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(Circulation. 1997;95:1098-1100.)
© 1997 American Heart Association, Inc.

Articles

Stent Thrombosis

Closing in on the Best Preventive Treatment

Donald S. Baim, MD; Joseph P. Carrozza, Jr, MD

the Interventional Cardiology Section, Beth Israel–Deaconess Medical Center (East Campus), Boston, Mass.

Correspondence to Donald S. Baim, MD, Chief, Interventional Cardiology Section, Beth Israel–Deaconess Medical Center (East Campus), 330 Brookline Ave, Boston, MA 02215.

Key Words: Editorials • platelets • thrombosis • stent • angioplasty

	Introduction

Top Introduction References

 
Amazing progress has been made in the use of metallic endoprostheses (stents) in the human coronary circulation since the pioneering work of Sigwart 10 years ago. Of the three initial designs (the self-expanding mesh [Wallstent, Schneider], the coil stent [Gianturco-Roubin, Cook], and the slotted-tube stent [Palmaz-Schatz, Johnson & Johnson]), only the latter two designs are currently available in the United States (the Gianturco-Roubin since mid-1993 and the Palmaz-Schatz since mid-1994). Yet in that short time, coronary stenting has revolutionized catheter intervention. Stents (alone or in combination with other devices such as rotational atherectomy) are now used in >30% of interventions nationally and >50% of interventions in many laboratories, including our own. While their approval was based on abrupt or threatened abrupt closure (Gianturco-Roubin) and reduction of restenosis in focal de novo native lesions (Palmaz-Schatz), the majority of current use falls outside those narrow categories (and includes restenotic lesions, vein grafts, longer lesions, etc), for which registry data suggest clinical benefit over conventional angioplasty, although definitive trials to document benefit over conventional balloon angioplasty are still incomplete.

From the beginning of stent implantation, acute (<24 hour) and subacute (1- to 14-day) thrombosis of the stented segment has been one of the most feared complications. Despite use of heparin, aspirin, dipyridamole, and low-molecular-weight dextran, the incidence of this event was 24% in the early Wallstent experience¹ and 16% in the early Palmaz-Schatz experience.² The first response was to add further pharmacological barriers to thrombosis. Addition of oral warfarin (with an uninterrupted switch from heparin to warfarin) helped reduce the incidence of stent thrombosis to 3.5% in the STRESS³ and BENESTENT⁴ studies. This aggressive effort to prevent stent thrombosis, however, led to a dramatic increase in hemorrhagic complications (up to 10% in STRESS and BENESTENT), increasing both length of hospital stay (5 to 7 days) and hospital cost.⁵

In 1994, it became clear through the work of Colombo et al⁶ that incomplete expansion of the stent (documented by intravascular ultrasound but not necessarily evident on angiography) was a major contributor to the risk of stent thrombosis. By using high-pressure (14 to 20 atm) postdilatation with full-sized balloons, he was able to eliminate warfarin, dextran, and dipyridamole and replace them with oral ticlopidine, yet reduce the stent thrombosis rate to 1% to 2%. The reduced anticoagulation combined with better sheath removal techniques also brought the groin complication rate down to 1% to 2%. His findings with an ASA/ticlopidine regimen after "optimal" stent expansion have now been replicated by the French registry⁷ and the ISAR randomized trial (which found a thrombosis rate of 0.8% with ASA/ticlopidine versus 5.8% with ASA/warfarin).⁸ Several other trials of ASA/ticlopidine are well summarized in the article by Albiero et al.⁹ The apparent major remediation of the "terrible twins" of stent complications (clotting and bleeding) seen with ASA/ticlopidine, along with the perceived clinical benefit of stenting in an ever-broadening set of anatomic and clinical circumstances, have helped foster the explosive growth of what has been called "stent-o-mania."

The study reported by Albiero et al⁹ in this issue of Circulation is another effort to establish the adequacy of the ASA/ticlopidine regimen for preventing stent thrombosis and the second to attempt to evaluate the incremental benefit of ticlopidine over aspirin alone. The study cases are drawn from 1322 interventions performed between mid-1993 and mid-1995, 67% of which included placement of a coronary stent. In total, 801 of the 890 patients who underwent stent placement were treated with either ASA alone (264 patients) or ASA plus ticlopidine (537 patients). In most of these cases, the choice of drug regimen was made at the discretion of the operator, although 226 cases in which drug therapy was assigned randomly were also included.¹⁰ The overall stent thrombosis rates (1.9% versus 1.9%) as well as the subacute thrombosis rates (1.3% versus 1.9%) were similar for the ASA and ASA plus ticlopidine groups. As in other studies, however, virtually all of the stent thromboses were associated with major adverse events (death in 25%, nonfatal myocardial infarction in 75%), underscoring how important it is to prevent this complication. Hemorrhagic complications were infrequent in both arms (0.8% and 0.2%), and adverse reactions to ticlopidine were present at a low incidence (skin rash, 0.9%; gastrointestinal upset, 0.4%; and neutropenia, 0.6%, including 1 patient with sepsis).

Although larger than the 226-patient randomized study of ASA versus ASA and ticlopidine conducted previously by these investigators,10 the study unfortunately remains less than conclusive because of the heterogeneity of patients and lesions, the use of six different types of stents (although most were Palmaz-Schatz stents), the small size of the ASA-alone arm, and the nonrandom assignment of drug regimen that created evident imbalances between the two groups (selection bias). Thus, although it further supports the use of purely antiplatelet regimens after stenting, the Albiero study does not answer the fundamental questions of whether aspirin alone is adequate or whether ticlopidine adds further benefit. Nor does it address whether antiplatelet therapy alone is adequate in stenting done for other indications (abrupt closure, acute myocardial infarction) or with suboptimal stent results (incomplete expansion, unstentable distal dissection), in which the proclivity for stent thrombosis is clearly higher than in elective "optimal" stenting. Given the number of stent implantations currently being performed worldwide (an estimated 300,000 per year), these are still important issues. Whether intravascular ultrasound is needed to achieve such results (it was used in 85% of the cases reported) should be added to this list of unanswered questions.

Initial results from the STARS, in which 1650 patients who underwent optimal Palmaz-Schatz stenting in a setting of low clinical risk for thrombosis (no myocardial infarction within 7 days, no dissection or slow flow during the procedure, no unstented dissection) were randomized to receive aspirin, aspirin plus ticlopidine, or aspirin plus warfarin, were released at the 69th Scientific Sessions of the American Heart Association, New Orleans, La, November 1996.¹¹ The reported 30-day subacute thrombosis rate in the aspirin plus ticlopidine group (0.6%) was lower than that seen in the aspirin or the aspirin plus warfarin arms (each 2.5% to 3%). The incidence of subacute thrombosis in the 300-patient registry of those excluded from randomization (due to interim dissection before stenting or suboptimal results after stenting) was 2% despite use of aspirin plus ticlopidine (and frequently other antithrombotic agents as well). The CRUISE substudy, in which each STARS center agreed to use either iterative ultrasound to optimize the stent result as advocated by Colombo, documentary ultrasound after angiographically guided stent implantation, or no ultrasound at all, is still being analyzed. Final results of both the STARS and the CRUISE substudy are expected shortly.

Even STARS is not the end of this story, however. There are suggestions that individual stent designs (among the >20 stents now under clinical investigation) may have a higher or lower thrombotic tendency than the index Palmaz-Schatz stent because of differences in geometry, materials, or surface finish.¹² Because the design of the study protocols for all but one of the seven devices now under testing in the United States is based on an 800- to 1000-patient comparison of the new stent with the Palmaz-Schatz stent, with an empirical regimen of aspirin and ticlopidine, it should be possible to evaluate major stent-to-stent differences in thrombotic potential. Beyond intrinsic stent design, various passive or active stent coatings may further alter the profile of stent thrombosis. This appears to be the case with covalently endpoint-attached heparin fragments, as tested in the BENESTENT II trial,¹³ which reported just 1 thrombotic event in 600 implants (200 in the pilot phase and 400 in the randomized comparison with conventional angioplasty). The current use of ticlopidine just scratches the surface of the coming wave of potent newer antiplatelet agents, however. The new oral agent clopridogril appears to overcome many of the troublesome side effects of ticlopidine, and intravenous agents (including abciximab or newer intravenous/oral blockers of the glycoprotein IIb/IIIa receptor)¹⁴ might give more complete inhibition of platelet function and more rapid onset compared with the 2- to 3-day delay to peak activity seen after initiation of ticlopidine therapy.

In summary, stent thrombosis is the major downside to this revolutionary technology, which must be prevented rather than just accepted and treated when it occurs. The study by Albiero et al⁹ is another milestone along the trek to eliminate this troublesome side effect, confirming its reduction to 1% compared with the 3.5% rate seen in the STRESS and BENESTENT trials. The mounting data have established fairly clearly that the use of an aggressive antiplatelet regimen (for now, aspirin and ticlopidine) is the best current therapy, although further refinements in drug therapy will almost certainly be needed (particularly for suboptimal stent results or stenting in certain high-risk clinical situations). Although the road toward the goal of eliminating stent thrombosis still stretches off into the distance, this is an appropriate time to pause and reflect on how far we have come in controlling this serious complication (reducing it by an order of magnitude over the last 10 years) by appreciating the central importance of full stent expansion and optimization of the antiplatelet regimen.

	Selected Abbreviations and Acronyms

 

ASA = acetylsalicylic acid, aspirin BENESTENT = BElgian NEtherlands STENT (study) CRUISE = Can Routine Ultrasound Improve Stent Expansion ISAR = Intracoronary Stenting and Antithrombotic Regimen study STARS = STent Antithrombotic Regimen Study STRESS = STent REStenosis Study

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

	References

Top Introduction References

 

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