American Heart Journal
Volume 157, Issue 5 , Pages 802-804, May 2009

Getting real with drug-eluting stents: 5-year follow up of a real-world cohort

  • Rahul Sakhuja, MD, MPP

      Affiliations

    • Division of Cardiology, Massachusetts General Hospital, Boston, MA
    • ,
  • Deepak L. Bhatt, MD, MPH

      Affiliations

    • VA Boston Healthcare System and Brigham and Women's Hospital, Boston, MA
    • Corresponding Author InformationReprint requests: Deepak L. Bhatt, MD, MPH, VA Boston Healthcare System and Brigham and Women's Hospital.

Received 15 December 2008; accepted 20 December 2008. published online 01 April 2009.

Article Outline

 

The advent of coronary stenting ushered in a whole new era in the treatment of coronary artery disease. Concerns over stent thrombosis and in-stent restenosis limited the use of intracoronary stents. Some centers reported that up to 10% of patients receiving uncoated or “bare metal” stents (BMS) had acute thrombotic occlusion of their stents, requiring intervention.1 Evolving procedural and antiplatelet strategies significantly reduced the rates of stent thrombosis.2, 3 Nevertheless, restenosis remained a significant problem—ranging from 15% to as high as 40%.4

To a large extent, drug-eluting stents (DES) succeeded in providing a solution to restenosis. Many trials have proven that DES significantly reduce in-stent restenosis and the need for repeat procedures.5 Initial excitement was reflected by the rapid uptake of DES into clinical practice. In many instances, DES were used before publication of the pivotal trials; approximately half were used for off-label indications.6, 7

Although DES significantly reduced the need for repeat procedures, longer-term follow-up raised concerns as the issue of late stent thrombosis resurfaced, related to incomplete stent apposition, localized hypersensitivity, and/or delayed arterial healing.8, 9, 10 Large multicenter registries have reported a cumulative incidence of stent thrombosis after DES implantation of around 3% at 4 years.11 Of greatest interest was that as many as 20% of the documented stent thromboses occurred “very late” or >1 year after stent implantation.12 In large randomized trials of sirolimus- (SES) and paclitaxel-eluting stents, the incidence for re-adjudicated stent thrombosis was no different than for bare metal stents.13 However, when including randomized studies which also enrolled patients with small vessels, diabetes, or acute myocardial infarction (MI), it appeared that DES conferred a small, but significantly increased, risk for late stent thrombosis.14 Moreover, despite the limited incidence, acute thrombotic episodes were often associated with poor outcomes.15 Large-scale “real-world” data on patients post percutaneous coronary intervention even called into question the overall safety of DES.16 DES use began to fall dramatically as many began to wonder whether DES safety had been adequately assessed.

Some of the differences between the findings of randomized data and observational studies might be explained by “on-label” versus “off-label” usage. One study only observed late stent thromboses in patients receiving off-label DES.6 Therefore, while on-label use of DES as reflected in randomized studies appeared safe, concern surrounding rampant off-label use persisted.

With growing concerns over late events, the US Food and Drug Administration (FDA) convened a meeting in 2006 to try to address these issues.17 The FDA required 5-year follow-up on patients in randomized trials as well as registry studies to collect data on real-world use. Multiple studies aimed to help clinicians navigate the stent thrombosis-restenosis risk/benefit landscape of drug-eluting stents.18, 19 Given the particular concern over late outcomes among drug-eluting stents used for off-label indications, real-world studies with longer-term follow-up have been awaited.

In this issue of the Journal, Goy et al20 (p. 883) provide one of the first such studies which addresses the FDA mandate for 5-year follow-up. This prospective cohort study describes the longest follow-up to date for a real-world cohort of its size. The authors followed up 344 consecutive patients treated with SES in 2002. Patients underwent percutaneous coronary intervention at 1 of 3 Swiss referral centers, which likely reflect a broad catchment area as well as an array of complex coronary interventions. Twenty percent of the population presented with an acute coronary syndrome, 19% were diabetic, and 15% had prior coronary artery bypass grafting; approximately 25% were treated for ≥1 off-label indications overall. Finally, clinical follow-up was obtained in 98%, commendable by any standards for longer-term observational studies.

Their results are encouraging. Over the course of 5-year follow-up, SES appear to provide durable benefit, particularly with regard to reducing target lesion revascularization (TLR) and the need for repeat procedures. In this study, 26 patients (8%) with complete follow-up died and 26 patients (8%) underwent clinically-driven TLR. Using a standard definition, only 2% of patients were diagnosed with a recurrent MI in follow-up.

The rates reported by Goy et al20 are similar to prior data, showing durable longer-term results of SES. The only other 5-year comparison is the long-term follow-up of the RAVEL study, which randomized 238 patients to either SES or BMS.21 In the SES group in RAVEL, the 5-year rates of death, MI, and TLR were 12.1%, 8.9%, and 10.3%, respectively (vs 7.1%, 6.9%, and 26.0%, respectively, for BMS). Four-year pooled analysis of 4 major randomized trials of SES reported similar rates.22

The authors also raise the issue of a “catch-up” phenomenon. It has been shown that most target lesion–related events in BMS occur within the first year, whereas the risk of TLR among SES appears low but persistent over time.23 The authors noted the same persistent risk of TLR in their cohort out to 5 years of follow-up. However, although the risk of TLR persists, the low overall risk of TLR at 5 years seems to argue against a catch-up phenomenon. In addition, 4-year follow-up of the SIRIUS and TAXUS patients notes a persistent reduction in TLR, confirming that a catch-up phenomenon is unlikely within available follow-up to date.24

With respect to safety, Goy et al20 report that SES appear to be safe over the course of longer-term follow-up. Using the Academic Research Consortium definitions, stent thrombosis occurred in 12 patients, 6 of which were definite, 1 was probable, and 5 were possible for an overall incidence of approximately 3.6%. All but one occurred >1 year after the index procedure. By assuming an equal rate over time, they calculated an annual rate of stent thrombosis of 0.4% per year. The mortality rate of stent thrombosis was largely driven by possible stent thrombosis or “unexplained death” after 30 days of the index procedure. These results were similar to a recent report, in which, stent thrombosis occurred in 192 of 8,146 patients followed up for up to 4 years—a cumulative incidence of 3.3%, and the calculated yearly incidence of 0.4% to 0.6%.11 In contrast, the cumulative incidence of stent thrombosis between years 1 and 4 was 0.4% to 0.6% among the initial randomized trials, likely reflecting the selected populations included in these trials. This underscores the need to pre-specify the endpoint of stent thrombosis in clinical trials13

As the authors acknowledge, there are limitations to the study inherent to its design. First, as a descriptive study, there is no comparison group. Although the rates appear similar to other trials, and the rates appear lower than those in BMS arms of other analyses, the relative safety has not been directly addressed. Although a rate of stent thrombosis of 0.4% per year is argued to be safe by the authors, one decision-analytic model suggests that even this limited risk might favor a strategy of BMS.19 Second, while the characteristics of the population appear similar to many other observational trials, caution must be advised when applying these results to patients receiving DES in the United States. This study, in Switzerland, was conducted within a system of compulsory basic health insurance where the cost of pharmaceuticals is capped. Therefore, access to and compliance with medications such as clopidogrel may be greater. Moreover, the off-label use of DES was lower than some other registries. This could account for some of the observed safety of DES in this study. Third, while the follow-up is formidable, the data are susceptible to recall bias.

The authors also recognize that this study, albeit the largest of its kind to date, is limited by its size. This reduces certainty around the reported point estimates. Even minor variations in follow-up can significantly affect event rates in a small study. For example, follow-up information was obtained in 344 of 350 patients. Assuming that none of the patients lost to follow-up had stent thrombosis, the incidence would be approximately 3.5% (2.0% definite/probable), whereas if all of these patients suffered stent thrombosis, the incidence could be as high as approximately 5.1% (3.7% definite/probable). That said, these data are consistent with much larger cohorts and pooled analyses with follow-up to 4 years.11, 24

Ultimately, small studies can facilitate detailed characterization of the patients that experience events, which is often hypothesis generating. In addition to acute MI, diabetes, and stent length, “premature” clopidogrel cessation may be the most significant risk factor for stent thrombosis.18, 25, 26 Despite its size, this study was able to find that 2 of the patients with documented antiplatelet regimens at the time of stent thrombosis had stopped clopidogrel within weeks of documented stent thrombosis.

There are still unanswered questions. What is the role (eg, optimal duration) of dual-antiplatelet therapy for DES? How do the newer generations of DES alter the risk/benefit ratio? The article by Goy et al20 has begun to provide answers to some of these longstanding questions. And, fortunately for those millions of patients harboring DES, these initial 5-year data are reasonably encouraging with regards to DES safety and efficacy in the real world.

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Disclosures 

Dr Bhatt discloses the following relationships: Research Grants: Bristol Myers Squibb (Princeton, NJ), Eisai (Tokyo, Japan), Ethicon (New Brunswick, NJ), Heartscape (Columbia, MD), Sanofi Aventis (Paris, France), The Medicines Company (Parsippany, NJ); Consultant/Advisory Board: Arena (San Diego, CA), Astellas (Tokyo, Japan), Astra Zeneca (London, UK), Bayer (Leverkusen, Germany), Bristol Myers Squibb (Princeton, NJ), Cardax (Honolulu, HI), Centocor (Horsham, PA), Cogentus (Palo Alto, CA), Daiichi-Sankyo (Tokyo, Japan), Eisai (Tokyo, Japan), Eli Lilly (Indianapolis, Indiana), Glaxo Smith Kline (Philadelphia, PA), Johnson & Johnson (New Brunswick, NJ), McNeil (New Brunswick, NJ), Medtronic (Minneapolis, MN), Millennium (Cambridge, MA), Molecular Insights (Cambridge, MA), Otsuka (Rockville, MD), Paringenix (Tucson, AZ), PDL (Redwood City, CA), Philips (Amsterdam, The Netherlands), Portola (San Francisco, CA), Sanofi Aventis (Paris, France), Schering Plough (Kenilworth, NJ), Takeda (Osaka, Japan), The Medicines Company (Parsippany, NJ), and Vertex (Cambridge, MA). Dr Sakhuja does not have any relevant disclosures.

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References 

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PII: S0002-8703(09)00131-8

doi:10.1016/j.ahj.2008.12.022

Refers to article:

  • Incidence of stent thrombosis and adverse cardiac events 5 years after sirolimus stent implantation in clinical practice , 26 March 2009

    Jean-Jacques Goy, Philip Urban, Urs Kaufmann, Charles Seydoux, Edoardo De Benedetti, Alexandre Berger
    American Heart Journal May 2009 (Vol. 157, Issue 5, Pages 883-888)

American Heart Journal
Volume 157, Issue 5 , Pages 802-804, May 2009

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