New York, NY - Longer duration of clopidogrel use was associated with a lower incidence of death/MI in diabetic patients undergoing stenting, regardless of the type of stent used (drug-eluting or bare-metal) in a new observational study [1]. The study also found that drug-eluting stents (DES) were associated with better outcomes than bare-metal stents in the patient group included who had overall good clopidogrel compliance.

Dr Somjot Brar

The study, published in the June 10, 2008, issue of the Journal of the American College of Cardiology, was conducted by a team led by Dr Somjot Brar (Columbia University Medical Center, New York).

Brar commented to heartwire: "Our results suggest that long-term clopidogrel would be beneficial to all stent patients, not just those receiving DES. In addition, our study gives some reassurance on the safety of DES, especially in diabetic patients."

In the paper, the authors note that about 25% of patients undergoing PCI have diabetes and that diabetics have an increased risk of restenosis. They point out that DES are considered by many as the standard of care for diabetic patients undergoing PCI, but several recent reports have shown a greater incidence of late stent thrombosis with such stents compared with bare-metal stents. While many predictors of stent thrombosis have been identified, with the strongest being premature discontinuation of clopidogrel, Brar et al report that the long-term outcomes with DES compared with bare-metal stents, adjusted for clopidogrel use, in patients with diabetes remain unknown.

They therefore performed an observational study exploring the relationship between stent type and clopidogrel use with long-term death and MI in a diabetic population undergoing PCI for de novo lesions.

The study population consisted of 749 consecutive diabetic patients who underwent initial PCI at the Kaiser Permanente Los Angeles Medical Center between October 1, 2002 and December 31, 2004. Of these, 251 patients received a bare-metal stent and 498 received a drug-eluting stent. Results showed that longer use of clopidogrel was associated with fewer events.

This was shown to be the case regardless of the type of stent used, shown in a "left-censored survival analysis" in which all patients who suffered death, MI, or underwent repeat revascularization within six months of the index PCI were excluded. The remaining patients were categorized into four groups by stent type and clopidogrel status. Results of this analysis showed reduced event rates for patients still taking clopidogrel and in those who received a drug-eluting stent rather than a bare-metal stent.

Brar told heartwire: "Our study strengthens the evidence for long-term clopidogrel use after stenting, especially in diabetic patients, regardless of the type of stent used. While the need for long-term clopidogrel after placement of a drug-eluting stent has been discussed previously, this requirement for patients receiving bare-metal stents has gone largely unrecognized. The guidelines recommend just one month of clopidogrel after placement of a bare-metal stent, but our results suggest that this is totally inadequate." But he noted that this study was conducted in a Kaiser Permanente managed-care center, where clopidogrel is reimbursed for as long as it is prescribed, so compliance was good. "This may not be so easy to achieve in patients who have to pay for clopidogrel themselves," he added.

On the comparison of drug-eluting and bare-metal stents, Brar commented: "Contrary to prior observations, we found that DES were associated with a lower incidence of death/MI than bare-metal stents. This gives us reassurance on the safety of DES, especially when clopidogrel is on board," Brar said. In the paper, the authors suggest that the difference between this report and the prior studies may be the populations involved. They note that this study relates specifically to patients with diabetes, whereas in the prior studies showing an increased rate of death/MI with DES the majority of the patients were not diabetic. They suggest that the biologic response to DES may be different in diabetics, who may have higher rates of endothelialization and thus lower rates of late stent thrombosis.

"This study gives us some guidance on stent type and clopidogrel usage, but this is still just observational data. I would like to see a large randomized trial addressing these issues," Brar concluded.

In an accompanying editorial [2], Drs Seung-Hyuk Choi, Anand Prasad, and Sotirios Tsimikas (Sungkyunkwan University School of Medicine, Seoul, Korea, and the University of California, San Diego) point out some shortcomings of the current study—the comparison between stent types is likely underpowered, data on nondiabetic patients are lacking, and this system of healthcare delivery is not representative of that for most patients who are receiving DES in the US. "Nonetheless, it provides important data in a patient subgroup that is at highest risk of stent thrombosis, restenosis, progression of atherosclerosis, and new thrombotic events," they say.

They note that the data extend the findings of a previous study by Eisenstein et al, which also showed that extended clopidogrel use was associated with lower adjusted rates of death and MI, although in that study, adjudication of clopidogrel use was less reliable because it was based on patient self-report, and the incidence and outcomes in diabetic patients were not reported.

"These two studies in composite provide reassuring data that extended clopidogrel use is associated with improved outcomes and substantiate the AHA/ACC recommendation for one year of clopidogrel in patients receiving DES. Both of these studies are limited by the observational nature, the presence of several important baseline differences in groups, lack of reporting on rates of major bleeding, and undeniable physician selection bias in choosing the duration of clopidogrel. Therefore, these findings need to be validated in randomized clinical trials," the editorialists conclude.

They add: "The continued evolution of thienopyridine therapy for stent thrombosis has reached a crescendo of 'treat as long as the patient can tolerate it,' and it will likely change again as new data are published, particularly with evolving data on the risk of bleeding with long-term thienopyridine use. In the meantime, in patients who have already received DES and who are not at high risk of bleeding, it seems prudent to continue dual antiplatelet therapy indefinitely until new data emerge demonstrating otherwise."

They further note that initial reports of increased death and MI with DES have not been confirmed in more recent analyses. But they add: "It is evident that significant improvements must be made in reducing restenosis in a safer manner and in a manner that does not hold patients and physicians captive to long-term thienopyridine use. These include newer generation of stents with low risk of thrombogenesis, novel pharmacologic therapies, and identification of factors mediating platelet resistance, particularly in diabetic patients."