In 1986, when pioneers such as Jacques Puel and Ulrich Sigwart implanted the first coronary Wallstents, no guidelines were available to determine the treatment after stenting. From the experience acquired with mechanical prosthetic heart valves, it was inferred that chronic anticoagulation with coumarins was indicated. When the first cases of subacute occlusion were encountered, the anticoagulation regimen was further reinforced. The use of heparin, dextran, or thrombolytic agents during the procedure followed by warfarin, aspirin, sulphinpyrazone, and dipyridamole did not eliminate subacute thrombosis, which occurred in 18% of the first 117 stents implanted and was responsible for a higher incidence of hemorrhagic complications and prolonged hospital stay

Mario, C. (Carlo) di

Serruys, P.W.J.C. (Patrick)

Erasmus University Digital Repository

 DONATE   CirculationARTICLESWho Was Thrombogenic: The Stent or the Doctor?Patrick W. Serruys, Carlo Di Mario  https://doi.org/10.1161/01.CIR.91.6.1891Circulation. 1995;91:1891-1893Originally published March 15, 1995Editorials stents occlusions thrombosisIn 1986, when pioneers such as Jacques Puel and Ulrich Sigwart implanted the first coronary Wallstents, no guidelines wereavailable to determine the treatment after stenting. From the experience acquired with mechanical prosthetic heart valves, it wasinferred that chronic anticoagulation with coumarins was indicated. When the first cases of subacute occlusion wereencountered, the anticoagulation regimen was further reinforced. The use of heparin, dextran, or thrombolytic agents during theprocedure followed by warfarin, aspirin, sulphinpyrazone, and dipyridamole did not eliminate subacute thrombosis, whichoccurred in 18% of the first 117 stents implanted and was responsible for a higher incidence of hemorrhagic complications andprolonged hospital stay.When the first Palmaz-Schatz stents were implanted in the coronary arteries, Richard Schatz initially claimed that the soletreatment with antiplatelet agents was sufficient to prevent subacute occlusion (panel discussion, European Society ofCardiology Congress, Vienna, 1988). Unfortunately, a prohibitive early occlusion rate (18%) was observed with this regimen, soa stringent anticoagulation regimen was again recommended.  These two consecutive negative experiences identified coronarystents as highly thrombogenic foreign bodies and discouraged investigators from using coronary stenting as a primary treatmentfor coronary artery stenosis. Stenting was thus restricted to the treatment of acute complications after balloon angioplasty.It is to the merit of Antonio Colombo and his group to have broken this vicious circle and focused the attention of the communityof interventional cardiologists on the modalities of stent deployment, questioning the dogma of the intrinsic thrombogenic natureof the stents. Early experience with subacute stent occlusion despite optimal anticoagulation convinced Colombo and hiscoworkers that the key issue in the prevention of subacute occlusion was not the perfect control of hemostasis but theoptimization of stent implantation (panel discussion, Rotterdam Stent Course, December 1994). The major critical contribution ofthese investigators was to assume that the normalization of the rheology inside the stent as well as at its inflow and outflowwould render the anticoagulation treatment superfluous. Intravascular imaging played a pivotal role in revealing that most of theangiographically satisfactory stent implantations were in fact far from being optimal. Incomplete stent apposition, persistence ofresidual luminal narrowing due to incomplete or asymmetrical stent expansion, and presence of significant disease of theproximal and distal reference segment could not be easily detected with angiography, at least by visual assessment, and wererevealed only by intravascular ultrasound imaging. These observations prompted investigators to elaborate an original strategybased on oversizing of the balloon and high-pressure dilatation in order to obtain an optimal stent deployment.12The possibility of sizing the stent on the original dimensions of the vessel, measured with intracoronary ultrasound, can beconsidered an important step forward in the search for the “holy grail” of the restitutio ad integrum of the atherosclerotic coronaryvessel. The criteria proposed by Colombo to guide stent implantation (reduction of the residual plaque area to less than 40% ofthe total vessel area) corresponds to the area stenosis defined in pathology studies as the threshold above which a furtherplaque increase cannot be accommodated by the compensatory enlargement of the total vessel area, resulting in a progressiveluminal narrowing. More than 5 years ago, one of the authors of this editorial (P.W.S.)  wrote that “Stenting may be regarded asthe invasive cardiologist’s attempt to restore the ‘Glagovian’ balance between plaque and luminal area. . . .” Intracoronaryultrasound now offers to the interventional cardiologist the possibility of establishing whether this balance has been restored inall the cases treated. The achievement of a ratio between plaque and lumen below the critical level of 40% residual areastenosis appeared to be associated with a low incidence of subacute thrombosis and recurrence of symptoms, with a need forrepeated balloon angioplasty in 13.1% of patients by 6 months.  Restenosis, however, was far from abolished in this study,suggesting that different methods of limitation of intimal hyperplasia are still required to overcome the inescapable biologicalphenomenon triggered by wall injury. Having recognized the important educational role of intracoronary ultrasound in themodification of the strategy of stent deployment, the concept that intracoronary ultrasound guidance is imperative in performingoptimal stenting must nevertheless be questioned, since intravascular ultrasound is a time-consuming and costly investigation,with an inherent (although small) risk of complication. Although these limitations can be partially overcome by the use of acombined echo-balloon catheter for stent implantation and expansion,  in times of heavy financial constraints, the issue of cost-effectiveness must be specifically addressed and cannot be solved by a study that remains observational and uses only a visualassessment to define the angiographic end point.  The precise and accurate delineation of the angiographic contours providedby algorithms consistently validated for more than a decade  and now widely available on-line in the latest generation of digitalangiographic systems can be seen as the “poor man’s alternative” to intravascular imaging. Automated edge detection inmultiple views is the standard method used to detect the persistence of residual stenosis, but on-line videodensitometry alsoshould be tested as a monitoring technique for stent deployment. Since for most stents the recoil after balloon dilatation ispredictable, the on-line measurement of the dimensions of the balloon during inflation also can be used to optimize stentexpansion. A moderate enhancement of the radiopacity of the stent struts—without hampering the detection of the opacifiedvessel lumen (for example, as for the tantalum stents)—may be sufficient to permit an accurate automated radiographic contourdetection of the stent diameter without the need of contrast injections.The study of Colombo et al proposes two elements of novelty in its strategy for stent implantation—ultrasound guidance andhigh-pressure intrastent dilatation—and it remains unclear which of the two is the key issue to virtually abolish the risk ofsubacute occlusion. As the authors recognize, an initial aggressive strategy of high-pressure dilatation can reduce the need forfurther interventions triggered by ultrasound after the “final” angiographic assessment from 88% to 40% of the cases.  The initialreport from a large, observational, multicenter French trial conducted in 654 patients treated with ticlopidine and low molecularheparin after stenting supports this opinion, since a low subacute thrombosis rate was obtained without the use of ultrasoundguidance using a strategy of stent deployment largely influenced by the Colombo approach.  In the evolving strategy of theMilan group, it appears that the current approach is based on the achievement of a vessel lumen of uniform caliber in thereference and in the stented segments with high-pressure dilatation of a noncompliant balloon matching the size of theangiographically normal segment. Intracoronary ultrasound can rapidly and accurately detect incomplete stent expansion,especially if the high-resolution ultrasound cross-sectional images are collected during a motorized pull-back of the ultrasoundtransducer, allowing the application of on-line algorithms of automatic lumen detection and three-dimensional reconstruction.  Inmost cases, however, the detection of a residual intrastent narrowing also appears possible with the use of quantitativeangiography in multiple views. In diffusely diseased vessels, however, the sole use of angiography carries the risk of aninappropriate sizing of the stent on a falsely normal reference segment. A prerequisite for optimal stent implantation with high-pressure dilatation is that the implantation should cover the entire stenotic segment up to a relatively disease-free proximal anddistal artery. Meticulous attention to the treatment of segments of residual narrowing adjacent to the most severe stenosis andpotentially impairing the inflow and outflow of the stented segment is reflected by the use of multiple stents in 40% of thelesions.Although this study clearly demonstrates that the complete apposition and embedding of the metallic wires of the stent into thevessel wall minimize the stent thrombogenicity, other methods rendering the stent more thromboresistant are currently beingexplored. To date, the results of the pilot phase of the Benestent II trial (200 consecutive cases) indicate that no subacute345464784occlusion has occurred with a heparin-coated Palmaz-Schatz stent, although the optimization of the stent deployment wasmainly achieved with on-line quantitative angiography (67% of the cases), and only in 8% of cases was intravascular ultrasoundimaging used. The study of Colombo et al reports a large but single-center experience, so it seems dangerous to extrapolateresults obtained in an optimally equipped research laboratory with the meticulous work of highly experienced operators to thedaily practice of newcomers in the field. The work of Colombo et al demonstrates that it is the imperfect operator, and thus thesurgeon, who is responsible for a large part of the cases of subacute occlusion, but it would be foolish to completely deny thethrombogenic nature of the stent, demonstrated in in vitro and in animal work. Therefore, it can be argued that a lessthrombogenic stent, coated or biodegradable, eluting or not, may represent a safety net for the average interventionalist.It remains to be demonstrated in large cohorts of patients that the strategy of the Colombo group can be applied to stents withdifferent and less ideal scaffolding properties. In coil stents, high-pressure dilatation carries the risk of damaging themechanically less resistant structure of the stent, facilitating the protrusion of plaque remnants.The results of large randomized trials showing a significant reduction of recurrence of symptoms and late angiographicrestenosis after stent implantation   and the initial reports of the Colombo group   bolstered the application of intracoronarystenting. The exponential rise that has made intracoronary stenting, in some major European centers, the primary modality ofpercutaneous treatment of coronary lesions would not have been possible without the elimination of the prolonged hospital stayand of the increased risk of complications associated with the use of anticoagulation. Intracoronary ultrasound has beeninstrumental in the development of a more effective strategy of stent expansion that has almost eliminated the incidence ofsubacute thrombosis, without the need of anticoagulation. It has been associated with a remarkably low incidence of recurrentangina and angiographic restenosis despite the inclusion of lesions longer than 15 mm (16%), lesions in vessels smaller than 3mm (26%), chronic occlusions (8%), acute or threatened occlusion after balloon angioplasty (5%), and restenotic (12%) andunstable lesions (37%). Now that this strategy has been defined, the real and continued need of intravascular ultrasound forstent implantation cannot be established without randomized studies comparing the relative value of intracoronary ultrasoundand on-line quantitative coronary angiography in favorably altering the early and long-term follow-up after stenting.By the end of 1995, we will have results of three large multicenter trials aimed at the prevention of subacute thrombosis afterstent implantation: MUSIC, applying in a multicenter study the ultrasound criteria proposed by Colombo et al; MUST, withoutintracoronary imaging and studying the effect of a combined treatment with ticlopidine and aspirin; and BENESTENT II, using aheparin-coated stent in combination with ticlopidine and aspirin. Assuming that all these trials will be successful in virtuallyeliminating the incidence of subacute thrombosis, the winner will certainly be the one whose technique is less expensive, moreeasily applied, and demonstrates a greater efficacy in the prevention of long-term restenosis.FootnotesReprint requests to Dr Patrick Serruys, MD, PhD, Cardiac Catheterization Laboratory, Division of Cardiology, Thoraxcenter, Ee2332, Erasmus University, PO Box 1738, 3000 DR Rotterdam, Netherlands.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.Received January 30, 1995.Accepted January 30, 1995.Copyright © 1995 by American Heart AssociationReferences. Serruys PW, Strauss BH, Beatt KJ, Bertrand ME, Puel J, Rickards AF, Meier B, Goy JJ, Vogt P, Kappenberger L, Sigwart U. Angiographic follow-upafter placement of a self-expanding coronary artery stent. N Engl J Med. 1991;324:13-17.2. Schatz RA, Baim DS, Leon M, Ellis SG, Goldberg S, Hirshfeld JW, Cleman MW, Cabin HS, Walker C, Stagg J, Buchbinder M, Teirstein PS, Topol EJ,Savage M, Perez JA, Curry RC, Whithworth H, Sousa JE, Tio F, Almagor Y, Ponder R, Penn IM, Leonard B, Levine SL, Fish SL, Palmaz JC. Clinicalexperience with the Palmaz-Schatz coronary stent: initial results of a multicenter study. Circulation. 1991;83:148-161.9 10 11 123. Serruys PW, Strauss BH, van Beusekom HM, van der Giessen WJ. Stenting of coronary arteries: has a modern Pandora’s box been opened? J AmColl Cardiol . 1991;17:143B-154B.4. Colombo A, Hall P, Nakamura S, Almagor Y, Maiello L, Martini G, Gaglione A, Goldberg SL, Tobis JM. Intracoronary stenting without anticoagulationaccomplished with intravascular ultrasound guidance. Circulation. 1995;91:1676-1688.5. Mudra H, Blasini R, Kroetz M, Rieber J, Regar E, Theisen K. Ultrasound guidance of Palmaz-Schatz intracoronary stenting with a combinedintravascular ultrasound balloon catheter. Circulation. 1994;90:1252-1261.6. Keane D, Haase J, Slager C, Montabaun van Swijndregt E, Lehmann K, Ozaki Y, Di Mario C, Kirkeeide R, Serruys PW. Comparative validation ofquantitative coronary angiographic systems: results and implications from a multicenter study using standardized approach. Circulation. In press.7. Morice MC, Bourdonnec C, Lefevre T, Blanchard D, Monassier JP, Lienhart Y, Commeau P, Makowski S, Labrunie P, Cribier A. Coronary stentingwithout coumadin: phase III. Circulation. 1994;90(suppl 4):I-125. Abstract.8. Roelandt JRTC, Di Mario C, Pandian NG, Wenguang L, Keane D, Slager CJ, de Feyter PJ, Serruys PW. Three-dimensional reconstruction ofintracoronary ultrasound images: rationale, approaches, problems and directions. Circulation. 1994;90:1044-1055.9. Serruys PW, de Jaegere P, Kiemenelj F, Macaya C, Rutsch W, Heyndrickx G, Emanuelsson H, Marco J, Legrand V, Mateme P, Belardi J, Sigwart U,Colombo A, Goy JJ, vd Heuvel P, Delcan J, Morel MA, for the Benestent Study Group. A comparison of balloon expandable stent implantation withballoon angioplasty in patients with coronary artery disease. N Engl J Med. 1994;331:489-495.0. Fischman DL, Leon MB, Baim DS, Schatz RA, Savage MP, Penn I, Peter K, Veltri L, Ricci D, Nobuyoshi M, Cleman M, Heuser R, Almond D, TeirsteinPS, Fish RD, Colombo A, Brinker J, Goldberg S, for the STent REStenosis Study (STRESS) Investigators. A randomized comparison of coronarystent placement and balloon angioplasty in the treatment of coronary artery disease. N Engl J Med. 1994;331:496-501.. Nakamura S, Colombo A, Gaglione A, Almagor Y, Goldberg SL, Maiello L, Finci L, Tobis JM. Intracoronary ultrasound observations during stentimplantation. Circulation. 1994;89:2026-2034.2. Goldberg SL, Colombo A, Nakamura S, Almagor Y, Maiello L, Tobis JM. Benefit of intracoronary ultrasound in the deployment of Palmaz-Schatzstents. J Am Coll Cardiol . 1994;24:996-1003.CirculationAbout CirculationInstructions for AuthorsCirculation CMEStatements and GuidelinesMeeting AbstractsPermissionsJournal PoliciesEmail AlertsOpen Access InformationAHA Journals RSSAHA NewsroomEditorial Office Address: 200 Fifth Avenue, Suite 1020 Waltham, MA 02451 email: circ@circulationjournal.org  Information for:AdvertisersSubscribersSubscriber HelpInstitutions / LibrariansInstitutional Subscriptions FAQInternational UsersNational Center 7272 Greenville Ave. Dallas, TX 75231Customer Service1-800-AHA-USA-11-800-242-8721Local InfoContact UsABOUT USOur mission is to build healthier lives, free of cardiovascular diseases and stroke. That single purpose drives all we do. The need for our work isbeyond question. 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Who was thrombogenic: the stent or the doctor?

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Who was thrombogenic: the stent or the doctor?

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