The introduction of drug-eluting stents in 2003 was of epoch-making significance. Because it solved the problem of restenosis after stenting to some extent, coronary interventions entered a period of vigorous development with expanding indications, from long lesions to bifurcation lesions, from chronic occlusive lesions to left main stem, from chronic stable angina to acute myocardial infarction, the drug-eluting stents were unlimited and seemed to be the ultimate solution for coronary artery disease, with only some imperfections to be improved.
However, the good times did not last long, and soon the safety of drug-eluting stents was questioned. From sporadic case reports of late thrombosis to the ESC 2006 meeting when the RAVEL and BASKET-LATE trials and other studies showed a possible increase in late in-stent thrombotic events and long-term clinical adverse events (death and myocardial infarction) with drug-eluting stents compared with bare metal stents, the safety of drug-eluting stents has attracted widespread attention from interventionalists and patients worldwide. A total of 238 patients were randomized to drug-eluting stents (SES) and bare stents (BMS) in the trial. 5-year follow-up showed that the survival rate without adverse cardiac events was 74.2% in the SES group compared with 64.8% in BMS (P=0.034).
The aim of the BASKET-LATE trial was to compare the incidence of clinical events associated with stent thrombosis in the late phase (after 6 months of clopidogrel discontinuation) with drug-eluting stents (DES) and bare stents (BMS). death and those with events were excluded at 6 months after PCI, and the final At 12-month follow-up, the incidence of cardiac death or nonfatal myocardial infarction was 4.9% and 1.3% in the DES and BMS groups, respectively (P=0.01), and the incidence of thrombus-related clinical events was 2.4% and 0.8% in the DES and BMS groups, respectively (P=0.14), while the incidence of all thrombus-related events was 2.6% and 1.8%, respectively (P=0.14). The incidence of all thrombosis-related events was 2.6% and 1.3%, respectively (P=0.23).
One stone stirred a thousand waves, and over time, drug-eluting stents were severely challenged, and people began to re-examine the overuse of drug-eluting stents, and bare stents, which were already in a desperate situation, had some chances of survival. According to U.S. data, the use of drug-eluting stents declined from 94% in 2005 to 60-70% in 2007 due to concerns about the safety of drug-eluting stents.
Subsequently, the debate over the safety of drug-eluting stents became a hot topic, and the conclusions reached wavered due to inconsistent results from numerous clinical trials. A meta-analysis of drug-eluting stents presented at TCT 2006, only 1 month after ESC 2006, showed that drug-eluting stents did not increase the incidence of death or myocardial infarction and that the safety of drug-eluting stents was not in question.
The 3-year follow-up results of the Swedish Coronary Angiography and Interventional Registry Study (SCAAR), published in the New England Journal of Medicine in March 2007, further showed that the safety of drug-eluting stents (DES) is of concern. Although the composite endpoints of death and myocardial infarction did not differ significantly between the two groups at 3-year follow-up compared with bare stents (BMS), and there was a trend toward a lower incidence of the composite endpoint in the DES group during the first 6 months, after 6 months, the DES group had a 0.5% to 1.0% increased risk of death per year, an 18% relative increase in the total risk of death at 3 years, and a 32% relative increase in the risk of death between 6 months and 3 years.
Dramatically, the 4-year follow-up results of the SCAAR study, presented only 6 months later at the ESC 2007 annual meeting in September, showed that, unlike the 3-year follow-up results, total mortality at 4-year follow-up had become indistinguishable between the DES and BMS groups (RR 1.03 95% CI=0.94-1.14), both within 6 months (RR 0.92 95% CI=0.78-1.07) and between 6 months and 4 years (RR 1.09). period (RR 1.09 95% CI=0.96 to 1.25). However, the DES treatment group had a low incidence of the composite endpoint within 6 months (RR 0.85 95% CI=0.77-0.95) and an increased incidence of the composite endpoint between 6 months and 4 years (RR 1.17 95% CI=1.06-1.29), although this increased risk was offset by an early benefit. The results are quite convincing and demonstrate, at least to some extent, the safety of DES.
The 18-month follow-up results of the BASKET-LATE trial, also presented at the meeting, showed that the target revascularization rate was lower in the drug-eluting stent (SES) group than in the BMS group, and the incidence of cardiogenic death or myocardial infarction was 8.4% and 7.2% in the two groups, respectively, with no statistical difference. Still, the 2-year follow-up of the ST-segment elevation acute myocardial infarction part of the GRACE study presented at this meeting showed that the risk of death was more than 6 times higher in the DES group than in the BMS group (180-730 days).
A clinical meta-analysis of 38 clinical trials (18,023 patients) comparing rapamycin-eluting stents (SES), paclitaxel-eluting stents (PES), and bare stents (BMS) was published by Stettler C in The Lancet in September 2007. The occurrence of death, myocardial infarction, and definite stent thrombotic events after surgery. The results showed that neither DES increased mortality during the 4-year follow-up period compared with BMS.
At ACC 2008 Kirtane presented the largest meta-analysis to date, including 52 clinical trials of Cypher and Taxus drug-eluting stents versus bare stents in more than 180,000 patients with follow-up to 3-4 years. Of these, 22 randomized controlled studies (approximately 10,000 patients) showed a trend toward a reduction in death and infarction in the DES group and a significant reduction in target vessel revascularization (TVR) (55%). 30 clinical registry studies (174,000 patients) showed a 20% reduction in mortality, an 11% reduction in infarction, and a 47% reduction in target vessel revascularization in the drug-eluting stent group. Conclusion: Drug-eluting stents are as safe as bare stents, even when used “off label”.
The Massachusetts stent registry, also presented at ACC 2008, showed that drug-eluting stents reduced 2-year mortality and the incidence of reinfarction in non-ST-segment infarction in all acute myocardial infarctions compared with bare stents. The study enrolled 7217 cases of acute myocardial infarction from April 1, 2003, to September 30, 2004, with 4016 implanted drug-eluting stents (mainly Cypher) and 3201 implanted bare stents.
The decrease in mortality may be explained by the reduced risk associated with restenosis and revascularization with drug-eluting stents, and another important reason may be the benefit of long-term dual antiplatelet therapy after drug-eluting stents. Despite questions of stent selection bias, this trial still confirms the efficacy and safety of drug-eluting stents in the treatment of acute myocardial infarction and alleviates concerns about increased death and infarction with drug-eluting stents, especially in acute thrombotic events.
The results of a recent long-term retrospective study by Mehdi Shishehbor, published in the September 2008 issue of JACC, showed that drug-eluting stents reduced the risk of all-cause mortality by 38% compared with bare stents. The study enrolled 6053 patients treated with DES and 1983 patients with BMS from 2003 to 2007, with a total of 832 deaths over a follow-up period of up to 4.5 years.
At this point, the debate over the safety of drug-eluting stents is far from settled, and there are still questions about the interpretation of the trial results: did the “superiority” shown by drug-eluting stents stem from the stents themselves, or was it due to long-term adherence to dual intensive antiplatelet therapy, or was it an artifact of biased stent selection in the trial? However, at least a relatively objective conclusion can be drawn: in the real world, drug-eluting stents have a mildly increased risk of late (after 6 months) thrombosis compared with bare stents, but do not increase or even decrease the overall incidence of death and infarction. Therefore, drug-eluting stents are as safe as bare stents.
That said, the specter of late thrombosis with drug-eluting stents is already lingering. Theoretically, the susceptibility to induce thrombosis can be said to be a congenital defect brought from mother’s womb by drug-eluting stents. The drug inhibits the proliferation of smooth muscle cells and reduces restenosis while inevitably delaying the complete coverage of the stent by the endothelium. In addition, late malapposition, endothelial dysfunction, and local allergic vasculitis due to drug-eluting stents are possible triggers of late thrombosis.
In addition to the thrombus itself, the safety issues derived from the long-term dual antiplatelet therapy necessary after drug-eluting stents (increasingly longer, from 6 to 9 months, to 12 months, to longer and longer) should be given due attention. With such a long time window, if surgery is required for other diseases, one is immediately faced with the dilemma of choosing between stopping the antiplatelet drugs for fear of intra-stent thrombosis and often fatal; or not stopping the antiplatelet drugs, which can easily lead to intra-operative and post-operative hemorrhage, and stopping again after bleeding to face the risk of stent thrombosis.
With more and more patients receiving drug-eluting stents, this derived safety issue, which is gradually increasing, has become a new hot spot of concern. Thus, the safety of drug-eluting stents includes two aspects: thrombosis and the consequent necessity of long-term dual antiplatelet therapy derived from a series of problems.
The safety of drug-eluting stents will undoubtedly be improved by improvements in stent design and processes, including control of drug release time, degradation of coatings and even stents, uncoated drug delivery, endothelial cell capture, and other technologies. However, in addition to hope for stent development, the key to addressing the safety of drug-eluting stents lies in the rational use of drug-eluting stents by physicians.
The patient’s compliance with long-term oral dual antiplatelet agents, the risk of bleeding, and the possibility of surgery during the period should be fully evaluated before making the decision to choose a drug-eluting stent; the benefit of restenosis prevention should be weighed against the risk of thrombosis. It should be a wise decision to choose bare stents in cases of low restenosis risk, such as vessels ≥2.8 mm in diameter with limited lesions and no comorbid diabetes; and surgical bypass surgery in cases of high restenosis and thrombotic risk, such as when diabetes, small vessel disease, long lesions, involvement of bifurcation, chronic occlusion, and multi-branch lesions are present at the same time.
After all, there is no absolutely safe stent, only relatively safe physicians. It is the responsibility of every physician to balance the benefits and risks and make the choice that is in the best interest of the patient for his or her specific situation.