Stent Thrombosis, TLR Persist at Low Levels out to 5 Years with First-Gen DES

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Late adverse events—namely stent thrombosis and target lesion revascularization (TLR)—persist at low levels with first-generation drug-eluting stents (DES) out to 5 years, a concerning trend that needs to be addressed by newer stent designs, according to the authors of a large registry study appearing online December 27, 2011, ahead of print in Circulation.

Researchers led by Takeshi Kimura, MD, of Kyoto University Graduate School of Medicine (Kyoto, Japan), looked at 12,812 consecutive patients undergoing sirolimus-eluting stent (SES) implantation in the j-Cypher registry from August 2004 to November 2006 at 37 centers in Japan. The study population represented real-world practice in Japan, with high levels of diabetes, multivessel disease, end-stage renal disease, IVUS use, and CTO target lesions.

Over 5 years of follow-up, the incidence of all-cause death was 14.4% after SES implantation, with cardiac death (6.9%) and sudden death (2.5%) comprising more than half of these cases. Cumulative incidence of stent thrombosis remained low throughout the follow-up period (table 1).

Table 1. j-Cypher Registry: Stent Thrombosis Rates Through 5 Years

 

30 Days

1 Year

5 Years

Definite ST

0.3%

0.6%

1.6%

Definite/Probable ST

0.5%

0.8%

2.0%

Definite/Probable/Possible ST

0.5%

1.5%

5.4%

Abbreviation: ST, stent thrombosis.

Late and very late stent thrombosis continued to occur consistently without attenuation up to 5 years at a rate of 0.26% per year. Among 172 stent thrombosis events over this time period (44 early, 26 late, 102 very late), 151 (88%) resulted in MI. Overall, stent thrombosis was the cause of MI in 37% of 410 MIs in the study cohort. In addition, stent thrombosis resulted in death within 90 days in 14% of early cases, 35% of late cases, and 6.9% of very late cases.

Not surprisingly, cumulative incidence of persistent discontinuation of thienopyridine therapy increased over time from 25.1% at 6 months to 37.0% at 1 year to 56.1% at 5 years. Following this trend, adherence to dual antiplatelet therapy decreased over time in patients with stent thrombosis (89% in patients with early stent thrombosis; 54% in late stent thrombosis; 32% in very late stent thrombosis). In patients with late and very late stent thrombosis, 27% and 13%, respectively, discontinued both aspirin and a thienopyridine prior to stent thrombosis onset.

Cumulative incidence of both TLR and non-TLR were high, occurring at rates of 2.2% and 3.8% per year, respectively (table 2).

Table 2. j-Cypher Registry: Revascularization Rates Through 5 Years

 

30 Days

1 Year

5 Years

TLR

0.5%

7.3%

15.9%

Non-TLR

2.2%

16.1%

31.2%


Independent risk factors for stent thrombosis differed according to the timing of the event:

  • Early: ACS, target of proximal LAD
  • Late: side-branch stenting, diabetes, end-stage renal disease
  • Very late: current smoking at time of index procedure, total stent length greater than 28 mm

Independent predictors of late TLR were similar to those of early TLR within 1 year, encompassing various factors including hemodialysis, side-branch stenting, total stent length greater than 28 mm, diabetes, and PAD.

Very late stent thrombosis and late TLR “are clearly the ongoing late adverse events associated with the use of SES (a first-generation DES),” the authors write. “Very late stent thrombosis and late TLR together with the residual risk for early TLR clearly represent the unmet needs for coronary DES, which should be appropriately addressed by the future development of improved coronary stents.”

They add that it is currently unknown whether prolonged dual antiplatelet therapy could decrease the risk associated with these adverse events.

Lack of Event Plateau ‘Disturbing’

In an accompanying editorial, David P. Faxon, MD, of Brigham and Women’s Hospital (Boston, MA), calls the continued low but persistent rate of very late stent thrombosis “most disturbing,” especially the “lack of any evidence of a plateau up to 5 years.” He adds that the study “suggests that this may be a problem that continues for a very long period of time, and perhaps indefinitely, following stenting.”

In addition, since the registry was voluntary and industry-sponsored, with events determined by chart review and patient recall, events were likely underreported, the editorial notes.

“The long-term outcomes of drug-eluting stents in large registries have made it apparent that the stented segment continues to be at risk for thrombosis and neo-atherosclerosis for many years after implantation,” Dr. Faxon concludes. “The hope is that through a better understanding of the processes responsible, targeted therapy can improve the long-term durability and safety of drug-eluting stents.”

Glass Half Full, or Half Empty?

However, in a telephone interview with TCTMD, David E. Kandzari, MD, of the Piedmont Heart Institute (Atlanta, GA), called the low stent thrombosis risk “reassuring,” characterizing his and Dr. Faxon’s views as “looking at the same glass and saying whether it’s half empty or half full.”

He acknowledged that even at low rates, stent thrombosis is associated with a high risk of adverse events. But while “nobody in their right mind would ever argue against the fact that we would love to have a stent thrombosis rate of zero after this time period, we should also keep in mind that is not realistic even with bare-metal stents,” Dr. Kandzari said.

In addition, “looking at the glass half full, keep in mind with DES that atherosclerosis is a progressive disease, and most events that occur down the road are going to be related not specifically to the stent territory itself,” he said. “In trials like RESOLUTE, stent specific endpoints are only half of what happens to patients over 2 years with regard to MI occurring elsewhere in the coronary arteries.”

Rates Lower Than Other Registries

Dr. Kandzari noted that a couple of factors should reassure clinicians regarding the j-Cypher registry. First, the annualized stent thrombosis rates are considerably lower than those seen in other real-world registries such as Bern-Rotterdam, which reported a stent thrombosis rate of 0.6% per year through 4 years. Second, considering the Japanese patient cohort was high risk and complex, the adverse event rates are quite low, he pointed out.

As such, it is difficult to see next-generation stents improving the situation. “Any method to reduce stent thrombosis is certainly welcome, but we don’t have any data with more advanced-generation drug-eluting stents that would show us that they’re superior to the outcomes we’re observing here,” Dr. Kandzari said. “The very favorable outcomes in this registry at least for the Japanese population represent a high threshold for other stents to achieve superiority.”

 


Sources:
1. Kimura T, Morimoto T, Nakagawa Y, et al. Very late stent thrombosis and late target lesion revascularization after sirolimus-eluting stent implantation: Five-year outcome of the j-Cypher registry. Circulation. 2011;Epub ahead of print.

2. Faxon DP. Very late stent thrombosis and late target lesion revascularization: No end in sight. Circulation. 2011;Epub ahead of print.

 

Disclosures:

  • The registry was funded by Cordis Cardiology Japan and Johnson and Johnson.
  • Dr. Kimura reports serving as an advisory board member for and receiving honoraria from Cordis Japan.
  • Dr. Kandzari reports receiving research and grant support from and serving as an advisory board member for Abbott Vascular, Boston Scientific, and Medtronic.

 

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