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Original article
Prospective randomised trial evaluating a paclitaxel-coated balloon in patients treated with endothelial progenitor cell capturing stents for de novo coronary artery disease
  1. Jochen Wöhrle1,
  2. Ralf Birkemeyer2,
  3. Sinisa Markovic1,
  4. The-Vinh Nguyen1,
  5. Anil Sinha3,
  6. Tomislav Miljak2,
  7. Jochen Spiess1,
  8. Wolfgang Rottbauer1,
  9. Harald Rittger3
  1. 1Clinic of Internal Medicine II, University of Ulm, Ulm, Germany
  2. 2Innere Medizin III Kardiologie, Schwarzwald-Baar Klinikum, Villingen-Schwenningen, Germany
  3. 3Medizinische Klinik II, Klinikum Coburg, Coburg, Germany
  1. Correspondence to Dr Jochen Wöhrle, Department of Internal Medicine II, University of Ulm, Albert-Einstein-Allee 23, 89081 Ulm, Germany; jochen.woehrle{at}uniklinik-ulm.de

Abstract

Background Percutaneous coronary intervention with stent implantation is limited by the occurrence of re-stenosis and the risk of stent thromboses.

Objective To define the impact of paclitaxel-coated balloon angioplasty plus endothelial progenitor cell capturing (EPC) stent implantation in de novo coronary artery disease. This combination may reduce neointimal proliferation within the EPC stent and address the risk of stent thrombosis by facilitating rapid endothelialisation.

Methods In this prospective single-blind multicentre randomised trial, 120 patients with a de novo lesion in a native coronary artery were randomly assigned to undergo treatment with paclitaxel-coated balloon plus EPC stent or EPC stent alone. Dual antiplatelet therapy was prescribed for 3 months. Angiographic follow-up was scheduled at 6 months. The primary endpoint was in-stent late lumen loss. The secondary clinical endpoint was a composite of death from a cardiac cause, myocardial infarction attributed to the target vessel or target lesion revascularisation.

Results There was no difference in patient baseline characteristics or procedural results. The angiographic follow-up rate was 96%. Treatment with paclitaxel-coated balloon plus EPC stent was superior to EPC stent alone, with an in-stent late loss of 0.34±0.45 mm versus 0.88±0.48 mm (p<0.001). The re-stenosis rate was reduced from 23.2% to 5.1% (p=0.006) and the clinical endpoint was reduced from 17.2% to 4.8% (p=0.039). There was no definite or probable stent thrombosis.

Conclusions Paclitaxel-coated balloon plus EPC stent implantation is superior to EPC stent implantation alone for treatment of de novo coronary artery disease.

Trial registration NCT00732953.

  • Stents
  • restenosis
  • endothelialization
  • paclitaxel
  • coronary intervention
  • coronary stenting
  • coronary artery disease (cad)
  • clinical trials
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Drug-eluting stents have been shown to reduce the occurrence of re-stenosis and the subsequent need for repeat revascularisation. Long-term follow-up has uncovered a continuous risk for late stent thrombosis1 which has been attributed to incomplete endothelialisation of stent struts and an inflammatory response to the polymeric coating.2 Maximal concentration of the antiproliferative drug is around the stent struts.3 4 On the other hand, rapid endothelialisation of these struts is required to address the risk of stent thrombosis.

Endothelial progenitor cell capturing (EPC) stents with human anti-CD34 antibodies on the surface facilitate rapid endothelialisation of the stent struts and are associated with low rates of stent thrombosis,5 6 even in complex lesions.7 However, the antiproliferative impact of the EPC stent is inferior to drug-eluting stents.7 With use of a paclitaxel-coated balloon catheter, the administration of the antiproliferative drug is homogenous to the vessel wall. Hence, the combination of a paclitaxel-coated balloon plus an EPC stent might properly address both issues—a reduction of neointimal proliferation due to a homogenous administration of paclitaxel to the vessel wall and a reduction in the risk of stent thrombosis by facilitating rapid endothelialisation.

The aim of this prospective multicentre single-blind randomised trial, the PERfECT Stent study, was to compare paclitaxel-coated balloon angioplasty plus EPC stent implantation with an EPC stent alone for treatment of de novo coronary artery disease.

Methods

Patient population

From February 2009 to February 2010 we recruited 120 patients in three centres in the PERfECT Stent (A Prospective, Randomised Trial Evaluating a Paclitaxel-Coated Balloon in Patients Treated with EPC Stents for De Novo Coronary Artery Disease) study. Patients were eligible if they had a de novo lesion with diameter stenosis of more than 50% in a native coronary artery with a reference diameter of 2.5–4.0 mm and a maximal lesion length of 25 mm. Patients were stratified according to the presence of diabetes mellitus. Exclusion criteria were lesions in bypass grafts, left main or bifurcations, chronic total occlusions, re-stenosis and in stent re-stenosis, acute myocardial infarction, planned surgery within 6 months after the index procedure, childbearing potential, contraindication or known hypersensitivity to acetylsalicylic acid, clopidogrel, paclitaxel or heparin. The study complied with the provisions of the Declaration of Helsinki. The study protocol was approved by the ethics committee. All patients gave written informed consent.

Study design and procedures

Patients were randomly assigned to undergo treatment with paclitaxel-coated balloon catheter (SeQuent Please; B Braun, Melsungen, Germany) after EPC stent implantation (OrbusNeich Medical GmbH, Wiesbaden, Germany) or EPC stent implantation alone. In all patients predilation with an uncoated balloon was mandatory. The EPC stent was available in diameters of 2.5, 2.75, 3.0, 3.5 and 4.0 mm and in lengths of 9, 13, 15, 18, 23, 28 and 33 mm. The paclitaxel-coated balloon catheter was loaded with 3 μg paclitaxel per mm2 and was available in diameters of 2.5, 2.75, 3.0 and 3.5 mm and in lengths of 10, 15, 17, 20, 26 and 30 mm. The length of the paclitaxel-coated balloon catheter was chosen to overlap the EPC stent for at least 1 mm at the proximal and distal margin. Paclitaxel-coated balloons were inflated for 60 s at 10 bar. Patients received unfractionated heparin with an initial bolus of 70 U/kg, with subsequent boluses targeted to an activated clotting time of >250 s. Dual antiplatelet therapy with acetylsalicylic acid 100 mg per day and clopidogrel 75 mg per day was prescribed for 3 months in both groups.

Follow-up

Patients were followed by telephone or hospital visit at 2 months. Angiographic follow-up was scheduled at 6 months. Repeat revascularisation was indicated by a positive stress test or symptoms.

Quantitative coronary angiography

Coronary angiography of the target lesion before and after angioplasty and at follow-up was performed in the same projections after intracoronary application of glycerol trinitrate. Angiographic measurements were done with the CAAS 5.7 software (Pie Medical Imaging, Maastricht, The Netherlands).8–11 Quantitative coronary measurements in the same two orthogonal views were performed. Angiographic measurements were performed separately within the stent, within 5 mm proximal to the stent, within 5 mm distal to the stent and over the total segment. The following quantitative coronary angiography parameters were calculated: minimal lumen diameter, reference vessel diameter, percentage diameter stenosis, acute gain (difference between the post-procedure and pre-procedure minimal lumen diameter) and late loss (difference between the post-procedure and follow-up minimal lumen diameter). Binary re-stenosis was defined as diameter stenosis of >50% at follow-up angiography. The pattern of re-stenosis was classified according to Mehran et al.12

Statistical analysis and primary and secondary endpoints

This prospective single-blind multicentre randomised trial was powered for superiority testing of the primary endpoint, in-stent late loss at 6 months, on an intention-to-treat basis with a power of 80% and an α error of 0.05. In-stent late loss was assumed to be reduced by absolute 0.30 mm, from 0.75 mm with use of the EPC stent alone to 0.45 mm with paclitaxel-coated balloon angioplasty plus EPC stent. Sample size was calculated to be 60 patients per group with one lesion treated per patient and an angiographic follow-up rate of 80%. Patients were stratified according to the presence of diabetes mellitus. The random allocation sequence was blocked for every four patients in each of the three centres.

Secondary angiographic endpoints were binary re-stenosis, minimal lumen diameter and diameter stenosis in the stented segment and in the total segment. Secondary clinical endpoints were target lesion revascularisation, myocardial infarction, death and stent thrombosis. Major adverse cardiac events were defined as a composite of cardiac death, myocardial infarction (not clearly attributable to a non-target vessel) and target lesion revascularisation. Death was considered cardiac unless an undisputed non-cardiac cause was present. Myocardial infarction and stent thrombosis were defined according to the ARC criteria.13

Categorical variables are reported as counts and percentages, and between-group differences were assessed with the χ2 test or Fisher exact test. Continuous variables are presented as means±SD and were tested for normal distribution by the Shapiro–Wilks test, and between-group differences were assessed with the two-sample t test or Mann–Whitney U test. A two-sided p value of <0.05 was considered to indicate statistical significance. Statistics were calculated with Statistica release 7.1 (StatSoft Inc, Tulsa, Oklahoma, USA).

Results

Patients

Sixty-two patients were randomised to treatment with paclitaxel-coated balloon plus EPC stent and 58 patients to EPC stent implantation alone. Baseline clinical and angiographic characteristics were similar in the two groups (tables 1 and 2). The size and length of EPC stents were not different between groups. In patients randomised to treatment with paclitaxel-coated balloon plus EPC stent, the length of the paclitaxel-coated balloon was 20.2±7.6 mm, on average 3.9±2.7 mm longer than the length of implanted EPC stents (16.4±6.5 mm). All paclitaxel-coated balloon catheters were successfully applied and in all cases the length of the segment treated with paclitaxel-coated balloon catheters exceeded the proximal and distal ends of the EPC stent.

Table 1

Characteristics of patients at baseline

Table 2

Characteristics of revascularization procedures

Quantitative coronary angiography

Prior to percutaneous coronary intervention (PCI), lesion length, reference diameter, percentage diameter stenosis and minimal lumen diameter did not differ between groups (table 2). There was no difference in acute gain with 1.79±0.35 mm in patients treated with paclitaxel-coated balloon plus EPC stent compared with 1.80±0.37 mm in patients with EPC stent alone (p=0.89). After PCI the minimal lumen diameter and diameter stenosis for the stented segment and the total segment were not different. Five clinically asymptomatic patients refused angiographic follow-up. The angiographic follow-up rate was 95.8% and was obtained a median of 182 days after PCI.

In-stent late loss, the primary endpoint, was significantly lower in lesions treated with paclitaxel-coated balloon plus EPC stent compared with EPC stent alone (0.34±0.45 mm vs 0.88±0.48 mm, difference −0.54 mm, 95% CI −0.71 to −0.37, p<0.001; figure 1). Late loss for the total segment and the proximal segment were also significantly lower in patients treated with the paclitaxel-coated balloon catheter (table 3). Furthermore, in lesions treated with paclitaxel-coated balloon and EPC stent compared with EPC stent alone, minimal lumen diameter at follow-up was significantly larger and percentage diameter stenosis and the binary angiographic re-stenosis rate were significantly lower both for the stented segment and the total segment (table 3). The pattern of re-stenosis according to Mehran for patients with EPC stent only was focal (N=4) or diffuse (N=9) with pattern II (diffuse intra-stent) in four patients and pattern III (diffuse proliferative) in five patients. The pattern of re-stenosis in patients with paclitaxel-coated balloon plus EPC stent was focal (N=1) or diffuse (N=2; pattern II and III). There was no total occlusion.

Figure 1

Cumulative frequency curves of the primary endpoint—in-stent late loss—for the paclitaxel-coated balloon angioplasty plus endothelial progenitor cell capturing (EPC) stent group (solid line) versus EPC stent alone group (dotted line).

Table 3

Angiographic outcomes at 6 months

Clinical follow-up

Clinical follow-up was obtained in all patients. There was a strong trend towards a lower rate of target lesion revascularisation with use of the paclitaxel-coated balloon compared with stent implantation alone (4.8% vs 15.5%, table 4). Repeat revascularisations were performed in all three cases of re-stenosis in the paclitaxel-coated balloon group compared with 69% (9/13) in the EPC stent alone group. There was no myocardial infarction attributable to the target vessel and there was no definite or probable stent thrombosis in either group. One unexplained death occurred in the EPC stent group 4 months after PCI. The combined clinical endpoint defined by target lesion revascularisation, myocardial infarction attributable to the target vessel and cardiac death was significantly lower in patients treated with the paclitaxel-coated balloon catheter and EPC stent than in patients treated with the EPC stent alone (table 4).

Table 4

Clinical outcomes at 6 months

Discussion

In this prospective randomised multicentre trial the treatment strategy with paclitaxel-coated balloon plus EPC stent was superior to EPC stent alone with regard to the primary endpoint of in-stent late loss for treatment of de novo lesions in native coronary arteries. There was no definite or probable stent thrombosis. The combined clinical endpoint was significantly lower in patients randomised to paclitaxel-coated balloon plus EPC stent than in those treated with EPC stent alone.

Our study concept is based on the EPC stent which has been associated with a rapid endothelialisation due to human anti-CD34 antibodies on the surface,14 15 and the paclitaxel-coated balloon with homogenous drug administration to the vessel wall. With the combined treatment strategy we were able to demonstrate a significantly lower late loss, a significantly lower re-stenosis rate and a significantly better clinical outcome compared with EPC stent implantation alone. There was no definite or probable stent thrombosis with a 3-month course of dual antiplatelet therapy. In HEALING FIM,5 HEALING II6 and in a more complex patient population,7 no stent thrombosis was observed with the EPC stent. In the animal model a complete endothelialisation of the EPC stent struts has been shown within a few hours.14 However, our study was too small to allow any conclusion regarding the risk of stent thrombosis. On the other hand, the use of a paclitaxel-coated balloon could inhibit endothelialisation, increasing the risk of late stent thrombosis.

The late loss observed in our EPC stent alone group was higher than our assumed late loss (0.88 m vs 0.75 mm), but still in the reported range. Angiographic follow-up studies on the EPC stent revealed a late loss of 0.63±0.52 mm in HEALING FIM,5 0.78±0.39 mm in HEALING II,6 0.88±0.62 mm in a more complex population16 and 1.14±0.64 mm in a randomised trial with 47% angiographic follow-up rate.7 In a randomised setting, the EPC stent was inferior than the paclitaxel eluting Taxus stent with regard to late loss and repeat revascularisation,7 indicating a limited antiproliferative impact of the EPC stent compared with a drug-eluting stent.

We were able to demonstrate that, with the additional use of a paclitaxel-coated balloon, the late lumen loss and the occurrence of re-stenosis can be reduced within the EPC stent. Furthermore, this concept allows the length of the paclitaxel-coated balloon to be longer than the stented segment. This may be favourable since, with drug-eluting stents, about one-third of re-stenosis occurs proximal or distal to the stent margin.17 18 With the paclitaxel-coated balloon plus EPC stent, late loss in the proximal and distal segment to the stent was reduced by about 80%, supporting the concept of drug administration proximal and distal to the stent edges. The use of a paclitaxel-coated balloon after EPC stent implantation facilitated the selection of the diameter and length of the paclitaxel-coated balloon in order to completely cover the stented segment, including the proximal and distal adjacent segments. With use of a paclitaxel-coated balloon prior to stent implantation, the combined treatment strategy may be even more effective since the stent struts could interfere with drug administration into the vessel wall. Of note, the efficacy of the paclitaxel-coated balloon used has been demonstrated in several studies19 20 while others failed.21

Two other trials have studied the use of a paclitaxel-coated balloon for treatment of de novo lesions. In PEPCAD I the paclitaxel-coated balloon was used for treatment of de novo lesions in small vessels.20 Thirty-two of 114 patients required additional bare metal stent (BMS) implantation due to dissection or recoil. Late loss in patients treated with the paclitaxel-coated balloon alone was 0.16±0.38 mm compared with 0.62±0.73 mm in patients with additional BMS implantation. Since the stented segments were not covered by the paclitaxel-coated balloon, the high late loss in these patients with additional stenting may be explained by the geographic miss.

In PEPCAD III, 637 patients with de novo lesions were randomised to treatment with paclitaxel-coated balloon plus BMS or to the sirolimus-eluting Cypher stent.22 In this study the Coroflex Blue stent was premounted on the paclitaxel-coated balloon. This may have influenced the paclitaxel dose in the vessel wall, drug distribution and the residency of the drug in the vessel wall. In the PERfECT Stent trial the EPC stent and the paclitaxel-coated balloon catheter were two separate devices. In-stent late loss in PEPCAD III was 0.41±0.51 mm in the paclitaxel-coated balloon plus BMS group compared with 0.34±0.45 mm in our group with paclitaxel-coated balloon plus EPC stent. Direct stenting was performed in about half of the patients in PEPCAD III whereas predilation was mandatory in the PERfECT Stent trial. In PEPCAD III there was a 2.0% rate of definite or probable stent thrombosis with the paclitaxel-coated balloon plus BMS stent compared with 0.3% in the Cypher group and 0% in the two treatment groups in our study. Dual antiplatelet therapy was given for 6 months in PEPCAD III and for 3 months in the PERfECT Stent study. This important difference is probably due to the factors discussed above. Furthermore, the EPC stent—which captures endothelial progenitor cells from the blood resulting in a rapid endothelialisation of stent struts—may have led to a decreased risk of stent thrombosis.

Limitations of the study

The number of patients is limited since the study was powered for an angiographic endpoint. The results have been obtained in simple lesions and cannot be translated to lesions with a complex morphology. While the concept of rapid endothelialisation with use of an EPC stent is interesting, we are not able to prove this concept without using optical coherence tomography or intravascular ultrasound. There was no independent core laboratory. The study design was single-blind and not double-blind, with use of an uncoated balloon in the EPC stent group.

Conclusion

We conclude that paclitaxel-coated balloon plus EPC stent implantation is superior to EPC stent implantation alone for treatment of de novo coronary artery disease.

References

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Footnotes

  • JW, RB and HR contributed equally.

  • Funding Supported in part by an unrestricted grant from OrbusNeich Medical GmbH, Wiesbaden, Germany and B Braun, Melsungen, Germany.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the ethics committee, University of Ulm, Germany.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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