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Drug-Eluting Stents and Late Stent Thrombosis: Dealing with the Issues


Christopher M. Kramer, M.D., F.A.C.C.

Reports suggest that drug-eluting stents (DES) may be associated with delayed (or absent) endothelialization,1-2 localized hypersensitivity reactions,3-4 and late stent thrombosis. The reports have led to heated debate within cardiology and to contentious U.S. Food and Drug Administration (FDA) panel meetings.5

Stent thrombosis most commonly occurs in the first month after stent implantation, and in this interval, it is referred to as “subacute stent thrombosis.” However, numerous cases of “late” stent thrombosis have been described as occurring months or even years after stent implantation. These events have been largely limited to high-risk situations where DES is now often being used despite the fact that these devices were approved for low-risk lesions in low-risk patients.

In the majority of cases, stent thrombosis is a catastrophic event, resulting in life-threatening complications. In a pooled analysis of six trials and registries from the 1990s, the incidence of death or myocardial infarction (MI) associated with angiographically documented stent thrombosis was 64.4%.6 Mortality rates due to presumed or documented stent thrombosis range from 20-45%.7-9

Most recently, investigators conducted a meta-analysis of 14 clinical trials comparing DES placement to bare-metal stents (BMS). Very late thrombosis, defined as thrombosis occurring after 1 year, was 5.0 per 1,000 DES patients with no events in BMS patients (Slide 1).

On December 7-8, 2006, the FDA convened an advisory panel meeting to discuss stent thrombosis and the overall safety of DES.10 The panel concluded that there appears to be a numerical excess of late stent thrombosis with DES, but the magnitude is uncertain. They also noted that the off-label use of DES, as with BMS, is associated with increased risk when compared with on-label use.

Slide 1: Incidence of Early, Late, and Very Late Stent Thrombosis: A Meta-Analysis

Description: This meta-analysis included nine sirolimus trials, largely represented by the SIRIUS and RAVEL trials and five paclitaxel trials, represented by the TAXUS Trials. The overall incidence of thrombosis from all analyzed studies (not shown) was 9.3 events per 1,000 DES patients compared with 9.0 events per 1,000 BMS patients (p = 0.91). Increased risk with DES use was suggested as early as 1 month after revascularization, but over time this increased to a four- to five-fold excess of late thrombosis associated with DES versus BMS placement. The time to late thrombosis was equally protracted for both sirolimus and paclitaxel stents, with a median thrombosis time of 15.5 to 18 months after coronary intervention, respectively, which was 11 to 14 months longer than late BMS thrombosis.

Reducing Risk

Dual antiplatelet therapy with aspirin and a thienopyridine has been shown to reduce cardiac events after coronary stenting compared to aspirin alone or the combination of aspirin and warfarin (Slide 2). However, many patients and health care providers prematurely discontinue dual antiplatelet therapy, which greatly increases the risk of stent thrombosis, MI, and death.

In the February 13, 2007, issue of the Journal of the American College of Cardiology, a Science Advisory offers clinical advice on preventing premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents.11 The advisory looks at predictors of DES thrombosis (Slide 3), which suggest considering prolonged dual antiplatelet therapy, as well as factors related to premature cessation of thienopyridine therapy (Slide 4).

Slide 2: After Bare-Metal Stent Placement, Aspirin Plus Thienopyridine Reduces MACE* Compared with Aspirin Alone or with Oral Antithrombins

Slide 3: Predictors of DES Thrombosis: Consideration for Prolonged Dual Antiplatelet Therapy

Citation: Reproduced with permission from Grines CL, Bonow RO, Casey DE, et al. Prevention of Premature Discontinuation of Dual Antiplatelet Therapy in Patients With Coronary Artery Stents: A Science Advisory. J Am Coll Cardiol 2007;49:734-39. Copyright of the American College of Cardiology.

Slide 4: Factors Related to Premature Cessation of Thienopyridine Therapy

Description: A recent Science Advisory from the ACC and others reviewed factors related to the premature cessation of thienopyridine therapy. For example, in an analysis from the PREMIER registry, investigators concluded that “additional patient education about the rationale for and importance of continuing thienopyridine treatment may be needed – particularly for patients with less formal education.”

The advisory by Grines et al. stresses the importance of 12 months of dual antiplatelet therapy after placement of a DES and educating the patient and health care providers about hazards of premature discontinuation. It also recommends postponing elective surgery for 1 year, and if surgery cannot be deferred, considering the continuation of aspirin during the perioperative period in high-risk patients.

The Science Advisory addressed strategies that have the potential to reduce premature discontinuation of thienopyridine therapy, including:

Finally, adding a new wrinkle to the debate, the first issue of JACC in 2007 included a study by Meier et al. suggesting a previously unappreciated downside of DES: the late attenuation of collateral function.12 Although still largely a theoretical concern, should abrupt late occlusion occur after DES, the data suggest that normal collateral protection would be impaired to some degree, with more ischemia potentially permitting a larger ischemic insult and higher mortality risk than would otherwise occur.

In an accompanying editorial,13 Morton J. Kern, MD, FACC, noted that “No one would question the acceptance of this downside given the superior long-term restenosis results for the vast majority of our patients with DES.” Nevertheless, he added, “The observations from this study serve to focus our attention on how and why collaterals act to protect the heart and what the future might hold for pharmacologic manipulation of collateral function.”

In this interview, Albert E. Raizner, MD, FACC, suggests how the data available to date are changing clinical practice.


Dr. Block:
I am here with Dr. Al Raizner, from Houston, Texas. Al, one of the hottest topics right now in cardiology is the whole issue of drug-eluting stents. The late thrombosis debate introduced at Euro PCR last year (2006) has become a media gadfly. Do you think interventional cardiologists should change the way they use drug-eluting stents in the United States?

Dr. Bersin:
I certainly do, although my answer has to be qualified. The available data on late stent thrombosis leave us with a lot of questions unanswered. Clearly, there is an element of concern and we’re likely to see an entire spectrum of how interventional cardiologists respond to this.

At one end of the spectrum, there will be those who say this is not a paradigm-changing issue; you just continue aspirin and clopidogrel. On the other end of the spectrum, there will be some cardiologists who decide that they would rather avoid a drug-eluting stent in any situation where a bare-metal stent would work well.

Dr. Block:
That begs the question: If you are going to use a stent in a situation where a bare-metal stent would work well – such as larger arteries, short segment – is that now a given? We should just use a bare-metal stent, which would pretty much resolve the whole issue of late thrombosis?

Dr. Bersin:
I don’t think it’s a given. Bare in mind, in the pivotal SIRIUS and TAXUS IV trials in which relatively simpler lesions were treated, drug-eluting stents reduced restenosis and related clinical events even in larger vessels and shorter lesions. Over the next several years I am sure we will have more data on which we can base our decisions. First, we’re going to need agreement on a definition of late stent thrombosis, which will help in unifying the information so we can compare apples to apples. Second, we should see relevant studies identifying mechanisms and causes more specifically.

Soon we’ll be able to put this whole issue in proper perspective. It may be that the data will change the paradigm of stenting. On the other hand, it may be determined that it is not an unsolvable issue, in which case we’ll continue using drug-eluting stents driven by patient and lesion considerations rather than be deterred by concerns of late stent thrombosis.

Dr. Block:
Rather than the perfect situation for a bare-metal stent, like I outlined – a large artery and short segment – what does an interventionalist do when faced with a much more common situation: a 2.5 to 3 mm diameter artery that needs an 18 mm stent? In that case, the risk of restenosis using a bare-metal stent is significant higher than DES. Using a DES would probably be the right thing to do in that artery. How long do you keep that patient on clopidogrel?

Dr. Bersin:
That’s the big question we’re all facing right now. What I am currently doing is telling patients to continue clopidogrel for at least 1 year, and indefinitely when more complex or precarious lesions were treated. In time, we’ll be able to answer that question more precisely. We do know now that there are incidents of late thrombosis that have occurred between 1and 3 years. With more science and less emotion, we’ll have a better idea how long to continue dual antiplatelet therapy.

Also, we are perhaps simplistically assuming that the fundamental problem is stopping the clopidogrel and losing the antiplatelet protection, but we really are not sure at this point whether that is indeed the explanation for late stent thrombosis. Yes, many patients with late stent thrombosis were off clopidogrel, but there have been other patients who were still on clopidogrel but had thrombosis anyway. Clearly, there are multiple reasons why stents can thrombose late, but the simple remedy right now is to continue the aspirin and clopidogrel.

Dr. Block:
If you have to stop the clopidogrel, if your patient needs surgery, for example, do you cover them with another antithrombotic regimen or do you just cross your fingers?

Dr. Bersin:
I will continue the aspirin, unless it’s impossible for them to take it. I will almost never allow a patient to go for purely elective surgery or elective procedures within the first 6 months after a drug-eluting stent is placed. If they must undergo surgery, you have to weigh the importance of the surgery against the concern about stent thrombosis. At the end of the day, clinical judgment must prevail until clinical data provides better guidance.

In general, a short time off of antiplatelet therapy should not, by itself, lead to stent thrombosis. In the BASKET-LATE trial,8 the median time for thrombosis-related events was almost 4 months after stopping clopidogrel, with the earliest event occurring after 2 weeks. So, I would be surprised if being off clopidogrel for only 1 week or 10 days for surgery would present a problem, particularly if surgery were performed 6 months or more after stent placement.

Dr. Block:
One last question: There are stents in development that may not, as Renu Virmani has shown, have areas that never endothelialize completely like the Taxus and Cypher stents in use today. These new stents have new coatings that do not appear to affect the endothelium quite as much. Do you think these new stents may solve the issue for us?

Dr. Bersin:
The history of interventional cardiology suggests that every innovative technology leads to a new problem that we ultimately solve. Balloon angioplasty lead to the problem of abrupt vessel closure, and stents were designed to offset that problem. Bare-metal stents lead to high rates of restenosis, and we ultimately solved – or almost solved – that problem with drug-eluting stents. Just as we have in the past, I am quite confident that we’ll develop new technology that will solve the problems now associated with DES.


Smith SC Jr, Feldman TE, Hirshfeld JW Jr, et al. ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention-Summary Article: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention). J Am Coll Cardiol 2006;47:216-35.


  1. Joner M, Finn AV, Farb A, et al. Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk. J Am Coll Cardiol 2006;48:193-202.
  2. Kotani J, Nanto S, Morozumi T, et al. Angioscopic findings of the neo-intimal coverage over the sirolimus-eluting stent: nine months follow-up study. J Am Coll Cardiol 2006;47 Suppl B:27B.
  3. Nebeker JR, Virmani R, Bennett CL, et al. Hypersensitivity cases associated with drug-eluting coronary stents: a review of available cases from the Research on Adverse Drug Events and Reports (RADAR) project. J Am Coll Cardiol 2006;47:175-81.
  4. Virmani R, Guagliumi G, Farb A, et al. Localized hypersensitivity and late coronary thrombosis secondary to a sirolimus-eluting stent: should we be cautious? Circulation 2004;109:701-5.
  5. Shuchman M. Debating the Risks of Drug-Eluting Stents. N Engl J Med 2007;356;325-8.
  6. Cutlip DE, Baim DS, Ho KK, et al. Stent thrombosis in the modern era: a pooled analysis of multicenter coronary stent clinical trials. Circulation 2001;103:1967-71.
  7. Spertus JA, Kettelkamp R, Vance C, et al. Prevalence, predictors, and outcomes of premature discontinuation of thienopyridine therapy after drug-eluting stent placement: results from the PREMIER registry. Circulation 2006;113:2803-9.
  8. Pfisterer M, Brunner-LaRocca HP, Buser PT, et al., for the BASKET-LATE Investigators. Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents. J Am Coll Cardiol 2006;48:2584-91.
  9. Eisenstein EL, Anstrom KJ, Kong DF, et al. Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation. JAMA 2007;297:159-68.
  10. US Food and Drug Administration. Circulatory System Devices Panel. Available here. Accessed January 26, 2007.
  11. Grines CL, Bonow RO, Casey DE, et al. Prevention of Premature Discontinuation of Dual Antiplatelet Therapy in Patients With Coronary Artery Stents: A Science Advisory. J Am Coll Cardiol 2007;49:734-39.
  12. Meier P, Zbinden R, Togni M, et al. Coronary collateral function long after drug-eluting stent implantation. J Am Coll Cardiol 2007;49:15-20.
  13. Kern MJ. Attenuated coronary collateral function after drug-eluting stent implantation: a new downside of drug-eluting stents? J Am Coll Cardiol 2007;49:21-2


Fuente: Cardiosource. Conversations with experts

Ultima actualizacion: 25 DE MARZO DE 2007

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