The Safety of Drug-Eluting Stents: What the Trial Data and Real-World Experience Tell Us

Abstract: Data presented at the 2006 World Congress of Cardiology questioned the safety of drug-eluting stents (DES), causing a notable shift in clinical practice patterns in patients undergoing percutaneous coronary interventions (PCI). Results from Stettler’s large-scale network meta-analysis and assessment of multiple clinical registries published in 2007 challenged those findings. The pooled registry data demonstrated that after 4 years of follow up, DES implantation did not increase the risk of mortality or myocardial infarction when compared with bare-metal stents (BMS). The data analysis also showed that DES use dramatically reduced the need for repeat revascularization compared with BMS. Furthermore, the evidence suggested that although late stent thrombosis (> 1 year after stent implantation) was a complication of DES use, early (within the first 6 months after stent implantation) stent thrombosis occurred more frequently with BMS implantation; overall, however, the risk of stent thrombosis with both types of stents was comparable. A 6-month course of dual antiplatelet therapy (aspirin plus clopidogrel) can mitigate this risk. In addition, the long-term rates of target lesion revascularization were lower in patients who received DES as compared with their BMS-treated counterparts. Routine use of intravascular ultrasound before and after PCI to optimize stent implantation and positioning can contribute to successful procedures and favorable long-term outcomes. Taken together, the benefits of DES implantation outweigh the risks. Introduction In 2006 at the World Congress of Cardiology (WCC) meeting in Barcelona, Spain, two “Hot Line” presentations had an immediate effect on the world of interventional cardiology. Swiss physician Edoardo Camenzind presented the results of a meta-analysis of the published randomized clinical trials of the sirolimus-eluting stent (SES) and the paclitaxel-eluting stent (PES).1 Contrary to expectations, Camenzind indicated that the incidence of mortality and Q-wave myocardial infarction (MI) were 38% greater for SES and 16% greater for PES when compared with bare-metal stents (BMS). He stated that the “indiscriminate use” of drug-eluting stents (DES) should not be encouraged until safer, second-generation DES became available. He concluded that BMS use should be continued. The second presenter, Alain Nordmann, reported the results of a meta-analysis of 17 randomized trials in which DES and BMS were compared.2 He found that cardiac and all-cause mortality were comparable for SES and BMS over 4 years, and PES and BMS over 3 years, but there was an increased risk of noncardiac mortality (due to stroke, lung disease and cancer) in year 2 with SES versus BMS. These data are inconclusive, although they do seem to indicate that any increase in noncardiac mortality was not related to thrombotic events. The storm of controversy that followed these presentations stemmed largely from the unexpectedness of the findings. The safety and effectiveness of DES were reported in multiple large-scale clinical trials: RAVEL,3 SIRIUS,4 E-SIRIUS5 and C-SIRIUS6 for SES, and TAXUS I through VI7-9 trials for PES. Considered one of the greatest advancements in the treatment of coronary artery disease, DES dramatically reduced the need for repeat revascularization, even compared with BMS. The rates of both early and late stent thrombosis were low, comparable to the rates seen with BMS.3,4,8,9 Yet Camenzind’s review of the published evidence, which was presented in a Hot Line session at the WCC meeting and therefore was not subject to standard peer review, brought about an immediate dramatic change in patient management practices. At the 2006 WCC meeting, Dr. Salim Yusuf, chair of cardiology at McMaster University in Hamilton, Ontario, Canada, called for a moratorium on DES implantation until all of the data could be further reviewed and reevaluated. Within 1 year, the use of DES in the United States fell by nearly 20% (Figure 1).10 A comprehensive analysis of all randomized data has now been published, with reassuring results.11 Based on the findings in over 18,000 patients, Stettler and colleagues concluded that on key safety measures, such as overall and cardiac mortality, and stent thrombosis, DES and BMS produced comparable event rates.11 More importantly, patients who received DES experienced an impressive reduction in target lesion revascularization (TLR) rates. On balance, the benefits of DES appeared to greatly outweigh the risks. The sidebar to this article offers several reasons that might explain why the results of the Camenzind and Stettler meta-analyses differed so vastly. The tsunami of negative media coverage surrounding the DES controversy of 2006–2007 was inescapable and may have had an adverse impact on some patients undergoing percutaneous coronary interventions (PCI) during that period. Many patients who might have benefited from SES or PES implantation did not receive a DES; many who did were alarmed by this new information. Some patients began calling hospitals asking — even demanding — to have the DES removed from their body. Although not completely resolved, the dust has settled somewhat, and cath lab professionals can draw a number of practical conclusions from the controversy. These relate to the difference between early and late stent thrombosis, the role of dual antiplatelet therapy, the need for careful patient selection, and the importance of intravascular ultrasound (IVUS) in stent implantation. Before addressing these issues, it is useful to review the Stettler meta-analysis to see why its findings were so different from those presented just 1 year earlier at the 2006 WCC. Analyzing the Trial Data Using the recently developed standardized Academic Research Consortium (ARC) definitions of outcomes (i.e., definite stent thrombosis), Stettler and his collaborators reviewed patient-level data from 38 clinical trials that compared the two commercially available DES with BMS; this also included a comparison of SES with PES.11 Information on more than 18,000 patients, who were followed for periods of up to 4 years, was included in the meta-analysis. In comparison, Camenzind’s meta-analysis was comprised of 8 trials totaling 5,008 patients.1 The key prespecified outcomes in the Stettler meta-analysis were overall mortality, cardiac mortality, myocardial infarction (MI) including both Q-wave and non-Q-wave infarcts, a composite of death and MI, and definite stent thrombosis confirmed by angiography or postmortem examination. In contrast with the Camenzind report, Stettler and colleagues showed that mortality was essentially the same for all three comparisons (SES vs BMS, PES vs BMS, SES vs PES) (Table 1).11 There were no significant differences between the three stents in the likelihood of ARC-defined definite stent thrombosis at the end of follow-up (Table 2). The investigators also found that the incidence of target lesion revascularization was significantly lower for both SES vs BMS and PES vs BMS (70% and 58%, respectively; p The Real-World Experience Despite the care taken by Stettler et al in designing their collaborative assessment of the available safety and efficacy data, it remains a retrospective analysis. Fortunately, evidence from several international registries is available to allow a comparison between the meta-analysis of randomized clinical trials and “real-world experience”. Results from registry studies more closely reflect routine clinical practice patterns than those from the tightly controlled setting of a clinical trial. The Swedish Coronary Angiography and Angioplasty Registry (SCAAR) is a database that monitors the outcomes of more than 19,000 consecutive patients who have undergone PCI.12 The initial results, which covered the years 2003 and 2004, showed that DES were associated with an 18% increased risk of death, which appeared after 6 months. Like the Camenzind meta-analysis, the SCAAR data were widely reported by the popular media with sensationalized headlines. A subsequent SCAAR analysis, which included data from 2005, reached a different conclusion from the first. James and colleagues reported at the 2007 European Society of Cardiology meeting that DES use did not increase the overall risk of combined death and MI or MI alone after 4 years of follow-up compared with BMS implantation.13 Even though the risk of late stent thrombosis was higher with DES, that risk did not lead to an increased chance of death or MI over time. Although the likelihood of late stent thrombosis remained elevated after 6 months in patients receiving DES, it was balanced by a lower risk of death or MI during the initial 6 months (Figure 2). Worth noting, too, was the finding that the absolute reduction in restenosis was lower than in the randomized clinical trials (4% in SCAAR vs > 10% in the Stettler analysis). The investigators suggested that a lack of angiographic follow-up in the real world could be an explanation of this finding. Another analysis of 3,751 patients in the Cardiac Care Network of Ontario’s clinical registry of all patients undergoing PCI in Ontario, Canada reached a different conclusion.14 The Canadian study indicated that patients in the BMS group had a significantly higher 3-year incidence of death compared with those receiving DES, while the 2-year rate of MI was about the same (Figure 3). Like other studies, DES patients had a significantly lower revascularization rate than did BMS patients. Important registry evidence related to stent thrombosis in DES comes from two academic hospitals, one in Rotterdam, The Netherlands, and the other in Bern, Switzerland, although the registry is limited by the lack of a control BMS group. Between 2002 and 2005, 8,146 patients underwent PCI: 3,823 received SES and 4,323 received PES.15 The investigators found that the rate of stent thrombosis increased steadily (0.6% per year) during the first 3 years following DES implantation. Although early and late stent thrombosis occurred with both DES, the incidence of long-term thrombosis was greater with PES than with SES (1.8% and 1.4%, respectively; p = 0.031). The investigators concluded that late stent thrombosis appeared to have distinct pathophysiological factors that differed from those of early stent thrombosis, which could occur unpredictably at any time, even when dual antiplatelet therapy was prescribed. Together with acute coronary syndrome (HR 2.21; 95% CI 1.18–3.28) and younger age (HR 0.97; 95% CI 0.95–0.99), PES use (HR 1.67; 95% CI 1.08–2.56) was noted to be an independent predictor of late stent thrombosis.16 The results of these recent registry studies confirm those of the collaborative network meta-analysis: 1. DES implantation is not associated with an increased risk of death or MI compared with BMS. 2. DES is associated with a significantly lower incidence of restenosis in target lesions and vessels. 3. The risk of very late stent thrombosis appears greater with first-generation DES than with BMS. 4. This risk of late stent thrombosis appears to be balanced by the significantly reduced incidence of early events such as restenosis. These findings suggest that early and late stent thrombosis may be two distinct pathophysiological mechanisms with different contributing factors. Further research is necessary to identify these factors. Additional registry meta-analyses published after the Stettler meta-analysis have supported the use of DES. Researchers from the Melbourne Interventional Group compared outcomes with DES and BMS with a focus on stent thrombosis in 2,919 patients who underwent PCI.17 Outcomes at 30 days and 1 year were studied and predictors of stent thrombosis were identified. The incidence of early and late stent thrombosis was similar for BMS and DES (1.6% vs 1.4%; p = 0.66). DES use was not a predictor of stent thrombosis, but the absence of clopidogrel therapy at 30 days, renal failure, index procedure presentation with an acute coronary syndrome, diabetes mellitus, and total stent length were predictive of stent thrombosis. In another meta-analysis of 28 trials that included 5,612, 7,639 and 2,994 patients treated with DES, BMS, or balloon angioplasty, respectively, DES use did not have a significant effect on stent thrombosis compared with BMS or angioplasty.18 Implications for the Catheterization Lab What are the practical implications of this body of research? Perhaps the most important consideration involves the use of IVUS in stent placement, which was used in some of the registry clinical trial cases. The results suggest that routine utilization of IVUS imaging before and after DES deployment may contribute to high procedural and device success rates.19 Prior to implantation, IVUS can confirm lesion severity and whether stent implantation is warranted. IVUS also can identify appropriate proximal and distal stent “landing zones” and help determine the size and length of the device. Following stent deployment, IVUS can be used to confirm proper stent expansion and any malapposed struts, which can contribute to stent thrombosis and restenosis. IVUS also can confirm full lesion coverage and a proper match between the stented and adjacent vessel segments. Finally, IVUS can detect any important complications, such as edge dissections or hematomas, which the operator will need to address. In short, employment of routine IVUS can improve PCI outcomes with both BMS and DES.20–22 Based on a level of evidence that supports the efficacy of IVUS, the 2005 American College of Cardiology/American Heart Association/ Society for Cardiovascular Angiography and Interventions (ACC/AHA/SCAI) 2005 Guideline Update for PCI states that the use of IVUS is appropriate to assess the adequacy of coronary stent deployment, including the extent of apposition and minimum luminal diameter within the stent; to determine the cause of stent restenosis and guide selection of appropriate therapy; to evaluate coronary obstruction in a patient with a suspected flow-limiting stenosis when angiography is difficult due to location; and to assess a suboptimal angiographic result following PCI.20 The proper role of dual antiplatelet therapy is another practical problem associated with the use of DES. The network meta-analysis and the registry studies confirmed that late stent thrombosis was a serious risk in DES patients. Current recommendations indicate that 6 months of treatment can reduce the risk of thrombosis; the benefits of longer use are still under investigation. In a recent meta-analysis of DES vs BMS in patients with and without diabetes, Stettler et al found that DES were safe and effective when dual antiplatelet therapy was administered for 6 months or longer in both patients with and without diabetes.23 The benefits of longer duration of therapy must be weighed against the possible risks (e.g., bleeding). Evidence of a bleeding risk with clopidogrel also is mixed. Some studies reported that patients with cardiovascular disease who took both clopidogrel and aspirin had an elevated likelihood of hemorrhage.24 The CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial suggested that most bleeding events occurred early in treatment, with little difference in rates of bleeding later on.25 Thus, the long-term risk of bleeding linked to dual antiplatelet therapy may be exaggerated. What is not exaggerated is the importance of the body’s resistance to antiplatelet therapy. It is becoming apparent that a poor response to aspirin and clopidogrel is more common than previously recognized.26,27 Aspirin and clopidogrel resistance is associated with poor clinical outcomes, particularly stent thrombosis, cardiac death, and MI. In fact, non-responsiveness to clopidogrel may cause a 4-fold increase in the risk of stent thrombosis and the combined endpoint of cardiac death/MI.28 Among the causes are cellular and genetic mechanisms as well as clinical factors, which include a failure to prescribe, patient noncompliance, and poor drug absorption. Increasing the loading dose of clopidogrel from 300 to 600 mg can help overcome hypo-responsiveness. However, it is unclear whether higher doses will improve outcomes in resistant patients. In contrast, higher aspirin doses offer no benefit. Patients who may be at risk of poor clopidogrel response include those who weigh > 220 pounds and those who have diabetes, congestive heart failure, or a history of MI. For these reasons, patient education on the need to comply with antiplatelet treatment and the elimination of the use of “competing” substances, such as naproxen and COX-2 inhibitors, are imperative. Newer antiplatelet drugs now in development that have the potential for greater potency and a more consistent response may help overcome this problem.29 Compliance with a 6-month course of dual antiplatelet therapy is essential. Current ACC/AHA recommendations support 1 year of dual antiplatelet therapy in patients at low risk for bleeding complications.30 Patients with multiple comorbidities may have economic burdens that make it difficult for them to afford clopidogrel. It is important to remember that coronary DES are currently FDA-approved for use in simple de novo lesions. Outlook for DES The 2006 WCC meeting was a “shot heard around the world” with regard to DES safety. Now that much new evidence has been evaluated, it seems reasonable to conclude that the level of concern expressed at that congress was unfounded. Results from the largest collaborative meta-analysis and multiple clinical registries demonstrated that the 4-year rates of death, MI, or combined mortality/MI did not differ for DES and BMS. Although very late stent thrombosis appears numerically higher with DES, early stent thrombosis was numerically higher with BMS; thus, the overall incidence of thrombotic events was about the same. Adherence to a 6-month course of dual antiplatelet therapy can reduce the risk, and current ACC/AHA recommendations support 1 year of dual antiplatelet therapy in patients at low risk for bleeding complications. Meta-analyses of randomized studies also confirmed that DES deployment produced a significant and dramatic decline in the rate of restenosis and repeat revascularization, ranging from about 50% to 70%. Routine use of IVUS before and after stent implantation can prevent these adverse events and identify complications requiring medical treatment.20,21 It will be interesting to see, now that additional DES are becoming available and investigations on bioabsorbable stents have begun, how the interventional cardiology field may change. The recent draft research guidance document issued by the Food and Drug Administration in March 2008 is a result of the increased growth in the field.31 Today, the evidence affirms that, when used as indicated in appropriate patients, DES can improve outcomes and contribute to lower healthcare costs. The author can be contacted at gorskik@ccf.org This article received double-blind peer review from members of the Cath Lab Digest editorial board. Acknowledgments BioScience Communications of New York, New York, participated in the editorial production of this paper. Cordis Corporation provided financial compensation to BioScience for its participation. The author wishes to thank BioScience for its assistance.

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