Long-Term Clinical Performance of Paclitaxel-Eluting Stents Coated With a Bioactive Polymer (P-5) Containing a Triflusal Derivative: Results of the REWAC Registry

Abstract: Aims. Although drug-eluting stents have dramatically reduced angiographic restenosis and clinical need for repeat revascularization procedures, some adverse effects, such as late stent thrombosis, have been described. We evaluated clinical performance of paclitaxel-eluting stents coated with a new bioactive polymer system (P-5) based on a copolymer of an acrylic derivative of triflusal in patients with coronary artery disease. Methods and Results. This was a multicenter, observational, prospective study to assess the incidence of target lesion revascularization (TLR) at 6 months and clinical major adverse cardiac events (MACEs) at 1 and 6 months and 1 and 2 years post-stent implantation in 537 patients. After stent implantation, only 1 case of thrombus and acute occlusion was reported in 1 lesion (0.14%). The incidence of new TLR was 0.89% at 6 months, 1.08% at 1 year, and 1.49% at 2 years, with a cumulative incidence of 3.54%. MACEs included cardiac death (0.93%), myocardial infarction (0.37%), and cardiac surgery (0.19%). No cases of late or very late stent thrombosis were recorded. Conclusion. Under routine clinical practice, the implantation of paclitaxel-eluting stents coated with P-5 is associated with favorable clinical outcomes in both the short and long term (2 years) in patients with coronary artery disease. 

J INVASIVE CARDIOL 2013;25(8):391-396

Key words: drug-eluting stents, paclitaxel-eluting stents, target lesion revascularization, major adverse cardiac events, bioactive polymers, triflusal

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Percutaneous coronary intervention (PCI) with stenting is the most widely performed procedure for the treatment of symptomatic coronary disease.¹ Among the various approaches to optimize stent design, drug-eluting stents (DESs), including sirolimus, paclitaxel, zotarolimus, and everolimus,^2-4 have minimized the limitations of bare-metal stents (BMSs),¹ demonstrating superior performance in terms of antirestenotic efficacy and reduced need for revascularization procedures,^5-7 mainly by inhibiting neointimal proliferation.⁷ However, some adverse effects have been described,^2-4 such as arterial response, including delayed endothelialization,^7-10 late endothelial dysfunction,^7,11 impaired coronary collateral vessel function,^7,12 hypersensitivity reactions,^7-14 and late stent thrombosis.^7,15-17 

To address these issues, modifying and optimizing stent properties and performance so as to reduce unexpected side effects are tasks highly needed and currently under study.^4,18,19 For example, new DESs are being developed with novel materials, designs, and delivery systems, improved biocompatible polymers, and new antiproliferative agents.^4,18,20 In this context, the application of bioactive polymer coatings with inherent antithrombogenic activity is considered to improve the stent applications and guarantee non-thrombogenic activity in the long term.^4,18,20

Stents coated with hydrophilic polymers and phosphorylcholine-containing polymers carrying heparin have been used to decrease thrombosis. However, a high percentage of patients using these DESs still suffer from artery narrowing, restenosis, and thrombosis,^18,21 and even severe myocardial infarction, all of which result in the need for revascularization by reintervention or coronary artery bypass graft (CABG) surgery.^18,22-24

IHT Iberhospitex SA has developed and marketed two paclitaxel DESs (Active and Active Small), based on the platform, Apolo 3, to which a coating of paclitaxel has been applied using P-5 as the polymeric vehicle. P-5 is a new, bioactive, biocompatible, biostable, antiplatelet, and antiinflammatory polymer system based on a copolymer of an acrylic derivative of triflusal (a platelet aggregation inhibitor).⁴ 

In in vitro studies, this copolymer system showed excellent biocompatibility and good inherent inhibitory activity against platelet aggregation.⁴ In in vivo porcine coronary models, significantly lower percentages of restenosis were detected after implantation of the paclitaxel DESs coated with the bioactive P-5 polymer than with the BMS based on platform Apolo 3 and the same paclitaxel DESs but without the polymer.²⁵ Moreover, a swine coronary model and clinical studies performed with Irist simvastatin-eluting stents (IHT Iberhospitex SA) coated with the same bioactive P-5 polymer have demonstrated the efficacy and safety of this polymer.^26-28

Since the use of paclitaxel stents with these new P-5 biopolymers had not been fully evaluated in routine clinical practice, the present international, multicenter, observational, prospective, non-randomized study (REWAC registry) was conducted to assess the clinical performance of implanted paclitaxel DESs containing P-5 (Active and Active Small stents) over a period of 2 years in patients with coronary artery disease in the context of routine clinical practice. 

Methods

Between December 2008 and May 2011, a multicenter, observational, prospective, non-randomized study was conducted in patients with coronary artery disease (occurring in native coronary arteries) treated with Active and Active Small stents. 

Patients from 18 hospitals in 5 different countries (Spain, Greece, Cyprus, Cuba, and Mexico) were consecutively included in the REWAC registry (Real World Active stent registry of coronary angioplasty). 

Patients with the following characteristics were eligible for inclusion: age between 18 and 75 years; stenotic lesions on native coronary arteries causing cardiac ischemia; eligible for PCI; candidates for CABG; lesions located in arteries with diameters ≥2.0 and ≤4.5 mm by visual estimation that could be covered with a stent measuring up to 36 mm (1 stent per lesion, maximum of 3 treated vessels); and stenosis severity ranging from 70%-100%. 

Sizes of implanted stents ranged from 2-4.5 mm in diameter and from 9-36 mm in length. Active (3.0, 3.5, 4.0, and 4.5 mm) and Active Small (2.0 and 2.25 mm) stents were based on the platform Apolo 3, to which a coating of paclitaxel was applied using a polymeric vehicle (P-5 polymer, based on a copolymer of an acrylic derivative of triflusal) in a slow-release system (0.36 µg/mm²). 

The objective of the study was to evaluate the clinical performance of paclitaxel-eluting stents (Active and Active Small) over a period of 2 years. The primary endpoint of the study was target lesion revascularization (TLR) at 6 months, defined as revascularization of the target lesion due to restenosis or closure after stent implantation. The secondary endpoint was the incidence of clinical major adverse cardiac events (MACEs), defined as cardiac death, acute myocardial infarction, or TLR (by angioplasty or aortocoronary bypass surgery) at 1 and 6 months and 1 and 2 years post stent implantation. 

In the statistical analysis, qualitative variables are expressed as absolute numbers (n) or relative frequency (%). Quantitative variables are expressed as mean and standard deviation, median, interquartile range (IQR), the first and third quartiles (Q1 and Q3), minimum and maximum. Data have also been analyzed separately according to stent diameter and length. 

The study was approved by the local Clinical Ethics Committee at Hospital Arnau de Vilanova (Lleida, Spain) and conducted in accordance with the Declaration of Helsinki guidelines. 

Results

A total of 561 patients with 717 lesions were included. Of these, 537 patients with 722 lesions were followed through the end of the study (over a 2-year period). The number of patients followed at 1, 6, 12, and 24 months was 561, 559, 548, and 537 respectively. 

In terms of the patients’ baseline characteristics, a majority (78.6%) was male, mean age was 62 ± 8.7 years, 33.16% were smokers, and 19.8% had a family history of ischemic heart disease. Hypertension (69.5%), dyslipidemia (63.5%), and diabetes mellitus (30.48%) were the most common coronary risk factors, while 22.46% of patients had suffered a previous myocardial infarction and 17.3% and 3.57% of these patients had undergone previous PCI and CABG, respectively (Table 1). 

Reasons for PCI revascularization included unstable angina (45.99%), stable angina (40.46%), post acute myocardial infarction (5.17%), and silent ischemia (5.7%). Before PCI, most patients were treated with antiplatelet agents (aspirin or ticlopidine/clopidogrel) (Table 1). 

At baseline, approximately 60% of lesions had reference vessel diameters (RVDs) ≤2.7 mm, mainly affecting the left anterior descending (LAD), left circumflex (LCX), and right coronary artery (RCA) and belonging to the four American Heart Association/American College of Cardiology classes (A, 15.65%; B1, 41.55%; B2, 27.42%; C, 15.37%). Calcification and tortuosity were present in 37% of lesions and thrombus in 6%. TIMI 3 was the most common flow pattern (57.76%), followed by TIMI 1 (30.33%) and TIMI 2 (11.77%). Most patients had 1 vessel with stenosis >70% (23.20% with 2 vessels and 5.30% with 3 vessels). Left ventricular ejection fraction (LVEF) was normal in the majority of patients (89.30%) (Table 2). 

Balloon predilation of the target lesion was performed in 95.70% of lesions. Characteristics of the stents used are shown in Figures 1A and 1B. All available stent diameters were used, with the most commonly used diameters being 2.5 mm (23.27%), 3.0 mm (36.57%), and 3.5 mm (21.47%), and the most common lengths used being <15 mm (31.30%), 15-27 mm (46.12%), and >27 mm (22.30%) (Figure 1B). 

Additional stents were needed in 7.20% of lesions, due to incomplete lesion coverage (48.21%), dissection (41.07%), other reasons (8.93%), and initial stent failure (1.79%). Balloon postdilation was performed in 52.08% of lesions (using balloon diameters ≥2.7 mm in 92.82% of cases and balloon lengths <15 mm in 70.74% of cases). After PCI, TIMI 3 flow pattern was present in 99.5% of lesions, with residual stenosis (<30%) in all lesions. Thrombus causing acute occlusion was present in only 1 lesion (0.14%). 

During the 2-year follow-up, a total of 15 patients died (5 cardiac and 10 non-cardiac deaths) and loss to follow-up (n = 8) was registered from month 6. Three patients suffered myocardial infarction at 1 month, 6 months, and 2 years, respectively. Sixty-two patients had episodes of angina (11.55% of total), requiring hospitalization in 42 cases.

New procedures performed over the course of the follow-up period were: new coronary angiogram (n = 52), new PCI-TLR (n = 19), new PCI-target vessel revascularization (PCI-TVR; n = 4), new PCI-other (n = 7), and cardiac surgery (n = 1). 

With regard to the primary study endpoint, the incidence of new PCI-TLR at 6 months was 0.89%, occurring in 5 of 559 evaluated patients and representing 0.69% of all lesions. The incidence of new PCI-TLR subsequently increased to 1.08% at 1 year and 1.49% at 2 years, with a cumulative incidence of 3.54% (in relation to 537 evaluated patients at the end of the follow-up) and 2.74% of all lesions (in relation to 694 lesions at the end of follow-up) (Figure 2). 

Registered MACEs included cardiac death (n = 5; 0.93% of patients), myocardial infarction (n = 3), cardiac surgery (n = 1), and new PCI-TLR (n = 19). Over the course of the follow-up period, the cases of cardiac death appeared at 6 months (n = 2), at 1 year (n = 2), and at 2 years (n = 1), the acute myocardial infarctions occurred at 1 month (n = 1), 6 months (n = 1), and 2 years (n = 1), cardiac surgery took place at 2 years (n = 1), while new PCI-TLR was performed at 6 months (n = 5), 1 year (n = 6), and 2 years (n = 8). No cases of stent thrombosis were registered during the study (Figure 2). 

In the analysis of time to event, reported median days to MACE were 209 days for acute myocardial infarction, 247 days for cardiac death, 356 days for new PCI-TLR, and 732 days for cardiac surgery. Fifty percent of acute myocardial infarction cases occurred before 6 months and 75% of cases occurred within the first 15 months. In the case of cardiac death, 50% of cases occurred before 8 months and 75% occurred within the first 10 months, while new PCI-TLR was performed later (50% of cases were performed before 1 year and 75% were performed within the first 16 months). 

Reported median days to performing new PCIs were 192.5 days for new PCI-TVR, 323.5 days for new PCI-other, and 356 days for PCI-TLR. Fifty percent of new PCI-TVR cases occurred before 6 months, and 75% occurred within the first year. 

The lowest number of events was registered in the group of patients treated with stents longer than 26 mm and a diameter under 3 mm (2 events at 6 months and at 1 year), while the group of patients treated with stents longer than 15 mm experienced the highest number of events (1 event at discharge and at 1 month, 12 events at 6 months, and 15 events at 1 and 2 years). Registered events in this group were acute myocardial infarction (n = 2), cardiac death (n = 4), non-cardiac death (n = 8), new PCI-TLR (n = 16), new PCI-TVR (n = 3), and new PCI-other (n = 5). 

In the group of patients treated with stents longer than 26 mm (for a total of 161 lesions), events occurred from month 6 and included non-cardiac death (n = 4), new PCI-TLR (n = 7), new PCI-TVR (n = 3), and new PCI-other (n = 4). In the group of patients treated with stents with a diameter under 3 mm (for a total of 270 lesions), events were also registered from month 6 and included acute myocardial infarction (n = 1), cardiac death (n = 2), non-cardiac death (n = 5), new PCI-TLR (n = 14), new PCI-TVR (n = 2), and new PCI-other (n = 2). 

The patient group with stenosis in 1 vessel >70% (n = 400) suffered the highest number of events (n = 30: 9 at 6 months, 11 at 1 year, and 10 at 2 years), followed by the group with 2 affected vessels (n = 130) with 11 events. There were 4 events in the group with 3 affected vessels with stenosis >70% (n = 31). 

In the subgroup of patients with diabetes mellitus (n = 171), a total of 13 events (0.74%) were registered (4 at 6 months, 5 at 1 year, and 4 at 2 years). 

Lastly, the REWAC Registry included a total of 285 patients (50.8%) with acute coronary syndrome (ACS), considered as unstable angina, post acute myocardial infarction with ≤5 days since onset, and other (non-ST elevation myocardial infarction). TLR at 6 months in this subgroup of patients was 1.41%, in comparison with 0.36% in patients without ACS. The cumulative incidence of new TLR and MACE during the 2-year follow-up period was also higher in ACS patients (3.33% and 5.56%, respectively) than in non-ACS patients (3.75% and 4.87%, respectively). 

Discussion

Although DESs significantly improve the incidence of restenosis, some adverse effects, such as late stent thrombosis, have been described.^2-4 The application of bioactive polymer coatings with inherent antithrombogenic activity was proposed to improve stent applications and guarantee non-thrombogenic activity in the long term.⁴ 

Although the efficacy and safety of paclitaxel DESs have been extensively demonstrated,²¹ the use of paclitaxel stents with these new biopolymers with non-inflammatory and anti-platelet properties, such as P-5, had not been fully evaluated in routine clinical practice. The results of this international, prospective, observational, multicenter REWAC Registry have demonstrated that, under routine clinical practice conditions, implantation of paclitaxel-eluting stents coated with the bioactive P-5 polymer provides excellent results in both the short and long term (up to 2 years) in patients with coronary artery disease, including patients with unfavorable baseline characteristics and high-risk lesions. 

In fact, the baseline characteristics of the patients evaluated in our study were similar to previous randomized clinical trials evaluating conventional DESs and BMSs,^7,29 with a predominance of male patients. In a prospective, observational study including 3067 patients, although women had poorer baseline characteristics (5 years older and a higher rate of comorbidities such as diabetes mellitus or hypertension), no differences in outcomes were observed between men and women for ACS with contemporary DESs.³⁰ Increasing evidence shows, however, that the benefit of DESs is determined by a complex healing process with substantial inter-individual variations (including interaction of lesion characteristics, various stent technologies, genetics, molecular and metabolic response patterns, and biologic response over time).⁷ 

In line with other studies with DESs,^7,30,31 in our study, although 2.5, 3.0, and 3.5 mm diameters were the most common, all available stent diameters were used.

In terms of new PCI procedures, the incidence of new PCI-TLR (0.89% at 6 months and cumulative incidence of 3.54%) and PCI-TVR (n = 4; 0.74%) was low, thus highlighting better clinical outcomes for the newly-developed stents in comparison with conventional paclitaxel-eluting stents.^7,20,29 

In a recent randomized trial including 112 patients treated with sirolimus or paclitaxel-eluting stents, 5 lesions out of 108 (4.6%) treated with sirolimus-eluting stents and 3 lesions out of 110 (2.7%) treated with paclitaxel-eluting stents required repeat TLR using PCI at a follow-up period of 12 months. A need for TVR was observed in 2 lesions treated with paclitaxel-eluting stents and PCI (1.8%) and 3 lesions (2.7%) treated with paclitaxel-eluting stents required surgical treatment.⁷ In a pooled patient-level meta-analysis of randomized trials from January 2000 to June 2011, the use of DESs (mainly sirolimus and paclitaxel) reduced the occurrence of TVR compared with the use of BMSs (12.7% vs 20.1%, respectively).²⁰ In another pooled analysis of data from randomized clinical trials, during a 4-year follow-up period, PCI-TLR was required in 7.7% of paclitaxel-eluting stents versus 15.6% of BMSs (P<.001).²⁹ 

With regard to MACEs, we also reported a lower incidence of cardiac death (0.93%), myocardial infarction (0.37%), and cardiac surgery (0.19%) in comparison with other long-term studies.^6,7,30 In a randomized clinical trial that included 450 patients, the 5-year MACE rate was 27.3% in patients treated with polymer-free sirolimus stents and 31.7% in patients treated with permanent polymer paclitaxel-eluting stents.⁶ 

In a total of 274 coronary patients randomly allocated to paclitaxel-eluting stents, sirolimus-eluting stents (having the same biodegradable polymers), or BMSs (2:2:1 ratio), the pooled population treated with DESs had similar rates of cardiac death or myocardial infarction (9.0% vs 7.1%; P=.6), but lower risk of repeated interventions at 3 years (10.0% vs 29.9%; P<.01) than controls with BMSs. The cumulative 3-year incidence of definite or probable stent thrombosis in the pooled DES group was 2.3% and there were no significant differences in outcomes between paclitaxel- and sirolimus-eluting stents.³² 

Stent thrombosis, particularly late stent thrombosis (occurring from 30 to 360 days after the procedure) and very late stent thrombosis (occurring >1 year later),^33,34 is one of the most important issues raised with the use of DESs.^1,7,20,34,35 It is a catastrophic, albeit uncommon, complication that results in abrupt coronary artery closure, which can lead to myocardial infarction or sudden cardiac death.^34,36 

In our study, we only reported 1 case of acute stent thrombosis immediately after implantation, and no cases of late or very late stent thrombosis were registered during the study, confirming the contribution of the antiplatelet properties of the P-5 biopolymer. Moreover, the incidences of myocardial infarction (n = 3, at 1 month, 6 months, and 2 years) and cardiac death (n = 5, at 6 months), which could have been caused by stent thrombosis, were also low. 

It is known that DESs can induce atherosclerotic and thrombogenic lesions with a significantly higher incidence and at an earlier stage than BMSs.³⁴ However, the use of new bioactive polymers such as P-5, with antiplatelet and antiinflammatory properties, has been demonstrated to prevent the occurrence of late thrombosis events. 

In comparison with other polymers,^7,30 the new bioactive polymer system, based on a copolymer of an acrylic derivative of triflusal (a molecule with a chemical structure related to aspirin with inhibitory activity against platelet aggregation)⁴ is specific for DESs, has excellent biocompatibility and good inherent inhibitory activity against platelet aggregation.⁴ Moreover, ex vivo, the P-5 polymer has shown less platelet deposition than Dracon,³⁷ an approved polymer for medical use. 

Favorable results with the newly developed stent have also been observed in certain subgroups, such as patients with ACS and diabetes. The incidence of events was also low in the subgroup of patients with diabetes mellitus (0.74%), thus highlighting the feasibility of using our stents in this group of patients. Diabetes is another predictive factor for poorer outcome after stent implantation;^7,30 with early generations of DESs, diabetic patients had been reported to be at increased risk for mortality after revascularization.³⁸ In this regard, we are planning new studies to test Active stents in diabetic patients. 

Overall, despite its observational nature, we consider that our study provides new data on the efficacy and safety of new-generation paclitaxel-eluting stents coated with platelet aggregation inhibiting polymers in the context of routine clinical practice and in a large sample (over 500 patients). 

Conclusion

The results of this study have demonstrated that paclitaxel-eluting stents coated with the new bioactive polymer system, containing an acrylic derivative of triflusal, provide excellent clinical outcomes in terms of long-term efficacy and safety, thus supporting their clinical use in patients with coronary artery disease.

Acknowledgment. Our gratitude to Anagram ESIC, SL, for activities of clinical monitoring, data auditing, and statistical analysis. 

References

1. Park SJ, Kang SJ, Virmani R, Nakano M, Ueda Y. In-stent neoatherosclerosis: a final common pathway of late stent failure. J Am Coll Cardiol. 2012;59(23):2051-2057.
2. Ong AT, Hoye A, Aoki J, et al. Thirty-day incidence and six-month clinical outcome of thrombotic stent occlusion after bare-metal, sirolimus, or paclitaxel stent implantation. J Am Coll Cardiol. 2005;45(6):947-953.
3. Virmani R, Guagliumi G, Farb A, et al. Localized hypersensitivity and late coronary thrombosis secondary to a sirolimus-eluting stent: should we be cautious? Circulation. 2004;109(6):701-705.
4. Rodríguez G, Fernández-Gutiérrez M, Parra J, et al. Bioactive polymeric systems with platelet antiaggregating activity for the coating of vascular devices. Biomacromolecules. 2010;11(10):2740-2747. 
5. Tarantini G, Facchin M, Capodanno D, et al. Paclitaxel versus sirolimus eluting stents in diabetic patients: does stent type and/or stent diameter matter?: long-term clinical outcome of 2,429-patient multicenter registry. Catheter Cardiovasc Interv. 2013;81(1):80-89.
6. King L, Byrne RA, Mehilli J, Schömig A, Kastrati A, Pache J. Five-year clinical outcomes of a polymer-free sirolimus-eluting stent versus a permanent polymer paclitaxel-eluting stent: final results of the intracoronary stenting and angiographic restenosis - test equivalence between two drug-eluting stents (ISAR-TEST) trial. Catheter Cardiovasc Interv. 2013;81(1):E23-E28.
7. Kollum M, Heitzer T, Schmoor C, et al; the FreRace Trial Investigators. Intra-individual head-to-head comparison of sirolimus- and paclitaxel-eluting stents for coronary revascularization. A randomized, multi-center trial. Int J Cardiol. 2012 May 8 (Epub ahead of print). 
8. Frey D, Billinger M, Meier P, et al. Endothelialization of sirolimus-eluting stents with slow and extended drug release in the porcine overstretch model. J Invasive Cardiol. 2008;20(12):631-634.
9. Joner M, Finn AV, Farb A, et al. Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk. J Am Coll Cardiol. 2006;48(1):193-202.
10. Joner M, Nakazawa G, Finn AV, et al. Endothelial cell recovery between comparator polymer-based drug-eluting stents. J Am Coll Cardiol. 2008;52(5):333-342.
11. Shin DI, Seung KB, Kim PJ, et al. Long-term coronary endothelial function after zotarolimus-eluting stent implantation. A 9-month comparison between zotarolimus-eluting and sirolimus-eluting stents. Int Heart J. 2008;49(6):639-652.
12. Meier P, Zbinden R, Togni M, et al. Coronary collateral function long after drug-eluting stent implantation. J Am Coll Cardiol. 2007;49(1):15-20.
13. Guagliumi G, Virmani R, Musumeci G, et al. Drug-eluting versus bare metal coronary stents: long-term human pathology. Findings from different coronary arteries in the same patient. Ital Heart J. 2003;4(10):713-720.
14. Nebeker JR, Virmani R, Bennett CL, et al. Hypersensitivity cases associated with drug-eluting coronary stents: a review of available cases from the Research on Adverse Drug Events and Reports (RADAR) project. J Am Coll Cardiol. 2006;47(1):175-181.
15. Lagerqvist B, James SK, Stenestrand U, Lindbäck J, Nilsson T, Wallentin L; SCAAR Study Group. Long-term outcomes with drug-eluting stents versus bare-metal stents in Sweden. N Engl J Med. 2007;356(10):1009-1019.
16. Windecker S, Meier B. Late coronary stent thrombosis. Circulation. 2007;116(17):1952-1965.
17. Finn AV, Joner M, Nakazawa G, et al. Pathological correlates of late drug-eluting stent thrombosis: strut coverage as a marker of endothelialization. Circulation. 2007;115(18):2435-2441.
18. Guo QK, Lu ZQ, Wang JY, Li T. In vivo evaluation of a novel dexamethasone-heparin-double-coated stent for inhibition of artery restenosis and thrombosis. J Mater Sci Mater Med. 2011;22(6):1615-1623.
19. Palmerini T, Kirtane AJ, Serruys PW, et al. Stent thrombosis with everolimus-eluting stents: meta-analysis of comparative randomized controlled trials. Circ Cardiovasc Interv. 2012;5(3):357-364.
20. De Luca G, Dirksen MT, Spaulding C, et al. Drug-eluting vs bare-metal stents in primary angioplasty: a pooled patient-level meta-analysis of randomized trials. Arch Intern Med. 2012;172(8):611-621.
21. Stone GW, Moses JW, Ellis SG, et al. Safety and efficacy of sirolimus- and paclitaxel-eluting coronary stents. N Engl J Med. 2007;356(10):998-1008.
22. Matsumoto K, Morishita R, Moriguchi A, et al. Inhibition of neointima by angiotensin-converting enzyme inhibitor in porcine coronary artery balloon-injury model. Hypertension. 2001;37(2):270-274.
23. Hayashi K, Nakamura S, Morishita R, et al. In vivo transfer of human hepatocyte growth factor gene accelerates re-endothelialization and inhibits neointimal formation after balloon injury in rat model. Gene Ther. 2000;7(19):1664-1671.
24. Raisuke I, Yuji I, Akiyoshi M, Hiroyoshi N, Kazuhiro H. Predictors of restenosis after implantation of 2.5 mm stents in small coronary arteries. Circ J. 2004;68(3):236-240.
25. Casani L, Juan O, Serra A, et al. A new DES with antiinflammatory and antiproliferative activity reduces in-stent restenosis. Experimental studies in the pig coronary model. Presented at ESC (European Society of Cardiology), 2009. 
26. Pérez A, Pérez C, Cuellas C, et al. Vascular healing response to simvastatin-eluting-stent (IRIST) in a swine coronary model. Innovative coronary devices Part III. Abstract E103. EuroPCRonline, 2009. 
27. IHT internal report. Intra-stent restenosis inhibition by means of simvastatin. Multicentric, propective, randomized and double-blind comparison of P5/S1 recovered stent and Apolo 3 stent. Code: 252/05/EC. April 2008. 
28. Serra A, Miranda F, Vaquerizo B. Novedades en stents farmacoactivos. Actualización y futuros desarrollos. Rev Esp Cardiol. 2010;10:2C-11C. 
29. Mauri L, Hsieh WH, Massaro JM, Ho KK, D’Agostino R, Cutlip DE. Stent thrombosis in randomized clinical trials of drug-eluting stents. N Engl J Med. 2007;356(10):1020-1029. 
30. Fath-Ordoubadi F, Barac Y, Abergel E, et al. Gender impact on prognosis of acute coronary syndrome patients treated with drug-eluting stents. Am J Cardiol. 2012;110(5):636-642.
31. Freixa X, Carpen M, Kotowycz MA, et al. Long-term outcomes after percutaneous intervention of the internal thoracic artery anastomosis: the use of drug-eluting stents is associated with a higher need of repeat revascularization. Can J Cardiol. 2012;28(4):458-463.
32. Lemos PA, Moulin B, Perin MA, et al. Late clinical outcomes after implantation of drug-eluting stents coated with biodegradable polymers: 3-year follow-up of the PAINT randomised trial. EuroIntervention. 2012;8(1):117-119.
33. Cutlip DE, Windecker S, Mehran R, et al; Academic Research Consortium. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation. 2007;115(17):2344-2351.
34. Inoue K. Pathological perspective of drug-eluting stent thrombosis. Thrombosis. 2012;2012:219389 (Epub 2012 May 14).
35. Daemen J, Wenaweser P, Tsuchida K, et al. Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study. Lancet. 2007;369(9562):667-678. 
36. Kaul S, Shah PK, Diamond GA. As time goes by: current status and future directions in the controversy over stenting. J Am Coll Cardiol. 2007;50(2):128-137. 
37. Badimon L. Study of polymer-5 (p5) and pattern polymer (Cordis control): analysis of haemocompatibility [in vitro/static conditions]. Research project on coated stents for local treatment treatment of restenosis. Internal project, 2005.
38. Billinger M, Räber L, Hitz S, et al. Long-term clinical and angiographic outcomes of diabetic patients after revascularization with early generation drug-eluting stents. Am Heart J. 2012;163(5):876-886.