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Drug-eluting stents (DES) substantially reduce target vessel revascularization (TVR) following percutaneous coronary intervention (PCI) compared with bare-metal stents (BMS), and they do so without increasing adverse events including stent thrombosis, according to a large meta-analysis published online May 14, 2012, ahead of print in Circulation. However, efficacy and safety vary considerably among DES.

Investigators led by Sripal Bangalore, MD, MHA, of New York University School of Medicine (New York, NY), pooled data from 57,138 patients enrolled in 77 randomized controlled trials published up to mid-March 2012 that compared durable polymer/platform DES with BMS or with each other in at least 100 patients undergoing PCI of de novo coronary lesions. In all, there were 117,762 patient-years of follow-up.

Looking at Short and Long Term

In the short term (≤ 1 year), DES reduced TVR by 52% to 74% compared with BMS. Among DES, sirolimus-eluting stents (SES) showed the highest probability of being the most effective. Overall, SES, Resolute zotarolimus-eluting stents (ZES), and EES reduced TVR more than paclitaxel-eluting stents (PES) and non-Resolute ZES, which had similar efficacy.

Also in the short term, all DES except PES had similarly low rates of death (median < 0.3%) compared with BMS but yielded significant reductions in the risk of MI (33%-45% from a median BMS rate of 4.23%). In addition, there was no increased risk of any stent thrombosis with DES (median rate < 0.2% for all stents). In fact, EES reduced the odds ratio by 56% over BMS (0.08% vs. 0.18%), and bested other DES for that key safety endpoint. The results were largely similar for Academic Research Consortium-defined definite or probable stent thrombosis and definite stent thrombosis.

The short-term efficacy advantage of DES over BMS was maintained in the long term (> 1 year), with a 39% to 61% reduction in TVR. Among the DES, EES were most likely to provide the lowest TVR rate (table 1).

Table 1. Long-term Efficacy by Stent Type

^a Expressed as median rate per 1,000 patient-years to account for trial variability.

Also in the long term, there was no increase in mortality with DES vs. BMS. The short-term reductions in MI were maintained with all DES except PES, which again held no advantage over BMS. There was little difference in rates of any stent thrombosis among all stents, except for EES, which reduced the rate found with BMS by 49%. Overall, EES were better than SES, PES, and ZES, while SES were better than PES (table 2).

Table 2. Long-term Safety by Stent Type^a

^a Expressed as median rate per 1,000 patient-years to account for trial variability.

^b Academic Research Consortium defined.

For all of the above outcomes, sensitivity analyses, including those limited to trials with longer than 6 months of clopidogrel use and direct stent comparison, yielded consistent results.

Explaining a presumed trade-off between efficacy and safety with DES, the authors note that “because inhibition of smooth muscle cell proliferation by currently available DES is inseparably connected with inhibition of endothelial cell proliferation, delayed and incomplete healing has been hypothesized to result in the propensity for stent thrombosis. BMS [have] therefore been the benchmark for safety standards for stent evaluation.”

Yet the study showed no increased risk with DES, and in fact there was a reduction in stent thrombosis with EES. The finding “is difficult to explain but could result from extended dual antiplatelet therapy with DES in contemporary cohorts when compared with BMS,” Dr. Bangalore and colleagues write. “In addition, late and very late stent thrombosis with BMS is not as uncommon as once believed.”

New Analysis Mostly Confirmatory

 In a telephone interview with TCTMD, Gregg W. Stone, MD, of Columbia University Medical Center (New York, NY), observed that even before the study the interventional community was “very confident that there was a significant reduction in TVR and TLR with all DES compared to BMS. And we were pretty confident we knew the rank order for DES [efficacy].

“We also thought that there was no significant difference in death between the devices, and we had pretty good ideas about [the superiority of DES] for MI. But it’s nice to see [these ideas confirmed] in this large network analysis,” he added.

Dr. Stone did, however, have some methodological bones to pick with 2 study endpoints. Because the definitions of MI and of ‘any stent thrombosis’ varied from trial to trial, “personally I am not comfortable with [these] conclusions,” he said.

Nonetheless, he noted, the current stent thrombosis results are “almost identical” to those from his recent network meta-analysis (Palmerini T, et al. Lancet. 2012;379:1393-1402), which looked only at Academic Research Consortium-defined definite and definite/probable stent thrombosis.

“We don’t know why there seems to be less stent thrombosis with certain DES compared to BMS,” Dr. Stone commented. “The fact that it occurs within the first year—and, as we showed, within the first 30 days when all patients are taking dual antiplatelet therapy—shows that that is not a factor. So it is presumably due to thinner stent struts, less arterial injury, faster endothelialization, and—in the case of the everolimus-eluting stent, which has been shown to be the safest—presumably to the fluoropolymer, which has its own antiplatelet and antithrombotic properties.

“The increased antirestenotic efficacy of DES may also translate into improved safety, because a quarter or more of restenosis episodes present with an MI, and some of those patients will die,” he added. “But all of this is speculative.”

Case for Superior DES Safety Needs Bigger Numbers

But before concluding that DES generally are safer than BMS,“I think you would need 1 really adequately powered randomized trial, Dr. Stone cautioned, noting that prolonged dual antiplatelet therapy with DES is also an issue. “To me, it would seem that if a DES is safer than a BMS when both patients are on dual antiplatelet therapy, then most likely the DES would be safer than the BMS off dual antiplatelet therapy as well. But that has not yet been proven.”

Concern remains over the safety of DES in STEMI patients, Dr, Stone noted, especially in regard to very late stent thrombosis with PES and SES. A hint that the second-generation EES may reduce stent thrombosis vs. BMS in primary PCI was provided by the underpowered EXAMINATION trial. A large, adequately powered randomized trial is needed to pin that finding down, he added, and that may come with the planned HORIZONS-AMI II trial enrolling 7,000 to 10,000 patients.

 Study Details

 Sixty trials used clopidogrel for at least 6 months in the DES arm. Mean follow-up was 2.1 years (range 0.5-5 years).

Source:

Bangalore S, Kumar S, Fusaro M, et al. Short and long-term outcomes with drug eluting and bare metal coronary stents: A mixed treatment comparison analysis of 117,762 patient-years of follow-up from randomized trials. Circulation. 2012;Epub ahead of print.

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