A repeat angioplasty was performed in case of recurrence of angina and/or objective signs of ischemia in patients with a ⬎50% diameter stenosis (DS) on diagnostic angiography. Patients were treated with ELCA only if the in-stent stenosed segment had a minimum length of 10 mm as assessed by on-line QCA. The laser was a CVX 300 xenon-chloride excimer laser (Spectranetics, Colorado Springs, Colorado). The fluence used ranged from 45 to 60 mJ/mm2 (mean 51 ⫾ 7), with a pulse repetition rate of 25 to 40 Hz (mean 29 ⫾ 7). To ensure maximum debulking, we consequently used the largest diameter catheter available. At the onset of this study, this would be the 1.7-mm concentric catheter (n ⫽ 2). However, during the study, the 2-mm concentric (n ⫽ 8), and the 1.7-mm (n ⫽ 2) and 2-mm (n ⫽ 4) eccentric laser catheters became available. During activation of the laser, the laser catheter was moved forward at a speed of approximately 0.5 mm/s. To optimize the procedure, a saline flush was used as described elsewhere.12 The median number of pulses applied was 2,625 (range 725 to 16,000) in 3.7 ⫾ 2.7 passes. High-pressure postdilatation was performed in all cases (maximum balloon pressure of 15 ⫾ 3 atm) to achieve an optimal acute result (⬍20% DS). The nominal balloon diameter size ranged from 2.5 to 4.5
mm (mean 3.4 ⫾ 0.4, balloon-artery ratio 1.3 ⫾ 0.2), with a balloon length of 29 ⫾ 10 mm. Procedural success was defined as an average DS of ⬍50% in 2 orthogonal views by on-line QCA. Clinical success was defined as procedural success without death, Qwave myocardial infarction, coronary bypass surgery, or repeat angioplasty during the index hospital stay. A non–Q-wave myocardial infarction was defined as a postprocedure maximum serum creatinine of ⬎200 U/L in the absence of new Q-wave formation on the electrocardiogram. QCA analysis: Serial off-line QCA measurements were obtained at the initial stent implantation, before and after treatment of in-stent restenosis, and at intermediate-term follow-up, using an automated edgedetection algorithm (CAAS II system, PIE Medical, Maastricht, The Netherlands). The non– contrast-filled guiding catheter was used as the calibration standard.13 The reference diameter, minimal lumen diameter (MLD), and percent DS were calculated in multiple views and are given as the resultant average (Table II). The lesion length was measured in the view with the least amount of foreshortening. Patient follow-up: All patients had a 30-day and 6-month clinical follow-up. Angiographic follow-up was scheduled at 6 months after ELCA, or performed earlier if clinically indicated. Statistical analysis: Categorical data were presented as frequencies. Continuous data were presented as mean ⫾ SD, or in case of a non-normal distribution of values as median with range. Comparisons of continuous variables were performed using unpaired t tests. A p value ⱕ0.05 was considered statistically significant. Written informed consent was obtained from all patients.
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TABLE II Serial Quantitative Coronary Angiographic Measurements
I
Initial procedure (n ⫽ 16) After stent deployment Reference diameter Minimal lumen diameter Percent diameter stenosis
3.26 ⫾ 0.37 2.67 ⫾ 0.32 15 ⫾ 6
II
First follow-up (n ⫽ 16) Before ELCA Reference diameter Minimal lumen diameter Percent diameter stenosis Absolute loss Relative loss
2.71 0.60 76 2.06 0.78
⫾ ⫾ ⫾ ⫾ ⫾
0.44 0.41 16 0.59 0.27
III
After ELCA ⫹ PTCA (n ⫽ 16) Reference diameter Minimal lumen diameter Percent diameter stenosis Absolute gain Relative gain
2.97 2.28 22 1.68 0.57
⫾ ⫾ ⫾ ⫾ ⫾
0.45 0.50 8 0.67 0.21
IV
Second follow-up (n ⫽ 13) Reference diameter Minimal lumen diameter Percent diameter stenosis Absolute loss Relative loss Loss index
2.94 0.63 80 1.68 0.56 0.99
⫾ ⫾ ⫾ ⫾ ⫾ ⫾
0.43 0.84 25 0.94 0.35 0.61
RESULTS
Procedural results: ELCA ⫹ PTCA was performed in 16 patients with diffuse in-stent restenosis 6.6 ⫾ 3 months after the initial stent implantation. The median stent length was 36 mm (range 15 to 105), with a restenotic lesion length of 32 mm (range 10 to 90). Due to in-stent restenosis, the MLD had decreased from 2.67 ⫾ 0.32 mm (after stenting) to 0.60 ⫾ 0.41 mm (absolute loss 2.06 ⫾ 0.59 mm, p ⬍0.0001). In 4 patients the stent was totally occluded. After ELCA ⫹ PTCA the MLD increased to 2.28 ⫾ 0.50 mm (absolute gain 1.68 ⫾ 0.67 mm, p ⬍0.0001), whereas the DS was reduced from 76 ⫾ 16% to 22 ⫾ 8%. Despite this improvement, the MLD after ELCA ⫹ PTCA remained significantly smaller than the original MLD after stenting (2.28 ⫾ 0.50 vs 2.67 ⫾ 0.32, p ⬍0.011; Figure 1). Procedural complications: In 4 cases (25%), the ELCA procedure was complicated by intracoronary thrombus formation. After intravenous administration of abciximab and additional stenting, normal flow was restored. Because this involved left main stenting in 1 patient, this patient was referred for elective coronary artery bypass surgery during the same hospital stay. Adjunctive high-pressure balloon dilatation caused edge dissections in 2 patients, necessitating additional stent implantation. In 2 patients, the ELCA procedure was complicated by side branch occlusion, which resulted in a non–Q-wave myocardial infarction in 1. Postprocedural serum creatinine values were elevated in 7 patients (Table I). Finally, in 1 patient, the ELCA catheter did not cross the lesion, owing to an initial underdeployment of the stent (“pseudo in-stent restenosis”). This could be confirmed with intravascular ultrasound, after which the stent was redilated (Figure 392 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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2). Unfortunately, after the procedure, this 68-year-old female patient developed an intracerebral bleeding possibly related to the combined use of heparin, aspirin, and abciximab. Despite adequate neurosurgical drainage, her condition deteriorated and she died postoperatively from pulmonary complications. As a result, procedural success was achieved in all cases but clinical success in only 14 patients (88%). Clinical and angiographic follow-up: After an interval of 7.8 ⫾ 4 months, clinical follow-up was completed in all 15 remaining patients. All patients had a recurrence of angina (Canadian Cardiac Society classification): class II in 6, class III in 6, and class IV in 3 patients. Two symptomatic patients refused a repeat coronary angiography. Therefore, repeat coronary angiography was performed in 13 patients (87%). Of these, 6 segments were totally occluded, whereas an additional 6 segments showed a significant recurrence of in-stent restenosis (MLD 0.63 ⫾ 0.84 mm, absolute loss 1.68 ⫾ 0.94, loss index 0.99). In patients with stent reocclusion, the initial indication for stent implantation had been recanalization of a chronic total occlusion in 2, and optimization of a suboptimal balloon angioplasty result in 4. The recurrence of angina in the patient electively referred to coronary artery bypass surgery was explained by a combination of reocclusion in the ELCA-treated segment and a de novo stenosis at the site of the anastomosis of the left internal mammary artery with the left anterior descending artery. In 1 patient, a de novo lesion just distal to the segment previously treated with ELCA was held responsible for the recurrence of ischemia and subsequently treated with additional stenting.
DISCUSSION In-stent restenosis is typically the result of neointima formation within a stent.5,6 The mechanism of lumen enlargement after PTCA is probably a combination of tissue extrusion out of the stent and additional stent expansion.14 Given the possibility of tissue recoil into the stent after initial dilatation,7 a combined use of an atheroablative technique and balloon angioplasty appears to be a more logic approach. Recently, it became apparent that the extent of in-stent restenosis (diffuse or stent occlusion as opposed to focal intima hyperplasia) had a direct bearing on the recurrence rate, regardless of the type of ablative technology used.4 The patients reported in this study had a median stented segment length of 36 mm (range 15 to 105) with a lesion length of 32 mm (range 10 to 90). This patient cohort could very well represent a “worst case scenario”: despite aggressive laser debulking and high-pressure postdilatation with relatively oversized balloons, no more than 85% of the original MLD after stenting could be regained. Moreover, the number of procedural complications and the high percentage of target vessel failure at 6-month follow-up (46% reocclusion, 46% repeat restenosis, and 8% de novo distal disease) suggests that ELCA ⫹ PTCA—at least using the current methods—is not a suitable treatment for diffuse in-stent restenosis. The use of multiple and long stents has seriously broadened the scope of perAUGUST 15, 2000
FIGURE 1. Serial quantitative MLD measurements. I ⴝ post stent implantation; II ⴝ before ELCA; III ⴝ after ELCA ⴙ PTCA, IV ⴝ 6-month angiographic follow-up after ELCA ⴙ PTCA. Values are given as mean ⴞ SD.
nosis, the initial use of long stents, especially in the left anterior descending artery, should be reconsidered. An alternative concept of “spot-stenting” has been suggested within this context.16 Intracoronary brachytherapy with gamma irradiation has been shown to be potentially beneficial in the treatment of in-stent restenosis in a small patient cohort.17 Whether this finding will prove to be true for  irradiation in longer stents and in longer lesions remains to be seen. To preserve the acute improvement achieved with debulking, brachytherapy could be usefully combined with ELCA as a potential treatment for diffuse in-stent restenosis. The combination of aggressive laser debulking followed by  irradiation and balloon dilatation is currently under investigation in our department. Meanwhile, for patients with particularly diffuse in-stent restenosis, coronary artery bypass surgery must be considered as an alternative to the “intraluminal mechanistic approach.”18 The limitations of this study are (1) evolving catheter technology during the study: catheter diameters ranged from 1.7-mm concentric to 2-mm eccentric. Therefore, the ablation therapy efficacy might not have been uniform throughout the study. (2) The number of patients in this single-center study was limited. 1. Colombo A, Hall P, Nakamura S, Almagor Y, Maiello L, Martini G, Gaglione
FIGURE 2. Intravascular ultrasound image of “pseudo in-stent restenosis” due to stent collapse. A, in the stent, proximal to the stenosis; B, in the stent, at the site of the stenosis.
cutaneous revascularization, as a result of which multivessel disease is no longer the exclusive domain of the cardiac surgeon.15 However, if proved to be associated with an increased risk of diffuse in-stent reste-
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