Management of restenosis within the Palmaz-Schatz coronary stent (the U.S. multicenter experience)

less suitable method, because preparation of platelet-rich plasma takes time and may alter fragile platelets. Furthermore, in aggregometry, the conditions are artificial, and aggregation is provoked by agents such as adenosine diphosphate, collagen and thrombin.14 The bleeding time for estimations of platelet aggregation may be affected not only by platelet function, but also by vascular tone, which may change during the infusion of nitroglycerin. In conclusion, in healthy subjects, ASA and intravenous nitroglycerin, in the doses administered in this study, have comparable platelet antiaggregatory effects, and the effects appear to be additive. REFERENCES 1. ISIS-2

(Second International Study of Infarct Survival) Collaborative Group. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17187 cases of suspected acute myocardial infamtion. ISIS-2. Lancet 1988;

iiz349-360. 2. Yusuf S, MacMahon

S, Collins R, Peto R. Effect of intravenous nitrates on mortality in acute myocardial infarction; an overview of the randomized trials. fmcet 1988;i:1088-1094. 2. Didati I, Thdroux P, Latour JG, Lacoste L, Lam JYT, Waters D. Effects of nitroglycerin at therapeutic doses on platelet aggregation in unstable angina p&Otis

and acute myocardial infarction. Am J Cardiol 199Qti683-688. 4. Vesterqvist 0, G&n K. Urinary excretion of 2,3dinor-t B2 in man under normal condition, following drugs and during some pathological wnditions. Prostagkmdins 1984,27:627X44. 1. Mellion BT, Ignarro LJ, Myers CB, Ohlstein EH, Ballot BA, Hyman AL, Kadowitz PJ. Inhibition of human platelet aggregation by S-nitrosothiols. Heme- &pen dent activation of soluble guanylate cyclase and stimulation of cyclic GMP accumulation. Mel Pharmacol 1983;23:653-664. 6. Hornsbra G, ten Hoor F. The filtragometerz a new device for measuring platelet aggregation in venous blood of man. Thromb Diath Hamwrrh 1975;34:531-544. 7. Fleischmann AJ, Biemnbaum ML, Stier DJA, Sullivan A. In viva platelet aggregation and plasma catecholamines in acute myocardial infarction. Thromb Res 1975;6:205-207. 8. Karlberg KE, Totfghd K, Ahlner J, Sylvin C. Dose-dependent effect of intravenous nitroglycerin on platelet aggregation and correlation with plasma glyceryl dinitrate concentration in healthy men. Am J Cardiol 1992;69:802-805. 9. Torfg&rd K, Ahlner J, Norlander B. Simultaneous determination of glyceryl trinitrate and its hvo din&rate metabolites in plasma and tissues by capillary gas chrcmatography. J Chrormtogr 1990,534:19&201. 10. Dahlbcrg G. Statistical Methods for Medical and Biological Smdents. London: Georg Allen & Unwin, 1940,105. 11. Sathiipas P, Market GA, Sahaphong S, Duckert F. Detection of small iohibitoly effects of acetylsalicylic acid (ASA) by platelet impedance aggregomehy in whole blood. Thromb Res 1988;51:55-62. 12. Vesterqvist 0. Rapid recovery of in viva prostacyclin formation after inhibition by aspirin. Evidence from measurements of the major urinary metabolite of prostacyclii by GC-MS. Eur J Phmwcol 1986;30:69-73. 13. Cossum PA, Roberts MS. Nitroglycerin disposition in human blood. Eur J Clin Pharmacol 1985;29:169-175. 14. Mackie IJ, Jones R, Machin SJ. Platelet impedance aggregation in whole blood and its inhibition by antiplatelet drugs. J Clin Pat/ml 1984;37:874-878.

Management of Restenosis Within the Palmaz-Schatz Stent (The U.S. Multicenter Experience)

Coronary

Donald S. Bairn, MD, Marc J. Levine, MD, Martin B. Leon, MD, Sally Levine, RN, MEd, Steven G. Ellis, MD, and Richard A. Schatz, MD, for the U.S. Palmaz-Schatz Stent Investigators oronary stenting was introduced in the hope of C improving both the short- and long-term results of conventional balloon angioplasty.’ Nearly 2,000 patients have been treated with the balloon expandable PalmazSchatz stent in the United States since 1988, with a 98% acute placement success and minimal residual stenosis.2 Acute closure of the stent has been rate, but subacute thrombotic occlusion has been reported within the first several weeks after stent placement in almost 3% of patients, despite an anticoagulant program including aspirin, dipyridamole and CoumadinTM. The incidence of subsequent restenosis varies with the size, location and number of stents placed, but 220% of successfully stented patients show angiographic evidence of restenosis 6 months after stent placement.3~4 Despite the well-recognized incidence of in-stent restenosis, however, there have been no formal reports outlining how this type of lesion responds to various management alternatives in particular to repeat dilatation. Between January 1988 and July 1991, 1,189 patients underwent successfulstem placement at I of 16 participating U.S. centers (seeAppendix}. Baseline clinical and angiographic data were collected on each patient using a jiied case report form. Thesedata, as well as thosepertaining to clinical status were tabulated by the corporate sponsor (Johnson & Johnson Intervention& Systems,Warren, New Jersey). Acute procedural From the Charles A. Dana Research Institute and the Harvard-Thomdike Laboratory, Department of Medicine (Cardiovascular Division), Beth Israel Hospital, 330 Brookline Avenue, Boston, Massachusetts 02215. Manuscript received May 21,1992; revised manuscript received and accepted August 3, 1992. 364

THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 71

and protocol-spectfied late (4- to &month) angiograms were evaluated by each clinical site using caliper or visual techniques. Although separate computer-assisted analysis is underway at a core angiographic laboratory (Thomas Jefferson University Hospital), incomplete analysis dictates that the current report be based on complete angiographic data reported by the individual sites. Follow-up angiography was available in 880 of the patients (74%) who had successfulstents,at a mean interval of 6.0 f 2.0 months after the procedure. This angiography showedrestenosis(defined here according to a dichotomousdefinition of 250% diameter stenosissinside or within 5 mm of the stented segment)in 264 patients (30.0%). The characteristics of thesepatients (as well as 616patients without angiographic restenosis)are listed in Table I. Given the angiographic definition of restenosisused, it is not surprising that only 86 patients (32.5%) who had developed restenosis had moderate or severe (Canadian Cardiovascular Society 1 class2) angina at the time of follow-up angiography. Because the original protocol did not specify how in-stent restenosis should be treated, individual operators used their clinical judgment in assigning therapy. Medical therapy was selectedin 80 patients (30.3%) with restenotic stents. Thesepatients had a 69 f 19% mean diameter stenosisat 5.7 f I .Pmonth follow-up, but only 4 of these patients had moderate or severe (Canadian Heart class 22) angina. In contrast, 36 of the patients (13.6%) who had developed restenosis underwent bypass surgery for the treatment of an 80 f

FEBRUARY1,1993

13% stenosis present 3.9 + 1.7 months after stent placement. In addition to having an earlier time of restudy, 12 of the patients referred for bypass surgery had severe (290%) stenosis, and 21 (58.3%) had Mass 2 angina. Repeat dilatation was the most common therapy for in-stent restenosis, selected in 105 patients (39.770). The 80 f 14% diameter stenosis present at 5.3 f 1.9 months after stent placement, and the 46.6% incidence of moderately severe angina, were similar to those in patients referred for bypass surgery Dilatation was generally per$ormed with a balloon size equal to or slightly larger than the reference diameter. The outcome of repeat dilatation (Figure 1) was untformly successful, with a smooth postdilatation lumen and no instance of abrupt vessel closure. Although aspirin and dipyridamole therapy were continued, patients undergoing dilatation of an in-stent restenosis generally were not subjected to prolonged heparin administration or Coumadin anticoagulation as was administered to those with acute stent placement. Although not required by the original study protocol, 50 of the 105 patients (47.6%) who had repeat dilation underwent repeat angiography a mean of 7.0 + 6.3 months after in-stent redilatation. This angiography showed that 27 of these patients (54%) met criteria for recurrent restenosis (dejned as >50% diameter stenosis), with an average stenosis of 80 f 16%. Of these 27 patients with recurrent restenosis, 12 were managed medically, whereas 4 underwent bypass surgery, ana! 11 underwent an additional dilatation procedure.

New devices for coronary intervention may improve the quality and predictability of acute results in certain lesion types (e.g., eccentic, ostial, vein graft, calcified lesions) that are believed to be unfavorable for conventional balloon dilatation, but they have failed to eliminate either acute complications or subsequent restenosis. The Palmaz-Schatz balloon expandable stent may, however, yield a lower incidence of restenosis than conventional angioplasty under certain circumstances (e.g., single stents placed in native vessels or vein grafts >3 mm).4 This was reflected in the current study by resteno-

TABLE I Baseline Characteristics Subsequent Baseline

of Patients

With and Without

Restenosis Characteristics

Pt. no. Age (year) Men (no./%) Prior restenosis (%I Tandem stents (%) Treated vessel (%I LAD LC Right SVBG Reference diameter (mm) Baseline stenosis (%) Acute results Poststent diameter Residual stenosis (%) Follow-up results Time of follow-up (mos) Late lumen diameter Late stenosis (%I Angina 2 class 2(%)

With

Restenosis

Without

Restenosis

264

616

59.7? 11.4 214 (81.1) 190 (72.0) 39 (14.8)*

59.9

+ 10.7

525 (85.2) 352 (57.2) 45 (7.3)

30 (11.4) 95 (36.0) 52 (19.7) 3.2 + 0.6 85+ 11

181 70 227 135 3.4 a3

3.3 f 0.6 52 10

3.2 k 0.5 4 + 10

81 (30.7)

5.2 + 1.8 0.9 f 0.6 762 16 63/168

(37.5)*

6.4 2.6 17 231373

(29.4) (11.4) (36.9) (21.9) f 0.6 2 12

+ 2.0 f 0.8 f 16 (6.2)

*p
attery;

LC = left circumflex

artery;

SVBG =

sis rates of 28% for single stents (versus 46% for tandem stents) and 27% for stents in saphenous vein grafts, but randomized trials comparing stenting with balloon angioplasty are still needed to establish any net benefit over conventional angioplasty. It is clear, however, that restenosis can and does take place within stented segments: Using a dichotomous angiographic definition of diameter stenosis 250%, restenosis developed in approximately 30% of lesions examined 6 months after stenting. Operators must thus be prepared to recognize and appropriately manage instent restenosis when it occurs. While no systematic trial of different management strategies has been performed, the collected experience with >200 such patients in this study does provide some guidance. In the current series, medical therapy (i.e., antianginal drug treatment) was administered to 30.3% of pa-

FlWR2 1. Uilatian of imatent mstenosir mstmosiswithin2adjawntstentsin [email protected] lUlllWlCanbe~tOhaVerwUitdftoln

excessive intimal hypm@da within the stent (smsliawws). R@& immediately after sonwntional bdoen redilatation, the stentlumenqpemsamoothwithalumen diameter qtproximating that of the adjacent --.

BRIEF REPORTS

365

tients, mostly those with milder lesions, well-collateralized distal territory, or minimal angina. There is some encouragement for using this approach in mild (50 to 60%) restenosis lesions, since stented segments rarely show further progression in lesion severity after 6 months.2 When angina was more severe (or the restenotic anatomy was considered by the operator to be unfavorable for repeat dilatation) late bypass surgery was selected in 13.6% of the patients in the current study. The most common (39.7%) management for instent restenosis, however, was repeat dilatation. This parallels the management strategy used for restenosis after conventional angioplasty, where repeat dilatation has a somewhat higher subsequent restenosis rate than a primary dilatation procedure despite a somewhat better acute success and safety6 The current experience supports the extension of this treatment strategy to the management of in-stent restenosis, since all repeat dilatations were successful. Whereas the incidence of subsequent repeat restenosis appears to be roughly 50%, this is still within a range that makes repeat dilatation an acceptable clinical alternative. Because patients who decline restudy are more likely to be asymptomatic and to be free of restenosis than the cohort who return for restudy7 the true incidence of recurrence after dilatation of instent restenosis may actually be somewhat lower than the 54% rate that we observed. In performing in-stent redilatation, however, one must bear in mind that neither the mechanism of stent restenosis nor stent redilatation are fully established. To the extent that late stent compression contributes to lumen compromise, redilatation might cause stent reexpansion. On the other hand, to the extent that stent restenosis is due to excessive in-stent intimal hyperplasia,8 repeat dilatation may move this material outward either by further expanding the stent or by straining the hyperplastic material through static stent pores. In either event, the excellent postdilatation luminal appearance suggests that the previously placed stent continues to reduce the elastic recoil that otherwise tends to limits the degree of lumen improvement produced by routine conventional balloon dilatation.5 The smoothness of the postdilatation vessel lumen allows safe use of full-size dilatation balloons and supports our management strategy of using aspirin (but not oral Coumadin) after dilation of in-stent restenosis. With the recent (Fall 1990) Food and Drug Administration approval of directional coronary atherectomy, some investigators may be tempted to use this technique to manage in-stent restenosis. In fact, we did so successfully in 1 patient who developed restenosis at the distal end of a Palmaz-Schatz stentp retrieving intimal hyperplastic tissue characteristic of that seen in restenosis after other interventions. Given the favorable response to repeat conventional dilatation observed in the current study and the potential for mechanical injury to a delicate stent structure by the atherectoq device,l” howev-

366

THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 71

er, use of atherecto~ for the management of in-stent restenosis cannot be encouraged at this time. Limitations of this study include the fact that the choice of management for stent restenosis was left to the individual operator rather than being assigned randomly that angiographic follow-up after redilatation of stent restenosis was incomplete (54%), and that local site (rather than still-incomplete core laboratory angiographic readings) were used. Despite these important limitations, however, the current study still supports the conclusion that symptomatic or severe restenosis within a Palmaz- Schatz stent can be managed simply but effectively by conventional balloon redilatation. Because subsequent recurrent restenosis may develop in up to 50% of lesions so- treated, these patients should be followed carefully for signs of recurrent restenosis. APPENDIX Participating canters and investigators Arizona Heart Institute, Richard Heuser; Beth Israel Hospital, Boston, Donald Bairn, Marc Levine; Cedars-Sinai, Frank Litvak; Emory University, Spencer Ring, Neal Scott; Florida Heart Institute, Charles Curry; Lenox Hill Hospital, Jetfrey Moses; Methodist Hospital, Paul Overlie; Scripps Clinic, Paul Teirstein, Richard Schatz; Thomas Jefferson University Sheldon Goldberg; Terrebon Hospital, Craig Walkeq University of California, San Diego, Maurice Buchbinder; University of Michigan, Steve Ellis, Eric Topol; University of Pennsylvania, John Hirshfeld; University of Texas, San Antonio, Stephen Bailey; Washington Hospital Center, Martin Leon; Yale University, Henry Cabin, Michael Cleman.

1. Schatz RA. A view of vascular

stents. Circulation 1989;79:557-565. 2. Schatz R, Goldberg S, Leon M, Bairn DS, Hirshfeld .I, Cleman M, Ellis S, Top01 E. Clinical experience with the Palmaz-Schatz conmary stint J Am CON Cardiol 1991;17:155B-159B. a. Ellis SC?, Savage M, Fischman D, Leon M, Goldberg S, Hirshfeld JW, Bairn DS, Clanan MW, Teirstein PS, Walker C, Bailey S, Mullet DWM, Top01 EJ, Schatz RA. Restenosis after placement of Pabnaz-Schatz stems in native coronay arteries: Initial results of a multicenter experience. Circu&ion: in press. 4. Cartuzza JP, Kuntz RE, Levine MJ, Pomemntz RM, Fishman RF, Mansour M, Gibson M, Senerchia CC, Diver DJ, Satian RD. Bairn DS. Angiogmphic and clinical outcome of intracoronary stating: Acute and long-tam results from a large single-center experience. J Am Coil Cardiol 1992;20:328-337. 5. Kuntz RE, Safian RD. Levine UT, Reis GS, Diver DJ, Bairn DS. Novel approach to the analysis of restenosis after the use of three new coronary devices. J Am CON Car&l 1992$9:1493-1499. 6. Teimtein PS, Hoover CA, Ligon RW, Giorgi LV, Rutherford BD, McConahay DR. Johnson WL, Hart&r GO. Repeat coronary angioplasty: efficacy of a third angioplasty for a second restenosis. J Am CON Cardiol 1989;13:291-2%. 7. Kuntz RE, Keaney KM, Senerchia C, Bairn DS. Estimating the late. results of cormmy intervention from incomplete angiogmphic follow-up. Circulation: in press. 8. Levine MJ, Leonard BM, Burke JA, Nash ID, Safian RD. Diver DJ, Bairn DS. Clinical and angiogmphic results of Balkan expandable inhacomnaty stents in tight cmotmy artery stenosis. J Am Co11 Cardiol 1990,16:332-339. a. Safii RD, Gelbfish JS, Emy RE, Schnitt SJ, Schmidt DA, Bairn DS. Coronary atherectomy: clinical, angiographic and histologic tindings and obwwtions regarding potential mechanisms. Circulation 1990.82169-79. 10. Bowerman RE, Pinkerton CA, Kirk B, Wallet BF. Disruption of a coronary stent during atherectomy for restenosis. Cathet Cardiovarc Diagn 1991;24:24f+251.

FEBRUARY1,1993