Abstract
The development of bare metal coronary stents revolutionized the treatment of coronary artery disease by reducing rates of acute vessel closure and restenosis associated with balloon angioplasty. However, bare metal stents (BMS) resulted in high rates of restenosis and led to the development of drug-eluting stents (DES). Those first-generation DES were followed by successive generations of DES that included improvements, such as biodegradable and more biocompatible polymers. Despite the superiority of the current DES compared to BMS, a subset of patients still receives BMS. The following paper reviews the literature comparing the safety and efficacy of newer generation DES to BMS in such patients and ultimately challenges the use of BMS in contemporary current DES era.
1
Introduction
Bare metal coronary stents (BMS) were introduced in the early 1990s for treatment of acute coronary syndrome and stable ischemic heart disease. Following evidence of improved angiographic and clinical outcomes with BMS, they replaced balloon angioplasty as the preferred treatment . However, problems associated with BMS, such as in-stent neointimal hyperplasia and subsequent restenosis, spurred the development of drug-eluting stents (DES). The first generation of DES also led to such complications as stent thrombosis (ST) or stent failure but at different time points . Researchers have improved both stent design and adjunctive medical therapy in order to address those problems.
The current cardiac catheterization lab is now equipped with BMS and newer generations of DES, including biodegradable polymer DES and bioresorbable scaffolding. As a result, interventional cardiologists are faced with a wide range of choices. The question now is whether there remains any role for BMS in percutaneous coronary intervention (PCI) in this age of contemporary DES. The following review briefly discusses the history of coronary stent development, compares the performance of DES to BMS in a variety of patient subsets and clinical scenarios, and questions the role of BMS utilization in the era of the newest generation of DES.
2
BMS versus DES in perspective
Coronary stenting became widely accepted after the publication of the landmark BENESTENT and STRESS trials, which demonstrated improved safety and superiority of stenting over balloon angioplasty when adequate technique and anticoagulation therapy were applied . Over the years, BMS technology has evolved and refined, as well as technique and adjunctive medical therapy. Specifically, stainless steel has been replaced with cobalt–chromium and platinum–chromium alloy, allowing for thinner stent struts and high radiopacity, while maintaining adequate radial strength, deliverability, and conformability . Nevertheless, those changes did not resolve the major problem with BMS technology: neointimal hyperplasia and in-stent restenosis and revascularization rates of 20% to 30% . Attempts to minimize in-stent neointimal hyperplasia subsequently gave rise to another revolutionary change: the drug-eluting coronary stent.
Incorporating the advancements of BMS structure, DES were also coated with anti-inflammatory or immunosuppressant medications to combat neointimal hyperplasia. The “first-generation” DES comprised sirolimus or paclitaxel drugs. The sirolimus-eluting stent (SES) and paclitaxel-eluting stent (PES) both had lower restenosis rates than BMS . However, the enthusiasm for DES in the interventional cardiology community was soon tempered by reports of an increase in ST and associated morbidity and mortality . Specifically, late and very late ST (> 1 year from PCI) occurred in 0.36% to 0.6% of patients per year for at least 5 years after implantation . ST mortality rates can be as high as 50% . Concerns about the safety of first-generation DES led to a steep decline in their use as operators opted for BMS and contributed to longer duration of DAPT treatment.
Several changes were implemented in second-generation DES to address the shortcomings of first-generation DES: These included elimination of paclitaxel and using more biocompatible polymers with the aim of reducing inflammation. Randomized trials have since demonstrated the safety and efficacy superiority of second-generation zotarolimus- and everolimus-eluting stents compared with BMS .
Recently, the NORSTENT Investigators published results of a large randomized study comparing long-term risks and benefits of contemporary DES (everolimus- and zotarolimus-eluting) versus BMS. At 6-year follow-up, there was no significant difference between groups in the primary outcome of composite death from any cause and nonfatal spontaneous MI. However, the TLR was twice the rate in the BMS group compared with the DES group. The rates of definite ST were 0.8% and 1.2% in the DES and BMS groups, respectively ( p = 0.0498) . Overall, the results show that the second-generation DES are safe and, reduce the need for TLR.
Is stent thrombosis of DES still an issue? A retrospective analysis that compared the relative risk of ST between three different stent generations over a 3-year period in >18,000 patients demonstrated a cumulative incidence of 1.0% with second-generation DES, the majority of which were zotarolimus- and everolimus-eluting stents, and no difference in risk compared with BMS . In addition, a recent large meta-analysis of prospective, randomized, controlled trials compared the risk of ST of various contemporary second-generation DES. The primary end point of definite or probable ST at 1 year was available in 110 studies (111,088 patients). The analysis demonstrated that all durable-polymer DES, except for PES, were superior to BMS . Currently, there is growing evidence from several head-to-head trials that the rate of ST with DES is similar to or numerically lower than that of BMS, with the caveat, however, that DAPT duration in DES patients is often longer and perhaps protects from ST regardless of stent type.
2
BMS versus DES in perspective
Coronary stenting became widely accepted after the publication of the landmark BENESTENT and STRESS trials, which demonstrated improved safety and superiority of stenting over balloon angioplasty when adequate technique and anticoagulation therapy were applied . Over the years, BMS technology has evolved and refined, as well as technique and adjunctive medical therapy. Specifically, stainless steel has been replaced with cobalt–chromium and platinum–chromium alloy, allowing for thinner stent struts and high radiopacity, while maintaining adequate radial strength, deliverability, and conformability . Nevertheless, those changes did not resolve the major problem with BMS technology: neointimal hyperplasia and in-stent restenosis and revascularization rates of 20% to 30% . Attempts to minimize in-stent neointimal hyperplasia subsequently gave rise to another revolutionary change: the drug-eluting coronary stent.
Incorporating the advancements of BMS structure, DES were also coated with anti-inflammatory or immunosuppressant medications to combat neointimal hyperplasia. The “first-generation” DES comprised sirolimus or paclitaxel drugs. The sirolimus-eluting stent (SES) and paclitaxel-eluting stent (PES) both had lower restenosis rates than BMS . However, the enthusiasm for DES in the interventional cardiology community was soon tempered by reports of an increase in ST and associated morbidity and mortality . Specifically, late and very late ST (> 1 year from PCI) occurred in 0.36% to 0.6% of patients per year for at least 5 years after implantation . ST mortality rates can be as high as 50% . Concerns about the safety of first-generation DES led to a steep decline in their use as operators opted for BMS and contributed to longer duration of DAPT treatment.
Several changes were implemented in second-generation DES to address the shortcomings of first-generation DES: These included elimination of paclitaxel and using more biocompatible polymers with the aim of reducing inflammation. Randomized trials have since demonstrated the safety and efficacy superiority of second-generation zotarolimus- and everolimus-eluting stents compared with BMS .
Recently, the NORSTENT Investigators published results of a large randomized study comparing long-term risks and benefits of contemporary DES (everolimus- and zotarolimus-eluting) versus BMS. At 6-year follow-up, there was no significant difference between groups in the primary outcome of composite death from any cause and nonfatal spontaneous MI. However, the TLR was twice the rate in the BMS group compared with the DES group. The rates of definite ST were 0.8% and 1.2% in the DES and BMS groups, respectively ( p = 0.0498) . Overall, the results show that the second-generation DES are safe and, reduce the need for TLR.
Is stent thrombosis of DES still an issue? A retrospective analysis that compared the relative risk of ST between three different stent generations over a 3-year period in >18,000 patients demonstrated a cumulative incidence of 1.0% with second-generation DES, the majority of which were zotarolimus- and everolimus-eluting stents, and no difference in risk compared with BMS . In addition, a recent large meta-analysis of prospective, randomized, controlled trials compared the risk of ST of various contemporary second-generation DES. The primary end point of definite or probable ST at 1 year was available in 110 studies (111,088 patients). The analysis demonstrated that all durable-polymer DES, except for PES, were superior to BMS . Currently, there is growing evidence from several head-to-head trials that the rate of ST with DES is similar to or numerically lower than that of BMS, with the caveat, however, that DAPT duration in DES patients is often longer and perhaps protects from ST regardless of stent type.
3
Current BMS utilization
Despite the improved safety and efficacy of the newest generation of durable-polymer DES, about 10% to 20% of patients still receive BMS in today’s catheterization laboratory . The decision to opt for a BMS is often based on lingering safety concerns stemming from the first-generation DES, including the risk of very late ST and the requirement for prolonged DAPT. In addition, the current ACC/AHA guidelines tend to support the choice of BMS in the setting of those concerns . Patients in whom BMS are often favored over DES include those with large vessel diameter, STEMI, advanced age, high bleeding risk, or indications for long-term anticoagulation. BMS may also be preferred for cost-effectiveness or reimbursement reasons and in patients in whom early cessation of DAPT is anticipated, such as those with poor medication compliance or undergoing urgent non-elective surgery ( Fig. 1 ) .
3.1
Large vessel diameter
BMS perform well in large-diameter vessels. There is an inverse relationship between vessel size and incidence of adverse clinical outcomes with the use of BMS, with most reports describing good clinical outcomes after PCI in coronary arteries ≥3.5 mm. Outcomes with DES are comparable, if not superior, to BMS.
The BASKET-PROVE (Basel Stent Kosten Effektivitats Trial Prospective Validation Examination) trial, a large, prospective, randomized multicenter study published in 2010, compared the performance of BMS, first-generation DES (sirolimus-eluting), and second-generation DES (everolimus-eluting) in ≥3.0 mm coronary arteries. At 2 years, a pooled analysis found a lower risk of cardiac death or MI with DES compared with BMS (RR 0.6; 95% CI 0.39–0.93; p = 0.02). In addition, target vessel revascularization (TVR) rates were significantly reduced in the DES groups .
The BASKET-PROVE II trial compared outcomes in newer biodegradable-polymer (BP) DES with second-generation everolimus-eluting durable-polymer (DP) DES and a thin-strut BMS in ≥3.0 mm coronary arteries, corroborated the results of BASKET-PROVE. The cumulative incidence of cardiac death, MI, or clinically driven TVR within 2 years was similar for BP-DES (7.6%) and everolimus-eluting DES (6.8%) but superior to BMS (12.7%) . There is limited evidence to support the preferential use of BMS over second-generation DES in large coronary arteries given improved outcomes with the latter and similar safety profiles ( Table 1 ).
| Indication/Population | Observational favoring DES ( N ) | RCT favoring DES ( N ) | Meta-analysis favoring DES ( N ) | No significant difference ( N ) |
|---|---|---|---|---|
| CTO | Ma et al. (1678) a b Yang et al. (9140) a Lanka et al. (6705) Colmenarez et al. (4394) a | |||
| SVG | Chakravarty et al. (246) a | Alam et al. (812) a Lupi et al. (7090) a Sanchez-Recalde et al. (5543) a Hakeem et al. (7994) a Shi et al. | Goswami et al. (379) a | |
| Calcification | Bangalore et al. (1537) a | Zhang et al. (2440) a | ||
| Bifurcation | Grundeken et al. (497) Costopoulos et al. (192) | |||
| Large vessel | KAMIR (985) Na et al. (240) | BASKET-PROVE (2314) BASKET-PROVE II (2291) | Geng et al. (4399) | Hseih et al. (1096) Naghshtabrizi et al. (745) Abe et al. (401) |
| STEMI | Abe et al. (401) Yano et al. (380) | EXAMINATION (1498) DEDICATION (626) COMFORTABLE AMI (1161) | Palmerini et al. (12,453) Suh et al. Wang et al. (7592) Philip et al. (9673) Bangalore et al. (34,068) | |
| Old age | Puymirat et al. (293) | XIMA (800) BASKET-PROVE (405) | Gao et al. (2088) | |
| Cost effectiveness | Zbinden et al. (2278) | Ferko et al. (4896) Milic et al. (6454) b Baschet et al. | ||
| High bleeding risk | ZEUS (1606) LEADERS FREE (2385) | |||
| Non-cardiac surgery | Holcomb et al. (20,590) | Hawn et al. (41,989) Mahmoud et al. (24,313) |
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