Drug-Eluting versus Bare-Metal Stents: When and for Whom?

Percutaneous coronary intervention (PCI) is the most commonly performed treatment modality for obstructive coronary artery disease. Stents are an indispensable component of PCI, allowing substantial improvement in acute and long-term results compared to plain balloon angioplasty. However, the use of bare-metal stents (BMS) is sufficiently limited by angiographic restenosis in as many as 20–40% of patients (depending upon patient and lesion characteristics), caused mainly by excessive neointimal formation.
The introduction of drug-eluting stents (DES) represents a key landmark in the development of PCI. The pivotal, largescale, prospective, multicenter, randomized trials provided strong and consistent evidence that DES significantly reduce restenosis and enhance event-free survival compared with BMS after implantation in relatively simple and moderately complex lesions in native coronary arteries.^1–4 This rapidly resulted in unprecedented rapid adoption of this technology of up to 80–90% rates of DES use for revascularization procedures in a broad variety of patients and lesions in the United States. However, there are two major concerns associated with the use of DES. The first, and most important, is an increased incidence of late stent thrombosis raising serious concerns about the safety of DES technology⁵ and mandating long-term use of dual antiplatelet therapy. Second, the introduction of DES resulted in escalating procedural costs that have become a serious economic burden for the patient and for the healthcare system. This is true with regard to the costs related to both DES and associated prolonged dual antiplatelet therapy. Both concerns dictate thorough patient and lesion selection to optimize clinical outcomes and to minimize the patient’s risk.
In this regard, the study by Bertrand et al published in this issue of the Journal is very timely.⁶ The authors present a comparison of short- and long-term clinical outcomes of 362 consecutive patients undergoing multilesion PCI, using exclusively DES for all comers in any clinical and angiographic scenario, i.e., regardless of lesion/vessel characteristics, versus selective use of DES in indications provided by the local authorities/health agencies/cardiologists in the Quebec province of Canada. These indications included the presence of diabetes mellitus, location of the target lesion in the proximal segment of the left anterior descending artery, diameter of the target vessel < 2.9 mm and length of the target lesion ≥ 15 mm. A similar policy has been adopted by several countries and is based primarily on the knowledge of key predictors of restenosis after BMS implantation including diabetes, longer lesion length and smaller vessel size.⁷ At a mean follow up of 412 days, major adverse cardiac events occurred in less than 20% of the patients, without significant difference between the two groups. Rates of target lesion revascularization were also very low (< 10%) and quite similar between the two groups. However, the patients treated exclusively with DES had remarkably higher rates of stent thrombosis, assessed by the Academic Research Consortium criteria, than did patients treated with the selective DES approach (3.7% vs. 0.5%). The high incidence of stent thrombosis in patients in the exclusive DES group was probably related to the significantly worse clinical and angiographic profile of the patients and/or lesions in this group. In fact, patients in the exclusive DES group had a significantly higher incidence of diabetes mellitus, history of coronary artery bypass grafting and longer lesions.
Obviously, this study suffers from all the major limitations of a retrospective trial with nonrandomized comparison. However, despite the uneven clinical and angiographic characteristics as a result of the study design, the current analysis shows that contemporary PCI with selective use of either DES or BMS provides excellent clinical outcomes and potentially improves long-term procedural safety.
The study triggers several comments. Large-scale, randomized clinical trials provided strong evidence that DES significantly reduce restenosis and associated clinical events compared with BMS across most lesion subsets.^1–4 However, the increased incidence of late stent thrombosis related to the use of DES and the high cost of DES continues to raise serious concerns about using this technology.⁵ To combat stent thrombosis after DES-assisted angioplasty, prolonged dual antiplatelet therapy including aspirin and clopidogrel is indicated. Initially recommended for 3 months in patients treated with a sirolimus-eluting stent and for 6 months for patients treated with a paclitaxel-eluting stent, the current recommendation for the duration of a dual antiplatelet regimen is at least 1 year regardless of the type of DES used. After the period of 1 year, there remains considerable debate as to how long clopidogrel therapy should be maintained. Although there is growing evidence supporting the effectiveness of prolonged clopidogrel therapy post PCI, there is concern about its broad application, given the cost of treatment (approximately $100 per month).^8,9 In many countries, there is no comprehensive medication coverage that includes clopidogrel, thus the financial burden of clopidogrel therapyfalls primarily on patients. Premature cessation of clopidogrel is the main predictor of late stent thrombosis after DES implantation, and apart from the high cost of the medication, it may occur due to noncardiac surgery, dental procedures, allergic reactions to clopidogrel, lack of patient compliance and lack of adequate patient instructions.
Another vital issue related to prolonged dual antiplatelet therapy is the risk of hemorrhagic complications. Although recent trials suggest that prolonging therapy for up to 1 year after PCI reduces cardiac events, patients treated with clopidogrel may have an increased risk of bleeding.^8,9 In Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) trial, the combination of clopidogrel with aspirin compared to placebo with aspirin was associated with an increase in major bleeding (3.7% vs. 2.7%; p = 0.001) and minor bleeding (5.1% vs. 2.4%; p < 0.0001).⁹ Elderly patients (≥ 75 years of age) had especially high rates of major bleeding when treated with dual antiplatelet therapy (5.9% vs. 3.6%; p < 0.001). The occurrence of serious bleeding events in patients after DES-assisted PCI raises a serious therapeutic dilemma with regard to subsequent antiplatelet treatment. Continuation of dual antiplatelet therapy may result in a life-threatening bleeding event, while cessation of such therapy is fraught with stent thrombosis and related devastating consequences.
One should also consider significant improvement in the long-term performance of the newer-generation BMS. Contemporary treatment of lesions with a low probability of restenosis (short lesions in medium- to large-sized vessels) with BMS results in < 10% rates of angiographic restenosis and a lower number of clinical events.¹⁰ One of the obvious advantages of BMS is the ability to apply incomplete plaque coverage, restricting stent surface to the segments with significant stenosis of the target vessel, leaving untreated luminal narrowing < 50% adjacent to the stenosed area. Shorter stents are known to decrease the probability of restenosis after BMS implantation. In contrast, the exposed margins of DES that do not cover the entire region of balloon injury are the primary sites of restenosis, which frequently occur at the stent margins especially in smaller vessels.² To avoid edge restenosis, the use of the longer DES to cover the entire plaque segment is recommended. In view of the above, the strategy presented here of lesion-based DES therapy in combination with BMS is timely and extremely important. We have adopted this strategy in our center from the early days of DES in Israel. We have observed this lesion-based DES approach as feasible and safe. This approach was maintained throughout the turbulent times of DES concerns and, in fact, the percentage of DES use in our institute with respect to BMS stands around 40%, without a major change today.
In conclusion, a selective DES/BMS approach appears not only viable, but also safe, for certain patient subsets. The clinical outcomes after such an approach are quite favorable and are associated with low rates of late stent thrombosis. The retrospective analysis by Bertrand et al generates the hypothesis that while the efficiency of both methods is similar, the safety profile of such a selective strategy may be sufficiently higher compared to an exclusive DES treatment modality, and calls for a large, prospective, randomized trial. The choice of DES or BMS should be thoroughly considered in each clinical and angiographic scenario. To achieve the best outcomes, the decision should carefully accommodate the clinical data (presence/ absence of diabetes, propensity for bleeding complications and tolerance of antiplatelet medications), angiographic characteristics (vessel size, lesion length and location), compliance with extended clopidogrel use and need for noncardiac surgery.

References

1. Morice MC, Serruys PW, Sousa JE, et al, for the RAVEL Study Group. Randomized study with the sirolimus-coated velocity balloon-expandable stent in the treatment of patients with de novo native coronary artery lesions. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002; 346: 1773– 1780.
2. Moses JW, Leon MB, Popma JJ, et al, for the SIRIUS Investigators. Sirolimuseluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349:1315–1323.
3. Stone GW, Ellis SG, Cox DA, et al, for the TAXUS-IV Investigators. A polymerbased, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med 2004; 350: 221– 231.
4. Stone GW, Ellis SG, Cannon L, et al, for the TAXUS V Investigators. Comparison of a polymer-based paclitaxel-eluting stent with a bare metal stent in patients with complex coronary artery disease: A randomized controlled trial. JAMA 2005; 294: 1215–1223.
5. Mauri L, Hsieh WH, Massaro JM, et al. Stent thrombosis in randomized clinical trials of drug-eluting stents. N Engl J Med 2007; 3 56 :1020–1029.
6. Bertrand OF, Faurie B, Larose E, et al. Clinical outcomes after multi-lesion percutaneous coronary intervention: Comparison between exclusive and selective use of drug eluting stents. J Invasive Cardiol 2008; 20: 99–104.
7. Cutlip DE, Chauhan MS, Baim DS et al. Clinical restenosis after coronary stenting: Perspectives from multicenter clinical trials. J Am Coll Cardiol 2002;40:2082–2089.
8. Steinhubl SR, Berger PB, Mann JT III, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: A randomized controlled trial. JAMA 2002; 288: 2411–2420.
9. Mehta SR, Yusuf S, Peters RJ, et al, for the Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: The PCI-CURE study. Lancet 2001; 358: 527–533.
10. Dietz U, Dauer C, Lambertz H. Combining short stent implantation and drug-eluting stenting for routine use yields a low restenosis rate. Curr Control Trials Cardiovasc Med 2005; 6: 18.