**7. Current challenges**

172 Coronary Interventions

of which DES has sustained the most improved clinical outcomes remains debatable depending on the patient needs and ability to adhere to the indicated dual antiplatelet therapy recommended of aspirin and clopidogrel, as per the DES PCI recommendations (King et al., 2007). The long-term follow-up available from key DES trials is presented in

> **Cardiac death %**

(all death)

0.3%

2.8%

BMS 7.1 6.9 26.0 2.6 6.8

BMS 3.6 6.5 24.2 30.5 1.8

BMS 4.5 7.4 20.5 27.4 2.1

BMS 1.6 5.4 22.3 0.7 P=0.04 P=0.005

1.0%

4.6% P=0.03

P=0.005

0.9% 2.5%

1.3% 3.9%

(P=0.02)

**MI % TLR % TVR %** 

12.1 8.9 10.3 2.7 3.3

4.1 6.2 9.4 16.5 1.2

P<0.001 P<0.001

4.4 7.2 9.1 16.9 2.2

P<0.0001 P<0.0001

8.1%

6.5%

1.7 2.1 6.5 9.9 1.1

2.4 4.9 6.1 10.9 1.7

2.6 4.4 7.6 13.4 1.4

2.6 6.6 10.3 16.1 1.6

6.9% (P=0.004)

3.8 8.4 16.3 Not

P<0.001 (all ARC)

available

16.9%

13.0%

4.5% 3.9% 0.42%

4.3%

**Stent Thrombosis (ARC def/prob %)** 

1.9

0.7%

0.9%

1.23% (P=0.008)

Table 6.

RAVEL (Morice et al., 2007)

TAXUS IV (Ellis et al., 2009a)

TAXUS V (Ellis et al., 2009b)

ENDEAVOR III (Kandzari et al., 2011)

ENDEAVOR IV (Leon et al., 2010)

SPIRIT III (Stone, 2010b)

SPIRIT IV (Stone, 2010a)

**Trial Treatment** 

SIRIUS CYPHER SES

**Arms** 

CYPHER SES

TAXUS

TAXUS

ENDEAVOR ZES

CYPHER SES

ENDEAVOR ZES

TAXUS Express PES

XIENCE V

TAXUS Express

XIENCE V

TAXUS Express

(Available significant P values (≤ 0.05) are included above).

Table 6. Long-term Clinical Outcomes Currently Available

Express PES <sup>5</sup>

Express PES <sup>5</sup>

**Follow-up Year** 

5

5

5

3

4

2

A challenge that remains when comparing DES head to head across trials is the inconsistency between definitions. In order to address this challenge, the Academic Research Consortium (ARC) developed standardized definitions for clinical trial endpoints (Cutlip et al., 2007). The ARC definitions have now become the gold standard for clinical trial endpoints and definitions of clinical events, such as cardiac deaths, MI, and ST. In addition, clinical events may be retrospectively adjudicated by Clinical Events Committees (CEC) using the ARC definitions for post ad-hoc analysis of events not initially evaluated using the ARC definitions. The ARC definitions particularly met the need of unifying the ST definition that differed across stent manufacturers and clinical trials. One of the main concerns with using DES initially was the additional risk of ST possibly due to delayed healing, inflammation or incompatibility between polymer and the vessel (Lagerqvist et al., 2007; Moreno et al., 2005). First generation DES have observed higher rates of very late ST compared to BMS (Camenzind et al., 2007; Daemen et al., 2007; Farb and Boam, 2007; Pfisterer et al., 2006). Several DES specific characteristics may contribute to the development of ST, such as choice of drug, polymer, and strut thickness. Other patient specific characteristics may contribute, such as patient co-morbidities (diabetes, renal failure and acute MI) and lesion characteristics. Compliance to DAPT and platelet responsiveness also plays a role in ST rates observed in DES (Bezenek et al., 2011). Procedural factors related to smaller luminal dimensions, such as stent under-expansion or malapposition are risk factors for ST, in addition to stent length, multi-stenting, persistent slow flow, positive remodeling, dissections, geographic miss, residual stenosis, and late stent malapposition which have all been related to ST (Bezenek et al., 2011). Furthermore, well established criteria for the duration and dose with existing antiplatelet medication, as well as the role of newly emerging antiplatelet medications does not exist currently. Although the ARC definitions did provide a common reference for ST definitions concerning timing and severity, the appropriate standardized dose of DAPT remains in question with DES use. Despite these challenges however, few DES have emerged as demonstrating a consistent numerically low rate of ST across clinical trials. The XIENCE V and XIENCE PRIME DES remain two of the DES with the lowest ST event profile across RCT, single-arm, and all-comer trials, despite reduced DAPT compliance observed at 2 years in the COMPARE all-comers trial; the combination of stent design, thin struts, bio-compatible polymer coating technologies, and drug may contribute to numerically low ST rates consistently observed (Bezenek et al., 2011).

#### **8. Additional stent technology**

In order to address the concern for potential increased risk of late/very late ST with DES, several manufacturers developed biodegradable polymers and bioabsorbable scaffolds that degrade over time. Durable polymers may be associated with increased complications and clinical events and new developments in DES are integrating dissolvable polymers and scaffolds to eliminate this potential problem. Abbott Vascular currently has the ABSORB™ clinical trial program that is evaluating the everolimus-eluting bioresorbable vascular scaffold (BVS) in global clinical trials. The ABSORB BVS clinical trial program is evaluating the safety and efficacy of fully bioabsorbable scaffold that is comprised of a poly-L-lactic acid backbone and has a poly-D, L-lactic acid coating that modulates the release of everolimus. The ABSORB international clinical trials that have enrolled patients thus far

DES Overview: A Historical and Current Review of Pivotal Clinical Trial Programs 175

next generation DES evaluated in the CYPHER, TAXUS, ENDEAVOR, and XIENCE V clinical programs significantly reduced restenosis compared to BMS and have demonstrated comparable safety outcomes. In order to address potential polymer induced inflammation or delayed healing related safety events in current FDA approved DES, new technologies using biodegradable polymers, polymer-free DES, and bioresorbable stent scaffolds have emerged to further enhance PCI options. Long-term clinical results have clearly supported the safety and efficacy of DES and more specialized DES designs and trials for specific

Abizaid A., Costa J.R., Jr., Feres F. (2011) First nine-month complete invasive assessment

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Camenzind E., Steg P.G., Wijns W. (2007) Stent thrombosis late after implantation of firstgeneration drug-eluting stents: a cause for concern. Circulation 115:1440-1455. Chevalier B. (2011) ABSORB Cohort B Trial - Evaluation of the ABSORB Bioresorbable

eluting stents for coronary artery lesions. Circulation 108:788-794.

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a large two-institutional cohort study. Lancet 369:667-678.

Cutlip D.E., Windecker S., Mehran R., Boam A., Cohen D.J., van Es G.A., Steg P.G., Morel

Daemen J., Wenaweser P., Tsuchida K., Abrecht L., Vaina S., Morger C., Kukreja N., Juni P.,

Dawkins K.D., Grube E., Guagliumi G., Banning A.P., Zmudka K., Colombo A., Thuesen L.,

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patient and lesion unmet needs continue to be pursued.

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77:52-3. DOI: 10.1002/ccd.22921.

10.1111/j.1540-8183.2011.00628.x.

**10. References** 

include ABSORB Cohorts A and Cohort B and ABSORB EXTEND. The ABSORB Cohort A trial enrolled 30 patients and was designed to evaluate the safety and performance of ABSORB BVS in single de novo lesions. The 4-year clinical event rates remain numerically low with no events of scaffold thrombosis occurring (Chevalier, 2011). The ABSORB Cohort B trial enrolled 101 patients and allowed up to two de novo lesions to be treated. Current 12 month results for Cohort B were presented at the American College of Cardiology (ACC) and reported that no scaffold thrombosis have occurred either by ARC or per protocol definitions as well (Serruys, 2011). The ABSORB EXTEND trial plans to enroll up to 1000 patients at up to 100 international sites and will continue to assess the safety and performance of ABSORB BVS in up to two de novo lesions, allowing for the evaluation of longer lesions and overlapping scaffolds.

As mentioned earlier, the NEVO stent was a new technology in development by Cordis Corporation, Johnson and Johnson, and used polylactic-co-glycolic acid (PGLA) loaded in reservoirs drilled through the struts of a cobalt chromium stent and has subsequently been removed from further development (Belardi, 2011; Otake et al., 2011b). The JACTAX™ biodegradable stent system is developed by Boston Scientific and uses D-lactic polylactic acid (DLPLA) mounted on the TAXUS Liberté stent whose outside coating elutes paclitaxel (Grube et al., 2010; Shand, 2010) . The Biolimus-A9 TM eluting BioMatrix™ stent system (Biosensors Interventional Technologies Pte Ltd, Singapore) incorporates a biodegradable polylactic acid (PLA) coated on the outside of the S-Stent stainless steel stent that scaffolds the artery (Abizaid et al., 2011; Shand, 2010). The Leaders trial was designed to compare the BioMatrix stent to the CYPHR stent and enrolled 1707 patients (randomized 1:1) with a composite clinical primary endpoint of cardiac death, MI, and clinically-indicated target vessel revascularization (Windecker et al., 2008). The primary endpoint was met and BioMatrix demonstrated non-inferiority compared to CYPHER (9.2% versus 10.5%; P=0.003) and has sustained numerically low rats of very-late ARC-defined definite stent thrombosis through 3 years, respectively (0.2% versus 0.9%), (Windecker, 2011; Windecker et al., 2008).

The CardioMind Sparrow is developed by CardioMind, Inc. and is a self-expandable nitinol stent with a PLA/PLGA copolymer biodegradable outside coating (Abizaid et al., 2011). The ELIXER-DES™ is under development by the Elixer Medical Group and has a cobaltchromium stent as the scaffold and uses polyester or polylactide based biodegradable polymer coating over the outside of the stent. Other technologies are moving toward polymer-free DES as well, such as the BioFreedom™ (Biosensors Inc.), the VESTAsync™ (MIV Therapeutics), and the Optima™ (CID S.r.I) with further specialized designs using biolimus A9, sirolimus, and tacrolimus, respectively (Abizaid et al., 2011). Lastly, endothelium progenitor cell (EPC) capture stents were developed (Genous™ manufactured by OrbusNeich, Florida, USA) coated with CD34 antibodies that were to bind to circulating EPCs. The EPC capture stents have yet to show clinical trials demonstrating safety and efficacy superior to DES and have not become mainstream treatment options to date (Garg et al., 2010).

#### **9. Conclusion**

In conclusion, DES has emerged as a treatment of choice for patients that are suitable candidates with no restrictions to physician recommended DAPT medication. The first and next generation DES evaluated in the CYPHER, TAXUS, ENDEAVOR, and XIENCE V clinical programs significantly reduced restenosis compared to BMS and have demonstrated comparable safety outcomes. In order to address potential polymer induced inflammation or delayed healing related safety events in current FDA approved DES, new technologies using biodegradable polymers, polymer-free DES, and bioresorbable stent scaffolds have emerged to further enhance PCI options. Long-term clinical results have clearly supported the safety and efficacy of DES and more specialized DES designs and trials for specific patient and lesion unmet needs continue to be pursued.

#### **10. References**

174 Coronary Interventions

include ABSORB Cohorts A and Cohort B and ABSORB EXTEND. The ABSORB Cohort A trial enrolled 30 patients and was designed to evaluate the safety and performance of ABSORB BVS in single de novo lesions. The 4-year clinical event rates remain numerically low with no events of scaffold thrombosis occurring (Chevalier, 2011). The ABSORB Cohort B trial enrolled 101 patients and allowed up to two de novo lesions to be treated. Current 12 month results for Cohort B were presented at the American College of Cardiology (ACC) and reported that no scaffold thrombosis have occurred either by ARC or per protocol definitions as well (Serruys, 2011). The ABSORB EXTEND trial plans to enroll up to 1000 patients at up to 100 international sites and will continue to assess the safety and performance of ABSORB BVS in up to two de novo lesions, allowing for the evaluation of

As mentioned earlier, the NEVO stent was a new technology in development by Cordis Corporation, Johnson and Johnson, and used polylactic-co-glycolic acid (PGLA) loaded in reservoirs drilled through the struts of a cobalt chromium stent and has subsequently been removed from further development (Belardi, 2011; Otake et al., 2011b). The JACTAX™ biodegradable stent system is developed by Boston Scientific and uses D-lactic polylactic acid (DLPLA) mounted on the TAXUS Liberté stent whose outside coating elutes paclitaxel (Grube et al., 2010; Shand, 2010) . The Biolimus-A9 TM eluting BioMatrix™ stent system (Biosensors Interventional Technologies Pte Ltd, Singapore) incorporates a biodegradable polylactic acid (PLA) coated on the outside of the S-Stent stainless steel stent that scaffolds the artery (Abizaid et al., 2011; Shand, 2010). The Leaders trial was designed to compare the BioMatrix stent to the CYPHR stent and enrolled 1707 patients (randomized 1:1) with a composite clinical primary endpoint of cardiac death, MI, and clinically-indicated target vessel revascularization (Windecker et al., 2008). The primary endpoint was met and BioMatrix demonstrated non-inferiority compared to CYPHER (9.2% versus 10.5%; P=0.003) and has sustained numerically low rats of very-late ARC-defined definite stent thrombosis through 3 years, respectively (0.2% versus 0.9%), (Windecker, 2011; Windecker et al., 2008). The CardioMind Sparrow is developed by CardioMind, Inc. and is a self-expandable nitinol stent with a PLA/PLGA copolymer biodegradable outside coating (Abizaid et al., 2011). The ELIXER-DES™ is under development by the Elixer Medical Group and has a cobaltchromium stent as the scaffold and uses polyester or polylactide based biodegradable polymer coating over the outside of the stent. Other technologies are moving toward polymer-free DES as well, such as the BioFreedom™ (Biosensors Inc.), the VESTAsync™ (MIV Therapeutics), and the Optima™ (CID S.r.I) with further specialized designs using biolimus A9, sirolimus, and tacrolimus, respectively (Abizaid et al., 2011). Lastly, endothelium progenitor cell (EPC) capture stents were developed (Genous™ manufactured by OrbusNeich, Florida, USA) coated with CD34 antibodies that were to bind to circulating EPCs. The EPC capture stents have yet to show clinical trials demonstrating safety and efficacy superior to DES and have not become mainstream treatment options to date (Garg

In conclusion, DES has emerged as a treatment of choice for patients that are suitable candidates with no restrictions to physician recommended DAPT medication. The first and

longer lesions and overlapping scaffolds.

et al., 2010).

**9. Conclusion** 


DES Overview: A Historical and Current Review of Pivotal Clinical Trial Programs 177

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**9** 

*Greece* 

Petros S. Dardas

*St Luke's Hospital, Thessaloniki* 

**Rotablation in the Drug Eluting Stent Era** 

In the field of interventional cardiology, heavily calcified coronary lesions (HCCL) pose great technical challenges and are associated with a high frequency of restenosis and target lesion revascularization (TLR) (Moses et al, 2004). The prevalence of severe calcium, defined as superficial (calcium at the intimal-lumen interface or closer to the lumen than to the adventitia) with greater than 180° arc, is estimated to present itself in 12% of cases using angiographic imaging. When IVUS guidance is used, it is seen in approximately 26% of

Fig. 1. Calcium distribution: Left: 1800, in the center: 2700, Right: superficial and deep

Occasionally, the degree of calcification and/or the geometry of the plaque prevent the crossing of the lesion with balloon or stent. Adequate lesion preparation before stent implantation remains an essential component of contemporary practice of coronary stent implantation in patients with complex lesions to improve both immediate and long-term outcomes. In heavily calcified lesions preparation with high-pressure balloon inflation may occasionally succeed but is often inadequate, or may create vessel wall rupture (undilatable

In an attempt to overcome challenges posed by calcification, a number of devices and techniques have been developed. One such advance is rotational atherectomy, in which a rotating brass burr (figure 3) mounted on a flexible drive shaft and coated with diamond chips pulverizes a portion of the fibrous, calcified, inelastic plaque, modifies the

**1. Introduction** 

cases (Figure 1) (Mintz et al, 2005).

lesion, figure 2) (Hoffmann et al, 1998).

coronary arteries: a quantitative coronary angiography and three-dimensional intravascular ultrasound study. Circulation 103:192-195.

