Overview
The field of coronary revascularization was revolutionized more than 50 years ago, when the first successful coronary artery bypass surgery was performed, followed shortly thereafter by the first percutaneous procedure to dilate and open coronary arteries. Advances in operative techniques and biomedical engineering over the past decades have greatly expanded the indications and possibilities for coronary revascularization, so much so that in the United States alone, more than 800,000 revascularization procedures are performed each year. This chapter focuses on the recent advances in coronary revascularization in the catheterization laboratory and in the operating room.
Advances in Coronary Stenting
Pre-Stent Era
The concept of coronary angioplasty was first introduced in 1964, when Dotter and Judkins used serially larger sized, rigid dilators over a guidewire to enlarge the lumen of a stenotic blood vessel. Unfortunately, the size and inflexibility of the dilators limited the ability of clinicians to deliver this therapy to small stenotic coronary arteries. Over the subsequent 15 years, a method designed specifically for coronary arteries was developed that utilized a small inflatable balloon to treat isolated lesions within atherosclerotic vessels; this was called balloon angioplasty. Throughout the 1980s and 1990s, the techniques and equipment related to balloon angioplasty were further refined and included the development of a moveable guidewire system, guidewires with tip designs of variable stiffness to aid in crossing complex lesions, and a collection of progressively smaller caliber guide catheters that could still provide necessary support during percutaneous interventions. These fundamental advances in balloon angioplasty allowed revascularization procedures to be performed percutaneously in a growing number of patients with coronary artery disease.
Despite these advances, the initial procedural success rate with balloon angioplasty was far from perfect, ranging between 60% and 80%. Early studies demonstrated that balloon inflation within the coronary vessel often led to the embolization of plaque and thrombus with resulting poor flow in the distal vessel. The risk of thrombotic complications was reduced with the use of systemic anticoagulation during balloon angioplasty. However, other issues with balloon angioplasty surfaced. Studies demonstrated that balloon inflation in a stenotic vessel segment could result in vessel recoil, which could lead to abrupt closure early after the procedure. In addition, development of intimal hyperplasia with eventual restenosis of the vessel over the subsequent 6 months was common. To address immediate elastic recoil and late restenosis that occurred commonly after balloon angioplasty, the concept of coronary stenting was born.
Bare-Metal Stents
The first stent was placed in a human coronary artery in 1987. Over the following years, the design of the stent was refined to allow for delivery in more tortuous, stenotic, and distal vessels. The benefits of stenting over balloon angioplasty were demonstrated in several studies. In the Belgium-Netherland Stent (BENESTENT) and Stent Restenosis Study (STRESS) randomized controlled trials (RCTs) in the early 1990s, intervention with the Palmaz-Schatz stent demonstrated lower rates of restenosis and cardiac events—including death, myocardial infarction (MI), stroke, or need for repeat angioplasty or coronary artery bypass grafting (CABG)—at 6 to 8 months when compared with balloon angioplasty (relative risk [RR], 0.68; 95% confidence interval [CI], 0.5 to 0.92; P = .02), a benefit that persisted in long-term follow-up.
Since the initial success of the Palmaz-Schatz stent, the physical design of stents has evolved to optimize their performance. Initial bare-metal stents were composed of stainless steel; however cobalt-chromium and cobalt-platinum alloys have allowed the engineering of stents with good radial strength but thinner and more flexible struts. The geometric configuration of stents has also undergone serial modifications. The Palmaz-Schatz stent was composed of rows of metallic slots, which would expand into diamond shapes with stent deployment (“slotted tube” formation). In an attempt to improve the flexibility of the stent, newer multicellular stents have been developed. These are generally categorized as either open-cell or closed-cell designs. Closed-cell stents have uniform patterns of cell shapes along the stent, which generally provide more constant vessel wall coverage but slightly less flexibility. Open-cell stents are more commonly used today and have patterns of varying cell sizes and shapes throughout the stent, thereby allowing for greater flexibility in the stent when maneuvering through a tortuous vessel.
Despite advances in stent deliverability, the risk of restenosis following bare-metal stent placement has remained fairly constant over time, with rates of restenosis as high as 20% to 40% on repeat angiography and a clinical need for repeat target lesion revascularization procedures in 14% to 17% of patients. Although the placement of a stent prevents vessel recoil after angioplasty and stenting has lower overall rates of restenosis than balloon angioplasty, the presence of a stent is associated with a greater amount of later development of neointimal hyperplasia than angioplasty alone. Diabetes mellitus, long lesion length, and small vessel diameter have all been identified as risk factors for higher rates of restenosis.
Several pharmacologic and procedural interventions were investigated to prevent in-stent restenosis. Brachytherapy (intracoronary radiation) was shown to be effective in treating in-stent restenosis but does not prevent it. Oral drugs—including cilostazol, rosiglitazone, everolimus, tranilast, and rapamycin—have also been evaluated for the prevention of restenosis after bare-metal stent placement, but in general, the reduction in restenosis rates with oral or intravenous agents has been modest at best. With the lack of both effective and convenient methods to prevent and treat restenosis with bare-metal stent placement, the stage was set for the introduction of the drug-eluting stent.
Drug-Eluting Stents
Development of Drug-Eluting Stents
To address the problem of high restenosis rates associated with bare-metal stents, researchers developed an intraarterial, localized, pharmacologic means to combat neointimal hyperplasia—the drug-eluting stent (DES). A successful DES would need to have three components: the drug, a delivery system for the pharmacologic agent (i.e., the polymer), and the stent platform itself. An ideal drug would need to target the proliferative response to vessel injury effectively without causing systemic side effects. An ideal drug delivery system would be able to store the drug effectively and release it in a measured time frame to provide the maximum effect on inhibition of restenosis, which would need to be accomplished without significant degradation or loss of function of either the drug or the drug vehicle. Lastly, the new stent platform would need to incorporate all the lessons learned from research with bare-metal stents: the importance of thinner struts, flexibility and conformability to the vessel wall, and optimization of the stent design for consistent drug elution to all areas of the atherosclerotic vessel.
DES development was not immediately successful. Trials investigating stents that used a new antiproliferative agent, actinomycin D, on the Tetra-D stent (Guidant, Santa Clara, CA) —or that used a tried-and-true paclitaxel derivative, taxane, but mounted into a novel polymer on the Quanam stent (Boston Scientific) —demonstrated higher rates of restenosis and greater rates of major adverse cardiac events at 1 year with these new technologies. Local drug toxicity or adverse reactions to the polymer used were possible sources of these disappointing results.
Drug-Eluting Stents Currently Available in the United States
Sirolimus-Eluting Stents
Using the lessons learned from failed DESs, investigators eventually developed the sirolimus-eluting stent, Cypher (Cordis Corporation, Warren, NJ), in the late 1990s, and this technology has revolutionized interventional cardiology. Sirolimus was initially approved as an immunosuppressive agent for the prevention of organ transplant rejection; however, it was discovered that the drug also inhibits smooth muscle cell proliferation and migration, thus making it a good agent to inhibit neointimal hyperplasia. Sirolimus was loaded into a polymer coat—a 2:1 combination of the polymers polyethylene-co-vinyl acetate and poly-n-butyl methacrylate, respectively—which acted to release the drug slowly over the following month; this polymer was subsequently placed onto a stainless steel, closed-cell metal stent, hence forming the Cypher stent.
In 1999, the first sirolimus-eluting stents were placed in 45 patients in Brazil. Follow-up studies of this pilot population demonstrated significant suppression of restenosis at 1 year with the sirolimus-eluting stent when compared with a bare-metal stent. Given the promising results of these pilot studies, two randomized, controlled trials (RCTs), the Randomised Study with the Sirolimus-Coated BX Velocity Balloon-Expandable Stent (RAVEL) and the Sirolimus-Eluting Stent in de Novo Native Coronary Lesions (SIRUIS) trials, were conducted to evaluate further the sirolimus-eluting stent. In the RAVEL trial, 238 subjects with simple, discrete coronary stenoses were randomized to receive either the sirolimus-eluting stent or an analogous bare-metal stent. At 6 months, rates of angiographically detected in-stent restenosis were significantly lower with the sirolimus-eluting stent (26.6% vs. 0%; P < .001). In the SIRIUS study, 1058 patients with more complex coronary artery disease (small vessels, long lesions) were randomized to receive either the sirolimus-eluting stent or the bare-metal stent. Again, rates of in-stent restenosis were significantly lower (35.4% vs. 3.2%; P < .001) with the sirolimus-eluting stent at 8 months, which translated to significantly lower rates of target lesion revascularization at 1 year and at 5 years. The positive results of these two trials led to U.S. Food and Drug Administration (FDA) approval of the sirolimus-eluting stent in 2003. Subsequent studies of this stent in specific populations—including patients with diabetes, ST-elevation MI (STEMI), and complex disease—have all demonstrated the superiority of the sirolimus-eluting stent over bare-metal stents in reducing angiographic restenosis at 6 to 12 months and in reducing ratesof repeat target revascularization for up to 5 years ( Table 11-1 ).
| SES vs. BMS (%) | ||||||||
|---|---|---|---|---|---|---|---|---|
| TRIAL | EXPERIMENTAL GROUP (n) | CONTROL GROUP (n) | CLINICAL POPULATION | ANGIOGRAPHIC/CLINICAL FOLLOW-UP PERIOD (mo) | ANGIOGRAPHIC BINARY IN-STENT RESTENOSIS | DEATH | MI | TLR |
| RAVEL | SES (120) | BMS (118) | Elective single lesions | 6/12 | 0.0 vs. 26.6 * | 1.7 vs. 1.7 | 3.3 vs. 4.2 | 0.0 vs. 23.7 * |
| SIRIUS | SES (533) | BMS (525) | Complex disease | 8/9 | 3.2 vs. 35.4 * | 0.9 vs. 0.6 | 2.8 vs. 3.2 | 4.1 vs. 16.6 * |
| 60 | NA | 8.4 vs. 8.4 | 6.2 vs. 6.5 | 9.4 vs. 24.2 * | ||||
| SCANDSTENT | SES (163) | BMS (159) | Complex disease | 6/7 | 2.0 vs. 30.6 * | 0.6 vs. 0.6 | 1.2 vs. 3.1 | 2.5 vs. 29.3 * |
| TYPHOON | SES (355) | BMS (357) | STEMI | 8/12 | 3.5 vs. 20.3 * | 2.3 vs. 2.2 | 1.1 vs. 1.4 | 5.6 vs. 13.4 * |
| SESAMI | SES (160) | BMS (160) | STEMI | 12 | 9.3 vs. 21.3 * | 1.8 vs. 4.3 | 1.8 vs. 1.8 | 4.3 vs. 11.2 * |
| 36 | NA | 3.2 vs. 5.0 | 2.5 vs. 2.5 | 7.0 vs. 13.5 * | ||||
| PASEO | SES (90) | BMS (90) | STEMI | 12 | NA | 3.3 vs. 6.7 | 4.4 vs. 6.7 | 3.3 vs. 14.4 * |
| 48 | NA | 7.8 vs. 12.2 | 8.9 vs. 13.3 | 5.6 vs. 21.1 * | ||||
| STRATEGY | SES (87) | BMS (88) | STEMI | 8 | 7.5 vs. 28.0 * | 8.0 vs. 9.1 | 6.9 vs. 9.1 | 5.7 vs. 20.5 * |
| 60 | NA | 18.0 vs. 16.0 | 22.0 vs. 25.0 | 10.3 vs. 26.1 * | ||||
| Diaz de la Llera et al | SES (60) | BMS (60) | STEMI | 12 | NA | 5.0 vs. 3.6 | NA | 0.0 vs. 5.7 * |
| DESSERT | SES (75) | BMS (75) | Diabetes | 8/12 | 3.6 vs. 38.8 * | 4.4 vs. 2.9 | 16.2 vs. 20.0 | 5.9 vs. 30.0 * |
| SCORPIUS | SES (98) | BMS (102) | Diabetes | 8/12 | 8.8 vs. 42.1 * | 5.3 vs. 4.1 | 4.3 vs. 5.2 | 5.3 vs. 21.1 * |
| DIABETES | SES (80) | BMS (80) | Diabetes | 9/24 | 3.9 vs. 31.7 * | 2.6 vs. 3.8 | 3.8 vs. 8.8 | 7.7 vs. 35.0 * |
| 48 | NA | 4.1 vs. 6.5 | 4.1 vs. 10.4 | 8.1 vs. 37.7 * | ||||
Paclitaxel-Eluting Stents
The Taxus paclitaxel-eluting stent (Boston Scientific, Natick, MA) was approved soon after the sirolimus-eluting stent. Paclitaxel is most commonly used as an antineoplastic agent because it has been shown to interfere with cell mitosis at high doses, thereby leading to cell death. At lower doses, paclitaxel can arrest the cell cycle without leading to cell death, and it can inhibit smooth muscle cell proliferation. The Taxus stent releases paclitaxel from a stainless steel metal stent via the polymer poly styrene-b-isobutylene-b-styrene.
The first paclitaxel-eluting stent, Taxus-Express, was evaluated in the pilot Treatment of de novo Coronary Artery Disease Using a Single Paclitaxel-Eluting Stent (TAXUS) study, in which 61 patients with simple coronary lesions were randomized to receive either the paclitaxel-eluting stent or a bare-metal stent. The study demonstrated significantly lower rates of angiographic in-stent restenosis with the paclitaxel-eluting stent (10.4% vs. 0%; P < .001) and significantly lower rates of target lesion revascularization at 1 year (10% vs. 0%; P < .05). The encouraging results of the first TAXUS study paved the way for several other trials—including TAXUS II, IV, V, and VI—larger RCTs that evaluated the use of paclitaxel-eluting stents in simple coronary lesions, complex lesions, and in the treatment of STEMI ( Table 11-2 ). In all these trials, paclitaxel was consistently associated with lower rates of angiographic restenosis and lower rates of target lesion revascularization for up to 5 years after stent placement.
| PES vs. BMS (%) | ||||||||
|---|---|---|---|---|---|---|---|---|
| TRIAL | EXPERIMENTAL GROUP (n) | CONTROL GROUP (n) | CLINICAL POPULATION | ANGIOGRAPHIC/CLINICAL FOLLOW-UP PERIOD (mo) | ANGIOGRAPHIC BINARY IN-STENT RESTENOSIS | DEATH | MI | TLR |
| TAXUS-I | PES (31) | BMS (30) | Elective simple lesions | 6/12 | 0.0 vs. 10.4 * | 0.0 vs. 0.0 | 0.0 vs. 0.0 | 0.0 vs. 10.0 * |
| TAXUS-II | PES Slow Release (131) | BMS (136) | Elective simple lesions | 6/12 | 2.3 vs. 17.9 * | 0.0 vs. 1.5 | 2.4 vs. 5.3 | 4.7 vs. 12.9 * |
| 60 | NA | 2.4 vs. 1.5 | 4.7 vs. 7.1 | 10.3 vs. 18.4 * | ||||
| PES Moderate Release (135) | BMS (134) | Elective simple lesions | 6/12 | 4.7 vs. 20.2 * | 0.0 vs. 0.0 | 3.8 vs. 5.4 | 3.8 vs. 16.0 * | |
| 60 | NA | 5.3 vs. 7.1 | 5.3 vs. 7.1 | 4.5 vs. 18.4 * | ||||
| TAXUS-IV | PES (662) | BMS (652) | Elective single lesions | 9/9 | 5.5 vs. 24.4 * | 2.4 vs. 2.2 | 3.5 vs. 3.7 | 3.0 vs. 11.3 * |
| 60 | NA | 10.0 vs. 11.2 | 7.2 vs. 7.4 | 9.1 vs. 20.5 * | ||||
| TAXUS-V | PES (577) | BMS (579) | Complex lesions | 9/9 | 13.7 vs. 31.9 * | 0.5 vs. 0.9 | 5.4 vs. 4.6 | 8.6 vs. 15.7 * |
| TAXUS-VI | PES (219) | BMS (227) | Complex lesions | 9/9 | 9.1 vs. 32.9 * | 0.0 vs. 0.9 | 8.2 vs. 6.2 | 6.8 vs. 18.9 * |
| 60 | NA | 2.8 vs. 3.2 | 11.2 vs. 8.2 | 14.6 vs. 21.4 | ||||
| PASEO | PES (90) | BMS (90) | STEMI | 12 | NA | 4.4 vs. 6.7 | 3.3 vs. 6.7 | 4.4 vs. 14.4 * |
| HORIZONS-AMI | PES (2257) | BMS (749) | STEMI | 13/12 | 8.2 vs. 21.0 * | 3.5 vs. 3.5 | 3.6 vs. 4.4 | 4.3 vs. 7.2 * |
| PASSION | PES (310) | BMS (309) | STEMI | 12 | NA | 4.6 vs. 6.5 | 1.7 vs. 2.0 | 5.3 vs. 7.8 |
Researchers subsequently refined the paclitaxel-eluting stent by changing the stent design to a hybrid of closed- and open-cell geometry, the result of which produced a more flexible stent (Taxus-Liberte, Boston Scientific) with thinner struts and more homogeneous drug delivery to the vascular wall. The TAXUS Assessment of Treatment with Lisinopril and Survival (ATLAS) trial (polymer-based, paclitaxel-eluting TAXUS Liberte stent in de novo lesions) confirmed the preserved effectiveness of this stent modification. Furthermore, in long coronary lesions (26 to 34 mm) in particular, the Taxus-Liberte stent was found to be associated with significantly lower rates of MI (1.4% vs. 6.5%; P = .002) when compared with the Taxus-Express stent, presumably because of lower rates of side-branch occlusion by stent struts. Most recently, a platinum-based stent system for the Taxus drug and polymer was approved for use in the United States (discussed below).
Several trials have compared paclitaxel-eluting stents with sirolimus-eluting stents. In general, the paclitaxel stent has been found to be associated with higher rates of angiographic restenosis with higher rates of total lesion revascularization. In the Sirolimus-Eluting Stent Compared with Paclitaxel-Eluting Stent in Coronary Revascularization (SIRTAX) trial, 1011 patients requiring coronary stent placement were randomized to receive either the paclitaxel-eluting stent or a sirolimus-eluting stent. At 8 months, the paclitaxel-eluting stent was associated with significantly higher levels of binary in-stent restenosis (7.5% vs. 3.2%; P < .05), which translated to higher rates of target lesion revascularization at 1 year (8.3% vs. 4.8%; P < .05), although the differences in target lesion revascularization had disappeared at 5 year follow-up (5.9% vs. 4.5%; P = not significant). Comparisons of the two stents in specific populations—such as in patients with diabetes, STEMI, and in small vessels and long lesions—have also demonstrated that the paclitaxel stent is associated with slightly higher rates of angiographic in-stent restenosis and resulting increased rates of target lesion revascularization. This finding may be exaggerated, however, by the performance of routine angiographic follow-up because other studies without angiographic follow-up have demonstrated no significant difference in target lesion revascularization or in major adverse cardiac events between the two stents.
Zotarolimus-Eluting Stents and Everolimus-Eluting Stents
The zotarolimus- and everolimus-eluting stents were approved by the FDA in 2008. Both use a cobalt-chromium stent, a durable polymer, and antiproliferative drugs that are analogues of sirolimus. The cobalt-chromium stent platform allowed for thinner stent struts and improved stent deliverability; hence, it was thought that these changes would allow for even lower rates of restenosis with the use of these two stents.
The zotarolimus-eluting stent has been shown to be superior to bare-metal stents in preventing in-stent restenosis, although it may not be superior to other drug-eluting stents on the market. The ENDEAVOR-II study randomized 1197 patients to receive either the zotarolimus-eluting stent or a bare-metal stent. Patients treated with the zotarolimus-eluting stent had significantly lower rates of angiographic restenosis at 9 months (33.5% vs. 9.4%; P < .001) and lower rates of target lesion revascularization (11.8% vs. 4.6%; P < .001). When compared with the sirolimus-eluting stent, the zotarolimus-eluting stent has been associated with higher rates of target lesion revascularization. Compared with the paclitaxel-eluting stent, a slightly higher restenosis rate was also seen with the zotarolimus-eluting stent in studies with follow-up angiography. Although significantly higher rates of in-stent late lumen loss were seen with the zotarolimus-eluting stent, this did not translate into a significant difference in the occurrence of target lesion revascularization ( Table 11-3 ).
| ZES vs. Control (%) | |||||||
|---|---|---|---|---|---|---|---|
| TRIAL | EXPERIMENTAL GROUP (n) | CONTROL GROUP(S) (n) | ANGIOGRAPHIC/CLINICAL FOLLOW-UP PERIOD (mo) | ANGIOGRAPHIC BINARY IN-STENT RESTENOSIS | DEATH | MI | TLR |
| ENDEAVOR I | E-ZES (100) | N/A | 12/12 | 5.4 | 0.0 | 1.0 | 2.0 |
| ENDEAVOR II | E-ZES (598) | BMS (599) | 9/9 | 9.4 vs. 33.5 * | 1.2 vs. 0.5 | 2.7 vs. 3.9 | 4.6 vs. 11.8 * |
| ENDEAVOR III | E-ZES (323) | SES (113) | 8/9 | 9.2 vs. 2.1 * | 0.6 vs. 0.0 | 0.6 vs. 3.5 * | 6.3 vs. 3.5 |
| SORT OUT III | E-ZES (1162) | SES (1170) | 9 | NA | 2.0 vs. 2.0 | 1.4 vs. 0.5 * | 4.0 vs. 1.0 * |
| 18 | NA | 4.4 vs. 2.7 * | 2.1 vs. 0.9 * | 6.1 vs. 1.7 * | |||
| ENDEAVOR IV | E-ZES (773) | PES (775) | 8/12 | 13.3 vs. 6.7 | 1.1 vs. 1.1 | 1.6 vs. 2.7 | 4.5 vs. 3.2 |
| ZEST | E-ZES (880) | PES (880) | 12 | NA | 0.7 vs. 1.1 | 5.3 vs.7.0 | 4.9 vs. 7.5 |
| SES (880) | NA | 0.7 vs. 0.8 | 5.3 vs. 6.3 | 4.9 vs. 1.4 * | |||
| RESOLUTE | R-ZES (139) | NA | 9/12 | 1.0% | 2.2% | 5.8% | 0.7% |
| RESOLUTE US | R-ZES (1376) | NA | 8/12 | 9.2% | 1.3% | 1.4% | 2.8% |
The everolimus-eluting stent (Xience V, Abbott Vascular, Abbott Park, IL; Promus, Boston Scientific) was first evaluated in the SPIRIT First trial, which was a study of 56 patients and compared the everolimus-eluting stent with the standard control of a bare-metal stent. The everolimus-eluting stent was found to have significantly lower rates of target lesion revascularization at 6 months and as far out as 5 years. This small study paved the way for larger trials to be conducted in which the everolimus-eluting stent could be compared with other DESs ( Table 11-4 ). Several randomized trials have compared the everolimus-eluting stent with the paclitaxel-eluting stent, the largest of which was the SPIRIT-IV trial of more than 3600 patients. At 12 months, the everolimus-eluting stent was associated with significantly lower rates of target lesion revascularization (2.5% vs. 4.6%; P = .001) and lower rates of MI (1.9% vs. 3.1%; P = .02). These results were essentially replicated in the smaller Second-Generation Everolimus-Eluting and Paclitaxel-Eluting Stents in Real-Life Practice (COMPARE) study, which also showed lower rates of MI, stent thrombosis, and target lesion revascularization with the everolimus-eluting stent when compared with the paclitaxel-eluting stent.
| EES vs. Control (%) | |||||||
|---|---|---|---|---|---|---|---|
| TRIAL | EXPERIMENTAL GROUP (n) | CONTROL GROUP (n) | ANGIOGRAPHIC/CLINICAL FOLLOW-UP PERIOD (mo) | ANGIOGRAPHIC BINARY IN-STENT RESTENOSIS | DEATH | MI | TLR |
| SPIRIT FIRST | EES (27) | BMS (29) | 6/6 | 0.0 vs. 25.9 * | 0.0 vs 0.0 | 3.8 vs. 0.0 | 3.8 vs. 21.4 |
| 60 | NA | 0.0 vs. 7.4 | 8.3 vs. 0.0 | 8.3 vs. 28.0 | |||
| SPIRIT II | EES (223) | PES (77) | 6/6 | 1.3 vs. 3.5 | 0.0 vs. 1.3 | 0.9 vs. 3.9 | 2.7 vs. 6.5 |
| 36 | NA | 0.5 vs. 4.3 | 3.6 vs. 7.2 | 4.6 vs. 10.1 | |||
| SPIRIT III | EES (669) | PES (333) | 8/12 | 2.3 vs. 5.7 | 1.2 vs. 1.2 | 2.8 vs. 4.1 | 3.4 vs. 5.6 |
| SPIRIT IV | EES (2458) | PES (1229) | 12 | NA | 1.0 vs. 1.3 | 1.9 vs. 3.1 * | 2.5 vs. 4.6 * |
| COMPARE | EES (897) | PES (903) | 12 | NA | 2.0 vs. 1.6 | 2.8 vs. 5.3 * | 2.0 vs. 5.3 * |
Efficacy and Safety of Drug-Eluting Stents
Efficacy of Drug-Eluting Stents
As described above, multiple studies have confirmed that DESs are extremely effective in reducing restenosis compared with bare-metal stents. Several meta-analyses have confirmed these findings, the largest of which involved more than 18,000 patients and demonstrated that target lesion revascularization rates over 4 years are reduced by 70% with sirolimus-eluting stents and by 58% with paclitaxel-eluting stents when compared with bare-metal stents. Furthermore, population-based studies and registries have shown a similar reduction in restenosis in patients who receive DESs for off-label indications (complex lesions, unstable clinical status), such as when the stents are used as initially studied for FDA approval. Across stent types, some modest variation in efficacy exists, particularly in patients with higher restenosis risk—such as patients with diabetes or those with small vessels or long lesions—but in general, it is accepted that DESs are beneficial in reducing restenosis rates when compared with bare-metal stents.
Safety of Drug-Eluting Stents
Following approval in 2003, DESs were almost universally adopted for percutaneous coronary intervention (PCI); PCI was therefore concurrently applied to more complex lesion and patient cohorts. It was in this environment that several reports surfaced in 2006 and 2007 suggesting that DESs may be associated with acute thrombotic occlusion a year or more after placement of the stent. The single-center Basel Stent Kosten Effectivitäts Trial–Late Thrombotic Events (BASKET-LATE) retrospectively analyzed the outcomes of 746 patients, who were randomized to receive either bare-metal stents or sirolimus-eluting stents for the treatment of both stable and unstable coronary artery disease. Excluding the first 6 months after treatment, when subjects with sirolimus-eluting stents had lower rates of repeat revascularization, death, and MI, the sirolimus-eluting stent was associated with a higher rate of death and MI between 7 and 18 months after stent placement. Although the authors proposed that this finding was due to an increased rate of stent thrombosis with DESs, interestingly enough, no significant difference was found in the rates of stent thrombosis between the two groups. Subsequent examination of this trial revealed that the conclusion that DESs lead to increased mortality may have not been entirely accurate because of several factors, including small sample size with the resultant underpowering of the study to detect infrequent events, such as stent thrombosis, and the premature cessation of dual antiplatelet therapy at 6 months in all patients, which has since been shown to be a significant risk factor for stent thrombosis in patients with DESs. More recently, the prospective, randomized 2300 patient BASKET Prospective Validation Examination (BASKET-PROVE) trial, which was designed specifically to address the safety concerns raised in the BASKET-LATE trial, demonstrated no significant difference in the rates of death, MI, or stent thrombosis among patients who received sirolimus-eluting stents, everolimus-eluting stents, or bare-metal stents. Although a few other nonrandomized studies or meta-analyses have suggested that DESs may be associated with higher rates of mortality, subsequent reanalyses using pooled patient-level data have demonstrated no significant differences in mortality between bare-metal stents and DESs. Furthermore, several subsequent large meta-analyses and registry studies evaluating more than 200,000 patients have been reassuring in showing no apparent increased risk of death or MI with DESs at either short- or long-term follow-up.
Despite these reassuring reports regarding the safety of DESs, the question of late stent thrombosis risk has remained. Although rare, stent thrombosis is associated with significant morbidity and mortality. Although no randomized studies have demonstrated a significant difference in the overall rate of stent thrombosis between bare-metal stents and DESs, these studies have been limited in size. On the other hand, analyses from several large registries and a number of meta-analyses have shown a higher risk of very late stent thrombosis with DES placement, although these findings should be considered critically, as residual confounding has been difficult to exclude.
Investigation into the cause of stent thrombosis has implicated several different factors that likely contribute to the development of this serious complication. Patient factors—such as unstable coronary artery disease, diabetes, renal failure, and prior brachytherapy—and lesion characteristics that include small vessel diameter, high degrees of calcification, long lesions, or complex lesions may predispose a patient to developing stent thrombosis. Characteristics of the DES itself may also predispose a patient to developing stent thrombosis. Although the purpose of a drug-coated stent is to interfere with neointimal hyperplasia and hence decrease restenosis, the side effect is that the endothelialization process is delayed, thereby increasing the exposure of thrombogenic molecules in the blood to the stent struts. Furthermore, the polymer in which the drug is loaded in a DES can lead to hypersensitivity reactions and vascular inflammation, both of which can promote thrombotic events. Procedural technique—such as if the stent is suboptimally expanded or undersized or if stent apposition is incomplete—has also been shown to be related to stent thrombosis.
Premature cessation of dual antiplatelet therapy, particularly within the first month of stent placement, is one of the most potent factors associated with increased risk of stent thrombosis, although the data as to what constitutes “premature cessation” are conflicting. The optimal duration of antiplatelet therapy after coronary stent placement therefore remains unknown. Although initial randomized trials of sirolimus-eluting stents used 3 months of dual antiplatelet therapy, observational studies suggest that at least 6 months, or even 12 months, of dual antiplatelet therapy after DES placement has been associated with lower rates of stent thrombosis and improved mortality. That said, the prolonged use of dual antiplatelet therapy is associated with an increased risk of bleeding. Although small RCTs have been performed to determine clinically significant differences in stent thrombosis or other cardiovascular events with varying durations of dual antiplatelet therapy, these studies have been underpowered. But several large, randomized trials powered to provide more clarity on the duration of therapy after DES placement are enrolling patients or have completed enrollment. The current national and international society guidelines on dual antiplatelet therapy duration and use are summarized in Table 11-5 .
| RECOMMENDATION | SOCIETY | CLASS OF RECOMMENDATION | LEVEL OF EVIDENCE |
|---|---|---|---|
| Aspirin | |||
| After PCI, aspirin should be continued indefinitely. | ACCF/AHA/SCAI | I | A |
| After PCI, 81 mg aspirin is reasonable in preference to higher doses. | ACCF/AHA/SCAI | IIa | B |
| After elective PCI or PCI for NSTE-ACS or STEMI, a bolus of 150-300 mg aspirin should be given, followed by 75-100 mg/day. | ESC | I | A, B, C |
| After ACS, 75-162 mg aspirin should be continued indefinitely. | CCS | I | A |
| P2Y 12 Inhibitors | |||
| After BMS or DES placement for ACS, P2Y 12 inhibitors—either clopidogrel, prasugrel, or ticragrelor—should be given for 12 months minimum. | ACCF/AHA/SCAI | I | B |
| After DES placement for a non-ACS indication, clopidogrel should be given for at least 12 months. | ACCF/AHA/SCAI | I | B |
| After BMS placement for a non-ACS indication, clopidogrel should be given for at least 1 month, ideally up to 12 months. | ACCF/AHA/SCAI | I | B |
| If bleeding risk is high and outweighs expected benefit of longer duration of P2Y 12 therapy, discontinuation of P2Y 12 therapy before 12 months is reasonable. | ACCF/AHA/SCAI | IIa | C |
| More than 12 months of P2Y 12 therapy may be considered in patients with DES placement. | ACCF/AHA/SCAI | IIb | C |
| After PCI for NSTE-ACS or STEMI, clopidogrel maintenance dosing for 9-12 months should be given. | ESC | I | B, C |
| After PCI for NSTE-ACS or STEMI, alternative P2Y 12 therapies (prasugrel or ticagrelor) can be given. | ESC | I, IIa | B |
| After PCI with BMS for ACS and elective PCI, clopidogrel should be continued for at least 1 month, up to 12 months in the absence of an excessive risk of bleeding. | CCS | I | B |
| After PCI with DES for ACS and elective PCI, clopidogrel should be continued for 12 months and can be considered for longer durations if the risk for stent thrombosis is high and risk of bleeding is low. | CCS | I, IIb | A, C |
| After PCI for ACS, prasugrel may be considered in patients with an increased risk of thrombosis. | CCS | IIa | B |
When to Use Drug-Eluting Stents
Although the benefits of the use of DESs are clear, such stents have generally been more expensive, and the precise risk of stent thrombosis has been uncertain. Furthermore, the use of DESs does also obligate patients to a longer duration of dual antiplatelet therapy, even if the precise duration remains a topic of ongoing study. As a result of these differences in risk, cost, and benefit, it is reasonable to consider how stents can be optimally used in individual patients and in patient populations. Certain lesion characteristics and patient characteristics confer a higher risk for restenosis, and it is in the patient with a higher risk of restenosis that a DES may carry the most benefit. A model derived from a 10,000-subject, real-world registry suggested that patients younger than 60 years, those with prior PCI, an intervention being performed either on the left main artery or a saphenous vein graft (SVG), and a stent diameter of less than 2.5 mm or a lesion length greater than 40 mm were at an increased risk for restenosis after stent placement. Similar results were demonstrated in the analysis of another larger registry, in which researchers reported that target vessel revascularization rates were no different between DESs and bare-metal stents in nondiabetic patients with short, noncomplex coronary lesions (<20 mm long) in vessels greater than 3 mm in diameter (5.3% vs. 5.9%; P = .61). Studies consistently show that patients with small vessels, longer stents, and diabetes; treatment of multiple lesions; or treatment for restenosis itself are at the highest risk of restenosis with bare-metal stents. Therefore, models to predict the absolute risk reduction in restenosis associated with DES placement have been developed to identify patients who are most likely to benefit from DES placement.
Before choosing a drug-eluting versus a bare-metal stent, consideration of obligate antiplatelet therapy is also important. Certain patients are at an increased risk for stopping dual antiplatelet therapy, such as those with preexisting anemia or upcoming surgeries, which can lead to an even greater risk of stent thrombosis. Therefore, for each patient and clinical situation, the risk of restenosis must be balanced against the necessity of a prolonged period of dual antiplatelet therapy. If the risk of restenosis for a patient is low, and the risk of stent thrombosis, including the risk of premature cessation of dual antiplatelet therapy, plus the risk of bleeding with dual antiplatelet therapy is high, a bare-metal stent might be the more appropriate choice. Conversely, if the risk of restenosis for a patient is high and the risk of stent thrombosis plus the risk of bleeding with dual antiplatelet therapy is low, then a DES should be used.
New Drug-Eluting Stents Available Outside the United States or Undergoing Investigation
Although many advances have been made in DES technology over the past 10 years, there continues to be room for improvement. Research has focused on alterations involving the stent platform itself, the types of drugs to be delivered, and the polymer used to control the release of the drug. Many stents currently available outside the United States still require further clinical evaluation before U.S. approval because of the requirement of substantial evidence of safety beyond 1 year before new stents are introduced in the U.S. market.
Products Involving Changes to the Stent Platform
Traditional Stent Platforms
Because platinum in combination with chromium is a stronger alloy than stainless steel or cobalt-chromium, a stent with thinner struts can be designed. Two DESs are available in Europe that use the platinum-chromium platform: the Promus Element stent (everolimus-eluting) and the Taxus Element stent (paclitaxel-eluting). A small, 100-subject, single-arm study evaluating the Promus Element stent demonstrated appropriate rates of late lumen loss (0.17 ± 0.25 mm) at 9 months. Results of the larger Prospective, Randomized, Multicenter Trial to Assess an Everolimus-Eluting Coronary Stent System (Promus Element) for the Treatment of up to Two de Novo Coronary Artery Lesions (PLATINUM) trial, which randomized patients to either the Promus Element stent or an everolimus-eluting stent with a cobalt-chromium platform are pending. The Taxus Element stent is also being evaluated in the ongoing Prospective Evaluation in a Randomized Trial of the Safety and Efficacy of the Use of the TAXUS Element Paclitaxel-Eluting Coronary Stent System (PERSEUS) trial, and substudies of this trial have yielded favorable results for the Taxus Element stent in comparison to bare-metal stents and the earlier version of the Taxus Express stent in terms of in-stent late lumen loss. Given these results, approval by the FDA for both the Taxus Element and the Promus Element stent is expected by 2013.
Biodegradable Stents
Theoretical benefits of a biodegradable stent are similar to the benefits of a stent with a biodegradable polymer; with the eventual absence of a foreign material in the vessel wall, there is less possibility for residual inflammation there, leading to a lower theoretical incidence of in-stent thrombosis. Furthermore, with fully biodegradable stents, the issues surrounding the difficulty of performing later procedures across jailed side branches might be avoided.
Although biodegradable stents have theoretical benefits, their design poses several practical challenges. Current biodegradable stents under investigation are composed of either polymers or metal alloys. Biodegradable polymers have been studied in other medical implants, such as sutures and orthopedic devices, but stents composed entirely of polymer require thicker stent struts to maintain radial strength comparable with metallic stents; this may result in less flexibility in manipulating these stents into smaller vessels. Furthermore, biodegradable materials are usually not radiopaque and will still require metallic stent markers to be visualized adequately. Lastly, although biodegradable, the deployment of the stent and the presence of the polymer, even if temporary, may still lead to neointimal hyperplasia and hence require drug suppression to achieve results comparable to DESs.
Several biodegradable stents are under investigation, but the most clinical data are currently available for the bioresorbable vascular scaffold (BVS) everolimus stent. This fully biodegradable stent utilizes the polymer poly-L-lactic acid combined with a coating of poly-D,L-lactic acid to release the drug everolimus to suppress neointimal hyperplasia. Clinical studies of this stent have shown that, although the acute gain in lumen diameter of these stents is slightly lower than conventional DESs, the combination of polymer and drug has good suppression of late neointimal hyperplasia.
Products Involving Changes to Drug Coatings
The chemical structures and presumed mechanism of action of drugs currently used are shown in Figure 11-1 . Several new derivatives of sirolimus have been applied to stent technology—including myolimus, biolimus, and novolimus—which, similar to sirolimus, inhibit mammalian target of rapamycin (mTOR). Besides sirolimus derivatives and antiproliferative agents, other novel agents have been applied to coronary stents that are currently available only in Europe. One example is CD34 antibodies, which have been shown to bind to endothelial progenitor cells circulating in the blood, and these can be used to coat the surface of a stent. Titanium–nitride oxide is another coating that has been associated with reduced neointimal hyperplasia compared with stainless steel stents and is currently under investigation.
Products Involving Changes to the Polymer Structure
Prior studies have demonstrated that the polymer drug delivery system may lead to prolonged inflammation in the arterial wall with delayed vessel wall healing; it therefore increases the risk of stent thrombosis. In an attempt to minimize this histopathologic response, investigation has concentrated on modifying the polymer used to release the drug. These efforts have ranged from alterations to prior durable polymers to the development of biodegradable polymers that break down over time to stents free of polymers altogether.
Stents with Durable Polymers
All the FDA-approved DESs currently available utilize durable polymers. Although these polymers have been successful in modulating sustained drug delivery during vascular healing, changes to durable polymers are being designed for existing stents to improve their clinical results. One such example is the Endeavor Resolute stent (Medtronic, Inc., Minneapolis, MN), which is similar to the Endeavor zotarolimus-eluting stent in that it uses a cobalt-chromium stent platform and zotarolimus as an antiproliferative agent. However, the polymer used to release the drug is novel and consists of three different polymers, which together allow for a delayed release of the drug compared with the Endeavor stent. The result of this change in polymer has been greater efficacy, as measured by reduced mean late loss in clinical studies, and similar clinical restenosis rates to current stents in randomized trials. The Randomized Comparison of a Zotarolimus-Eluting Stent with an Everolimus-Eluting Stent for Percutaneous Coronary Intervention (RESOLUTE) All-Comers Trial randomized 2300 patients to receive either the Endeavor Resolute stent or the everolimus-eluting stent and found that the two stents had similar rates of major adverse cardiac events (8.2% vs. 8.3%; P for noninferiority < .001).
Stents with Biodegradable Polymers
There may be a benefit to biodegradable polymers that can release a drug over a defined period and be subsequently degraded, thereby limiting the duration of exposure of the vessel wall to the polymer. Several stents using biodegradable polymers are under investigation or are approved outside the United States, and they can be categorized by the drugs they release.
Biolimus A9–based Stents
There are two currently available stents—the Biomatrix stent (Biosensors International, Singapore) and the Nobori stent (Terumo Europe, Leuven, Belgium)—that use biolimus, an analogue of sirolimus. The two stents use the same biodegradable poly-lactic acid (PLA) polymer and the same stainless steel stent platform. The Nobori stent has demonstrated similar rates of angiographic restenosis when compared with the sirolimus-eluting stent, and significantly lower rates of late lumen loss were noted when compared with the paclitaxel-eluting stent in two small trials. In the randomized Limus Eluted from a Durable Versus Erodable Stent Coating (LEADERS) trial of more than 1700 patients, the Biomatrix stent showed lower angiographic restenosis and similar rates of major cardiac adverse events compared with the sirolimus-eluting stent.
Myolimus-Based Stents
Myolimus is another analogue of sirolimus that has been investigated as a component of a cobalt-chromium stent coated with a biodegradable PLA polymer. Small, single-arm studies have demonstrated good angiographic results with use of this stent.
Paclitaxel-Based Stents
Two stents with biodegradable polymers that use paclitaxel are currently being investigated, the Jactax stent (Boston Scientific) and the Infinnium stent (Sahajanand Medical Technologies, Gujarat, India). Although both stents are loaded with paclitaxel on a stainless steel platform, the biodegradable polymer differs slightly between the two stents. Initial studies have demonstrated similar low rates of angiographic restenosis with the Jactax stent compared with a group of historic controls receiving the Taxus-Liberte stent. The Infinnium stent has been tested in more than 200 subjects in the randomized, controlled Percutaneous Intervention (PAINT) trial, which compared the Infinnium stent and Supralimus stent (Sahajanand Medical Technologies; see below) to a bare-metal stent and demonstrated lower rates of target vessel revascularization at 9 months and less late lumen loss with the Infinnium stent.
Everolimus-Based Stents
The SYNERGY stent (Boston Scientific) is composed of everolimus loaded onto a biodegradable poly-lactic-co-lactic acid (PLGA) polymer on a platinum-chromium platform. The efficacy and safety of this stent compared with a similar stent (everolimus-eluting stent on a platinum-chromium platform with a durable polymer) was demonstrated in the multicenter Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial.
Sirolimus-Based Stents
Each of the three sirolimus-eluting stents with biodegradable polymers currently under investigation uses a different biodegradable polymer. The Excel stent (JW Medical System, Weihai, China) uses a polylactic acid polymer on a stainless steel platform to deliver sirolimus, and recent analyses from registry data involving more than 2000 subjects have demonstrated low rates of major adverse cardiac events (3.1%) over 18 months of follow-up. The Supralimus stent also uses a stainless steel platform; the stent is then coated with a combination of biodegradable polymers loaded with sirolimus. In the small, randomized PAINT trial described above, the Supralimus stent was associated with significantly lower angiographic late lumen loss and lower target vessel revascularization than the bare-metal stent. The Nevo stent (Cordis Corporation) is the third sirolimus-eluting stent with a biodegradable polymer being studied. Unlike the Excel stent and the Supralimus stent, the Nevo stent uses a polylactic-co-glycolic acid polymer loaded into microscopic reservoirs on a cobalt-chromium stent. By using reservoirs of drug-loaded polymer, as opposed to surface coating the stent platform, the exposure of vessel wall to polymer is theoretically decreased. Investigation of the Nevo stent in a 394-patient study demonstrated significantly lower levels of late lumen loss (0.13 vs. 0.36 mm; P < .0001) compared with the Taxus Liberte stent.
Polymer-Free Stents
Removing the polymer as a drug delivery system altogether is another solution to the inflammation caused by the presence of a polymer; however, this is a challenge because the controlled release of the drug without a polymer delivery system is difficult to achieve. Direct-coating, microabrasion, and a microporous coating of the surface of the stents are all methods of drug delivery without polymers that have been investigated. Although initial pilot studies and observational studies have been promising, further RCTs are needed to evaluate the true safety and efficacy of this new technology.
Drug-Coated Balloons
Drug-coated balloons are designed to dilate the stenotic coronary artery while introducing medication to suppress neointimal hyperplasia. With a drug-eluting balloon, both the polymer and stent platform are absent; this completely eliminates the need for any foreign object within the vessel wall that might predispose to thrombus formation, and it could ease reintervention in jailed side branches or restenotic vessels. Furthermore, the absence of a stent would in theory lessen the need for a prolonged course of dual antiplatelet therapy, making it an attractive alternative for patients predisposed to bleeding. That said, the most immediate limitations of this technology are elastic recoil of the vessel and identification of effective carrier molecules for antiproliferative agents.
Most drug-coated balloons currently available in Europe or under investigation use paclitaxel as the antiproliferative agent of choice and have mostly been evaluated for treatment of in-stent restenosis and peripheral arterial stenosis, particularly in anatomic locations where stents are generally avoided because of mechanical stresses, such as the superficial femoral artery. In the Paclitaxel-Coated Balloon Catheter for In-Stent Restenosis (PACCOCATH ISR) I study, 52 subjects with in-stent restenosis were randomized to treatment either with standard balloon angioplasty or angioplasty with a drug-coated balloon. The drug-coated balloon was associated with significantly lower rates of major adverse cardiac events at 1 year (4% vs. 31%; P = .01), a finding that remained at the 2-year follow-up. The drug-coated balloon also performed well compared with restenting using a paclitaxel-eluting stent in a study of 131 patients with in-stent restenosis, with a trend toward lower rates of target lesion revascularization. Although these findings are promising, larger trials with longer term follow-up have yet to be conducted.
Although drug-coated balloons have showed promise in the treatment of in-stent restenosis, studies of drug-coated balloons in de novo coronary lesions have produced mixed results. The drug-coated balloon in combination with a bare-metal stent demonstrated better angiographic results compared with a bare-metal stent alone, but it failed to exhibit superiority over the DES. In the Paclitaxel-Eluting PTCA-Balloon Catheter in Coronary Artery Disease (PEPCAD) III study, 637 patients were randomized to treatment with either a sirolimus-eluting stent or a combination of a bare-metal stent and drug-coated balloon. Not only was in-stent restenosis significantly higher in the drug-coated balloon arm (10% vs. 2.9%; P < .01), the rates of MI, stent thrombosis, and total lesion revascularization were also significantly higher at 9 months. Similarly, the 57-subject Paclitaxel-Coated Balloon Versus Drug-Eluting Stent during PCI of Small Coronary Vessels (PICCOLETO) study demonstrated significantly higher rates of in-stent restenosis (32.1% vs. 10.3%; P = .043) and showed an insignificant but highly suggestive trend toward more adverse cardiac events in patients receiving a combination of the drug-coated balloon and bare-metal stent compared with those receiving a paclitaxel-eluting stent (35.7% vs. 13.8%; P = .54).
Advances in Revascularization in Specific Conditions
Saphenous Vein Graft Interventions
SVGs are commonly used during coronary artery bypass surgery in the treatment of multivessel coronary artery disease. Unfortunately, such grafts are subject to accelerated atherosclerotic processes and recurrent ischemia as a result of graft degeneration; hence, they are often the target of PCI. In a recent analysis of all PCIs performed in a 5-year period from the National Cardiovascular Data Registry, SVG interventions accounted for 5.7% of all procedures. Because this procedure is becoming more and more common, researchers have begun to study the optimal approach to this type of stenotic lesion.
Several small, randomized trials have compared DESs with bare-metal stents for SVG interventions. The Reduction of Restenosis in Saphenous Vein Grafts with Cypher Sirolimus-Eluting Stent (RRISC) study evaluated 75 patients, randomized to receive either a bare-metal stent or sirolimus-eluting stent for treatment of an SVG stenosis. Although in-stent restenosis was reduced at 6 months with use of the sirolimus-eluting stent, long-term follow-up revealed higher rates of mortality (29% vs. 0%; P < .001) with the sirolimus-eluting stent at a median follow-up of 32 months and an absence of any benefit with regard to long-term target vessel revascularization rates (34% vs. 38%; P = .74). These results were surprising given the multitude of retrospective data that have suggested DESs are safe and efficacious in SVG interventions. A randomized study of 610 patients, the recent publication of which compared drug-eluting with bare-metal stents for SVG interventions and showed a reduction in the composite of death, MI, and target lesion revascularization associated with DESs at 1 year, with a similar rate of stent thrombosis (1%) in both treatment arms. Taken together, these results suggest that DESs should be the stent of choice for SVG interventions.
Because SVGs often harbor a sizable amount of atherosclerotic debris secondary to the large nature of the vessel itself, it follows that interventions for a lesion within an SVG carry a high risk of distal embolization and resulting myocardial damage. Early studies failed to show a benefit of glycoprotein (GP) IIb/IIIa inhibitors in preventing embolic events during SVG interventions, so recent research has turned to the development of embolic protection devices for use during such interventions.
Three types of embolic protection devices are currently available. Distal occlusion devices consist of a balloon mounted on a wire that is passed beyond the lesion and inflated to occlude flow during lesion treatment, such that any embolic debris is trapped and can be aspirated prior to reperfusion of the coronary bed. The Saphenous Vein Graft Angioplasty Free of Emboli Randomized (SAFER) trial followed 801 patients who underwent SVG interventions either with a conventional guidewire or with the GuardWire distal occlusion device (Medtronic). At 30-day follow-up, a significant reduction was observed in major adverse cardiac event rates in patients treated with the GuardWire distal occlusion device (9.6% vs. 16.5%; P = .004).
Distal embolic filter devices capture embolized debris while allowing perfusion of the target vessel. Several randomized trials have compared distal embolic filter devices (FilterWire EF, EZ [Boston Scientific], Interceptor PLUS [Medtronic]), and all have demonstrated noninferiority to the distal occlusion device in regard to major adverse cardiac events within 30 days of SVG interventions.
Despite good results with distal embolic protection devices, embolization may still occur. Proximally placed occlusion devices have been developed to overcome some of the limitations of distally placed devices. Proximal devices consist of a guide catheter with a balloon placed proximal to the stenosis through which balloons, wires, and stents may be delivered, while antegrade flow is occluded. Embolic debris is aspirated after the intervention is complete, and antegrade flow is restored. This type of device may offer greater protection to a lesion that is so distal within an SVG that the distal device cannot be placed, or to a lesion that is located in a graft with a Y anastomosis, in which both limbs cannot be protected with a single distal device, or when a lesion is so narrow that it must be predilated before it can be crossed with a larger device. The Proximal Protection During Saphenous Vein Graft Intervention Using the Proxis Embolic Protection System (PROXIMAL) trial compared the Proxis proximal occlusion device (St. Jude Medical, St. Paul, MN) with both a distal occlusion and distal embolic device and found that the proximal occlusion device was noninferior to the distal embolic protection devices in the prevention of 30-day major adverse cardiac events. Currently, embolic protection with either distal or proximal devices has become the standard of care when treating an SVG lesion.
Chronic Total Occlusion Intervention
Chronic total occlusions (CTOs) are a common angiographic finding, accounting for 15% to 30% of patients who undergo cardiac catheterization. Nevertheless, clinical decision making regarding medications for revascularization, procedural technique in treating these lesions, or even whether a CTO should be opened may be challenging issues.
Observational studies have suggested that successful revascularization of a CTO is associated with reduced long-term mortality rates and improvement in left ventricular (LV) function. Because no randomized trials have been conducted, it is not clear whether these benefits are related to revascularization per se or that less complex cases are more likely to undergo successful procedures. Certain characteristics of CTO have been associated with a lower likelihood of success, including ostial or bifurcation lesions, lesions in difficult locations, an occlusive segment, significant calcification, or long lesions. Furthermore, patients with no clinical symptoms or evidence of nonviable myocardium at the site of the CTO may not derive much benefit from revascularization of such an occlusion. Thus, numerous determinants need to be considered when deciding whether to attempt revascularization of a CTO.
Overall, the acute procedure success rate for CTO is 50% to 60%, and improvements in technology and technique have improved the feasibility of CTO treatment. The primary technical challenge during PCI of a total occlusion is the crossing of the occlusion with a wire. Several new wires have been specifically designed for crossing chronic occlusions, characterized by variable tip stiffness and increased hydrophilic characteristics. In addition, microcatheters with low profiles and hydrophilic coatings have been developed to aid in crossing the lesion. When crossing is not feasible from an antegrade approach, retrograde crossing of the lesion via collaterals is an alternative approach. After successful crossing of the lesion with the wire and recanalization, DES placement is preferred over bare-metal stents to reduce the restenosis rate of these complex, long lesions. The Primary Stenting of Totally Occluded Native Coronary Arteries (PRISON) II study randomized 200 patients with CTOs to receive either a sirolimus-eluting stent or a bare-metal stent and found that the sirolimus-eluting stent significantly reduced the rates of binary in-stent restenosis at 6 months (7% vs. 36%; P < .001), which translated into significantly lower rates of target lesion revascularization at 3 years (7% vs. 27%,; P < .001). These findings of lower rates of target lesion revascularization with DES placement in CTOs have been consistently replicated in other RCTs, observational studies, and meta-analyses.
Bifurcation Lesion Treatment
Coronary bifurcation lesions are also relatively common and account for 15% to 20% of PCIs. Although revascularization for bifurcation disease has historically been associated with lower acute success rates and higher restenosis and thrombosis rates than nonbifurcation lesions, the use of DESs and specific procedural techniques have improved success rates significantly. First, several strategies are possible regarding where to place the stent or stents. One option is stenting the main branch of the diseased bifurcation but stenting the side branch only if significant stenosis remains in the side branch as determined by angiography, intravascular ultrasound, or fractional flow reserve measurements; this is called the provisional approach . Alternatively, a planned two-stent approach can be taken in which both the main vessel and the side branch are stented using a variety of catheterization techniques. Various techniques are possible for the two-stent approach, depending on the anatomic geometry of the bifurcation (e.g., T-stenting, culotte, crush, kissing, or stenting ; Figure 11-2 ). Although certain anatomic characteristics may require a two-stent approach, such as larger diseased side branches or a large area of at-risk myocardium, several small randomized trials have demonstrated no benefit to routinely treating both branches with stents. Furthermore, a recent meta-analysis involving 1553 patients suggested that a provisional strategy may be associated with a lower risk of MI (RR, 0.53; 95% CI, 0.37 to 0.78; P = .001).
