Determining the magnitude of any increased risk of stent thrombosis associated with the use of drug-eluting stents has proven difficult. The randomized trials were designed to compare the effectiveness of drug-eluting vs bare-metal stents in preventing the rate of restenosis. Attempts to use isolated trial data to detect a significant difference in the lower rate of stent thrombosis have been routinely underpowered, even when data have been aggregated into meta-analyses.15
In addition, the trial experience represents only on-label stent use. A substantial percentage of stents are placed in circumstances for which they have not been FDA-approved,36,37
which means that trial results have limited generalizability.
Observational studies have been better powered to detect a difference in stent thrombosis and better reflect on-label and off-label stent use but are limited by potential biases resulting from unobserved differences in case-mix, severity of illness, and coronary anatomy between drug-eluting and bare-metal stent cohorts. All studies have been challenged by difficulties in attributing the clinical events of death and MI to stent thrombosis when cardiac catheterization data were not available, and up until recently,38
there has been no consistent approach to this issue.
We have assessed the impact of drug-eluting stents on the outcomes of percutaneous coronary revascularization by comparing outcomes for the population of patients undergoing coronary stenting in the drug-eluting stent era with outcomes in the bare-metal stent era. Although such an analysis will not answer the question of what is the true rate of stent thrombosis with drug-eluting stent vs the rate with bare-metal stent, it does address the important question of whether, on-average, the population of stented patients is being helped or hurt by the widespread use of this technology.
Based on the experience of 67 003 Medicare enrollees, we found that following the introduction of drug-eluting stent repeat revascularization rates significantly decreased. The relative risk of repeat revascularization decreased by 16.7% in the drug-eluting stent era compared with the bare-metal stent era. This occurred without any discernable increase in the incidence of death and STEMI, at least some of which would be attributable to stent thrombosis. This was true for all patient subgroups and both shortly after the procedure, when subacute stent thrombosis might occur, and between 4 and 24 months after the procedure, when late stent thrombosis might occur. Contemporaneous with the introduction of drug-eluting stent, there has been a small decrease in the rate of STEMI.
The magnitude of the decrease in repeat revascularization at 2 years that we found in the drug-eluting stent era compared with the bare-metal stent era (3.8%) is smaller than has been reported for clinically driven revascularization rates in the randomized trials (11.8%-20.6%).14,39,40
In part, this is because the trials compared cohorts of patients who received drug-eluting stents only with patients who received bare-metal stents only while our drug-eluting stent era cohort contained a mix of patients, 61.5% who had received a drug-eluting stent and 38.5% who had received a bare-metal stent. It is also a consequence of trials having strict angiographic criteria consistent with the on-label use of stents while in everyday clinical practice the decision about when and where to stent is not under such stringent control. This likely explains why our results are more comparable with those from several observational studies. The Emilia Romagna Italian registry19
of 10 629 patients (28.8% drug-eluting stent) reported an adjusted 2-year incidence of target vessel revascularization of 9.1% for patients receiving drug-eluting stents vs 12.9% for those receiving bare-metal stents (absolute difference, 3.8%; adjusted HR, 0.68; 95% CI, 0.57-0.80). The Swedish registry17
of 19 771 patients (30.5% drug-eluting stent) reported a crude 3-year rate of any repeat revascularization of 15.2% for a drug-eluting stent cohort vs 16.5% for a bare-metal stent cohort (absolute difference, 1.3%; adjusted HR, 0.84; 95% CI, 0.77-0.92). The Ontario registry21
of 3751 matched pairs of patients receiving drug-eluting and bare-metal stents reported 2-year target vessel revascularization rates of 7.4% and 10.7%, respectively (absolute difference, 3.3%; P
Most recently, the New York State PCI registry reported a target vessel revascularization at 2 years of 11.2% in adrug-eluting stent era cohort vs 17.9% in the bare-metal stent era (adjusted HR, 0.60; 95% CI, 0.56-0.64).41
It is possible that if the incremental hospital reimbursement for the use of drug-eluting vs bare-metal stents did not meet the incremental cost of using drug-eluting stents, particularly for procedures requiring multiple stents, there may have been some incentive in the drug-eluting stent era to stage procedures, which would have resulted in our underestimating the true early benefit of drug-eluting stents on rates of repeat revascularization.
We found no difference in survival between the drug-eluting stent and bare-metal stent era cohorts. A small but statistically significant decrease in the unadjusted rate of STEMI in the drug-eluting stent era cohort began to emerge at 3 months and increased slightly through 2 years of follow-up. This coincided with the lower rate of repeat PCI in the drug-eluting stent era cohort, some of which was presumably target-lesion related and due to restenosis. Because PCI in a stable patient population has not been shown to decrease the risk of STEMI, it is possible that our findings could be attributable to temporal improvements in the overall quality of cardiovascular care, even though the maximum difference in enrollment dates between the bare-metal and drug-eluting stent era cohorts was only 15 months. We recognize that this difference in event rates for STEMI is small, that its statistical significance is driven by our large sample size, and that the differences in death or STEMI were not significant after risk adjustment ().
The patient-level meta-analyses of randomized trials comparing drug-eluting with bare-metal stents13-15
have not shown a significant difference in the rates of death or STEMI out to 4 years of follow-up, even though an insignificant trend toward a higher event rate existed among patients who received drug-eluting stents in the pooled analysis of the sirolimus stent group.15
The large Italian registry19
reported results similar to ours with 2-year rates of death or STEMI of 12.3% for bare-metal vs 10.9% for drug-eluting stent use (adjusted HR, 0.87; 95% CI, 0.73-1.04). The Ontario study21
reported 2-year rates of death or MI of 10.5% for bare-metal stent vs 9.3% for drug-eluting stent use, a significant difference (P
=.02) driven by a lower mortality rate among patients receiving drug-eluting stents (4.3% vs 6.1%) with no difference in MI rates.
The New York State PCI registry41
reported 2-year rates of death or MI of 9.9% in the drug-eluting stent era vs 10.8% in the bare-metal stent era (adjusted HR, 0.90; 95% CI, 0.83-0.97), with no significant difference in survival (adjusted HR, 0.94; 95% CI, 0.84-1.04) but a significant difference in non-fatal MI (adjusted HR, 0.86; 95% CI, 0.76-0.97).
Although the Swedish registry,17
reported no significant difference in the overall incidence of the combined end point between the drug-eluting and bare-metal stent cohorts when the entire 3 years of follow-up were assessed, a significant increased risk of drug-eluting stents did emerge at 6 months when a “landmark analysis” was performed and patients who died or had a STEMI from enrollment to 5 months were removed from the analysis. This was done to investigate any effect that might emerge when dual antiplatelet therapy was stopped, as had been suggested by others.4,18,42
From 6 months to 3 years, drug-eluting stent use was associated with a significantly increased risk of death or STEMI (adjusted HR, 1.20; 95% CI, 1.05-1.37). We performed a landmark analysis of our data, conditioned on the absence of death or STEMI during the first 3 months of observation and assuming that after 3 months patients would no longer be taking their thienopyridine, as was the recommendation for the sirolimus-eluting stent at that time. Unlike the Swedish registry, our landmark analysis () showed no increased risk of death or STEMI in the drug-eluting stent era cohort. Left censoring at 6 months (data not shown) did not change our results. To what extent differences in patient selection, procedural practices, or postprocedure medical management (including the use of antiplatelet agents) explain why the results of our landmark analysis differed from that of the Swedish registry is unknown.
Our study has several limitations. We could not assess the true rate of stent thrombosis associated with the use of drug-eluting vs bare-metal stents because the administrative data does not contain the details of coronary anatomy and procedural process necessary to control for any selection bias in the use of 2 types of stents.17,19
We did not have data on medication use and could not directly assess the influence of dual-antiplatelet therapy on our findings. We did perform a landmark analysis and could detect no increase in adverse event rates in the drug-eluting stent era after 3 months of observation when there was no recommendation for the ongoing use of a thienopyridine agent.
Our results are limited to the experience with the sirolimus-eluting stent, not the paclitaxel-eluting stent. We excluded patients who may have presented with a STEMI. There remains uncertainty as to whether compared with bare-metal stents, drug-eluting stents are associated with improved outcomes in this setting.43-45
Our results are also limited to patients who were at least 65 years (who undergo approximately half of all PCIs) undergoing a first revascularization. Differences between our study cohort and other patient populations with those comorbidities, coronary, lesion, and procedural characteristics predictive of adverse events following a percutaneous intervention, or differences in the use of antiplatelet agents or resistance to them could alter our findings.
Similarly, our data do not permit us to assess to what extent temporal changes in patient characteristics (eg, coronary anatomy and function), procedural characteristics (eg, completeness of revascularization), the use of antiplatelet agents, or the overall quality of cardiovascular care contribute to our findings. For example, we know that in a relatively short period, the availability of drug-eluting stents was associated with an increased number of patients receiving a coronary stent (). Assuming no large change in the population at risk, this suggests that physicians’ thresholds for stent placement may have changed. They may have been more willing to stent lesions in vessels already at somewhat low risk for restenosis or other adverse events, or they may have been more willing to attempt multivessel stenting in patients who previously would have undergone CABG, a patient population at high risk for restenosis and other adverse events. Our data do not allow us to disentangle the extent to which changing practice patterns such as these contributed to the results of this study. We do know there was no evidence of secular changes in the observable characteristics of patients over time () and there was no evidence of a positive trend in survival during the pre–drug-eluting stent era prior to 2003 (data not shown).
In summary, we have found that for the Medicare population undergoing nonemergent coronary stenting, the availability of drug-eluting stents has decreased the incidence of repeat revascularization and resulted in no increase in the risk of death or STEMI over 2 years of follow-up. Although other data may suggest some incremental risk of stent thrombosis with the use of drug-eluting stents, we can detect no adverse consequence to the health of the population. We speculate that whatever the increased risk of stent thrombosis associated with drug-eluting stent use is, it is more than offset by a decrease in the risk of developing restenosis and the attendant risk of a procedure to treat that restenosis.