Paclitaxel-coated balloon versus drug-eluting stent during PCI of small coronary vessels, a prospective randomised clinical trial. The PICCOLETO Study

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1 Paclitaxel-coated balloon versus drug-eluting stent during PCI of small coronary vessels, a rosective randomised clinical trial. The PICCOLETO Study Bernardo Cortese, 1 Andrea Micheli, 1 Andrea Picchi, 1 Amelia Coolaro, 1 Loria Bandinelli, 1 Silva Severi, 2 Ugo Limbruno 1 See Editorial, Interventional Cardiology Unit, Cardiovascular Deartment, Osedale della Misericordia, Grosseto, Italy 2 Cardiology Unit, Cardiovascular Deartment, Osedale della Misericordia, Grosseto, Italy Corresondence to Bernardo Cortese, Interventional Cardiology, Fondazione IRCCS Ca Granda Osedale Maggiore Policlinico, Via Sforza, Milano, Italy; bcortese@gmail.com Acceted 4 May 2010 ABSTRACT Background Percutaneous coronary intervention (PCI) of small vessels is limited by an increased risk of restenosis and adverse outcome, even when drug-eluting stents (DES) are emloyed. In recent years, the aclitaxelcoated balloon () has been shown to reduce neointimal roliferation and the need for target lesion revascularization (TLR) in an in-stent restenosis setting. The imact of a during PCI of small coronary vessels was evaluated and comared to one of the most widely used DES. Methods In the PICCOLETO randomised clinical trial, atients with stable or unstable angina undergoing PCI of small coronary vessels (#2.75 mm) were randomised to Dior (28 atients) or Taxus DES (29 atients). The rimary study end oint was er cent diameter stenosis at 6-month angiograhic follow-u (non-inferiority), secondary end oints were angiograhic binary restenosis and occurrence of major adverse cardiac events (MACE: death, Q-wave myocardial infarction, TLR) at 9 month follow-u. Results The two grous were not dissimilar regarding clinical and angiograhic characteristics. Study was interruted after enrolment of two-thirds of atients due to a clear sueriority of one study grou. The rimary end oint was not met, because the grou showed higher er cent diameter stenosis (43.6% vs 24.3%, ¼0.029); angiograhic restenosis was higher as well (32.1 vs 10.3%, ¼0.043), whereas MACE were 35.7% in the grou and 13.8% in the DES grou (¼0.054). Conclusions Dior failed to show equivalence to Taxus DES regarding angiograhic end oints during PCI of small coronary arteries. Clinical Trial Registration Number (EudraCT code): Percutaneous coronary intervention (PCI) of small calibre coronary vessels is a true challenge for modern interventional cardiology, due to the increased risk of restenosis and adverse outcome. 1 However, drug-eluting stent (DES) use, thanks to local delivery of theraeutic agents to reduce neointimal hyerlasia, has changed this scenario. 2 Nevertheless, the increased risk of stent thrombosis 3 4 or death 5 at any time after stent imlantation remains a matter of concern in all vessel calibres, even if secific scientific data are lacking. Comared to a standard, uncoated balloon, a aclitaxel-coated balloon () has been shown to reduce neointimal roliferation and the need for target lesion revascularisation (TLR) in an in-stent restenosis setting, 6 and recently DES. 7 Investigators of these two trials concluded that this new method of local drug delivery would not require stent imlantation to fight restenosis. The urose of this study was to evaluate the imact of a during PCI of small native coronary vessels comared to standard treatment with DES. METHODS The PICCOLETO study was a rosective, single centre, randomised trial comaring the efficacy of the Dior (Eurocor, Bonn, Germany) with Taxus Libertè DES (Boston Scientific Cororation, Natick, MA, USA) in small coronary arteries (diameter #2.75 mm). The study was entirely conducted at the interventional cardiology unit of Osedale della Misericordia in Grosseto, Italy. Between August 2007 and August 2008, after obtaining informed written consent, all consecutive atients of at least 18 years of age with stable or unstable angina and a clinical indication for PCI of at least one small coronary artery were randomised to treatment with or. Patients were excluded from the study if they met at least one of the following criteria: acute myocardial infarction within the revious 48 h, unstable haemodynamics, chronic renal insufficiency with a serum creatinine level of more than 2.0 mg/dl, known hyersensitivity or contraindication to asirin, hearin, cloidogrel or aclitaxel, sensitivity to contrast media that could not be controlled with remedication and life exectancy of less than 2 years. Randomisation was erformed in a 1:1 ratio by comuterised, oen-label assignment in consecutive blinded enveloes. A randomly ermuted blocks method was used to generate the randomisation lan. Although oerators were not blinded to the device used, the clinical end oints were adjudicated by two investigators blinded with regard to atients treatment allocation. A local ethics committee aroved the study. This clinical trial obtained an EudraCT code ( ). The Dior is a coronary dilatation catheter with a nanoorous balloon surface coated with aclitaxel microcrystals. Paclitaxel coating concentration is 3 mg/mm 2 of balloon surface area, homogeneously distributed. During inflation, the drug is released onto the vessel wall. Patients randomised to the control grou were treated with the Taxus Libertè DES described elsewhere. 8 were available in diameters of 2.25, 2.5 and 2.75 mm, and in lengths of 15e25 mm. Taxus Heart 2010;96:1291e1296. doi: /hrt

2 stents were available in diameters of 2.5 and 2.75 mm, and in lengths of 8e32 mm. Percutaneous coronary intervention was erformed according to current international guidelines. Prior to guidewire insertion all atients were administered unfractionated hearin (single bolus of 100 IU/kg, then adjunctive boluses following activated clotting time) or bivalirudin (bolus of 0.75 mg/kg followed by an infusion of 1.75 mg/kg/h for the duration of rocedure). A bailout glycorotein IIb/IIIa recetor inhibitor strategy was recommended in the two grous only in case of rocedural thrombotic comlications, big coronary clots and comlex or rolonged intervention. All atients undergoing PCI received asirin (either 100 mg/ day for at least 3 days rior to PCI or a re-pci 300 mg intravenous bolus), and cloidogrel (300 or 600 mg as a loading dose, followed by 75 mg daily). Patients were considered to be adequately loaded with cloidogrel if they were on chronic theray or had been treated with a loading dose of 600 mg >2h or 300 mg >6 h before PCI Predilatation was recommended in atients undergoing Taxus imlantation. In the grou, a gentle balloon deloyment was attemted, otherwise in case of resistance a redilatation with uncoated balloon was also recommended. In all cases of difficult ositioning, investigators were asked to change the device in order to maintain an adequate aclitaxel coating. Paclitaxel-eluting stent (ES) inflation time was 20e30 s, afterward all stents were ostdilated with a non-comliant, standard balloon; inflation time was 45 s reeated twice, and recommended dilatation ressures were between 8 and 16 atmosheres. In case of unsatisfactory angiograhic result after inflation (ersistent dissection other than A tye following National Heart, Lung and Blood Institute (NHLBI) classification 11 and/or final thrombolysis in myocardial infarction (TIMI) flow <3), atients underwent er rotocol bare metal stent (BMS) (ML Vision; Abbott Vascular, Abbott Park, Illinois, USA). Angiograhic success was defined, based on a visual estimation, as a final angiograhic residual stenosis of <30% with TIMI 3 flow and the absence of evident coronary dissection. Procedural success was determined based on a satisfactory angiograhic outcome and absence of any major in-hosital comlication (acute myocardial infarction, need for target vessel revascularisation or death). All atients continued asirin indefinitely and cloidogrel 75 mg daily for 1 month in cases of stable angina and lone use, 3 months in cases of and rovisional stent imlantation and 12 months in cases of unstable angina or Taxus imlantation. Clinical follow-u visits were scheduled 30 days, 6 months and 9 months after index rocedure in all study atients. All atients were also scheduled to undergo angiograhic follow-u between 6 and 8 months after index rocedure. An interim analysis was lanned after enrolment of 65% of atients. In the case of lack of equivalence between the two study grous regarding rimary end oint, it was lanned to sto enrolment. Angiograhy was erformed before and after all interventions and at 6 months follow-u. All measurements were erformed on cineangiograms recorded after 200 mg of intracoronary nitroglycerin administration. Identical rojections were used for each comarison. Quantitative analysis of the coronary angiograhic images was erformed by one of the study investigators. The CAAS II research system (Pie Medical Imaging) was used for automated contour detection and quantification. The arameters that were measured included: lesion length, reference vessel diameter, minimal lumen diameter and er cent diameter stenosis (difference between reference diameter and minimal lumen diameter divided by reference diameter and multilied by 100). Measurements included the inner stenotic area, the stented area with measurement shoulder to shoulder (in-stent) and the total stented area lus 5 mm of the roximal and distal area (in-segment); in the case of use without stenting, the area corresonding to the balloon length lus 5 mm roximally and distally was measured. Angiograhic restenosis was defined as stenosis of at least 50% of the luminal diameter. Study end oints were analysed by intention-to-treat. The resecified rimary end oint of the study was the er cent diameter stenosis of the culrit lesion at 6 months angiograhic follow-u obtained with QCA, where non-inferiority between the two study grous was hyothesised. Secondary end oints of the study were: eangiograhic binary restenosis at QCA (non-inferiority); eoccurrence of major adverse cardiac events (MACE: death, new ST elevation myocardial infarction 12 and TLR) at 9 months clinical follow-u (non-inferiority). It was decided not to use late lumen loss analysis, a common end oint in clinical studies with stents and angiograhic follow-u, 13 because in the authors oinion the ossible acute recoil in the grou would have underestimated the results in this grou. The samle size of the trial was calculated on the basis of the findings of a revious randomised trial 14 :a30618% diameter stenosis with the PES was exected at 6 months angiograhic follow-u. A similar result for the grou, with a +12% threshold, was hyothesised. To achieve this objective, with a ower of 80% and a two-sided a-level of 0.05, the target oulation for each study grou was 40 atients with follow-u angiograhy. The main analysis was erformed on an intention-to-treat basis. Data are resented as mean6sd or as roortions (%). The differences between grous were assessed by c 2 test or Fisher exact test for categorical data and t test for continuous data. The RR and its 95% CI were calculated for each study end oint. A two-sided value <0.05 was considered statistically significant. RESULTS Sixty atients were randomised in the PICCOLETO Study, 29 in the grou and 31 in the DES grou (figure 1). The lanned overall 80-atient oulation was not reached because investigators decided to sto the enrolment after scheduled interim analysis due to an evident sueority of one study grou. One atient in the grou, and two in the DES grou were lost at follow-u (¼0.63). Baseline clinical and angiograhic characteristics are shown in table 1. There were no significant differences between the two grous regarding main clinical and angiograhic data. Procedural characteristics are shown in table 2. There were no significant differences between study grous regarding multivessel PCI, target vessel and rocedural success. On the other hand, as exected, in the DES grou there were more stents imlanted (¼0.024), lesion redilatation was more common (¼0.001) and a bigger final lumen diameter was achieved (¼0.009). Comlete follow-u angiograhy at a median of 189 days (IQR: 172 to 201 days) was carried out in 57 atients (95% of enrolled atients). Angiograhic outcome is resented in table 3. The resecified rimary end oint of the study, er cent diameter stenosis at 6 months follow-u (non-inferiority 1292 Heart 2010;96:1291e1296. doi: /hrt

3 Table 2 Procedural characteristics Multivessel PCI 17 (60.7%) 19 (65.5%) 0.70 Target vessel, LAD 15 (53.6%) 15 (51.7%) 0.89 Target vessel, LCX 5 (17.9%) 3 (10.4%) 0.41 Target vessel, RCA 8 (28.5%) 11 (37.9%) 0.45 Need to change due to difficult 5 (17.9%) NA NA ositioning Stents imlanted er lesion Stent or balloon diameter6sd (mm) NA Stent or balloon length6sd (mm) NA Lesion redilatation (uncoated balloon) 7 (25.0%) 25 (86.2%) Maximal inflation ressure6sd (atmosheres) Final MLD6SD (mm) Final lesion stenosis6sd (% LD) Angiograhic success 96.4% 100% 0.30 Procedural success 96.4% 100% 0.30 LAD, left anterior descending artery; LCX, left circumflex artery; LD, lumen diameter; MLD, minimal lumen diameter;, aclitaxel-coated balloon; PCI, ercutaneous coronary intervention; RCA, right coronary artery. Figure 1 Flow chart of study oulation of the PICCOLETO trial., aclitaxel-coated balloon; PES, aclitaxel-eluting stent. hyothesised), was not met due to an evident sueriority of the Taxus grou ( % vs %, ¼0.029). The grou also showed a higher rate of angiograhic binary restenosis, an unmet secondary end oint of the study (10.3% vs 32.1%, ¼0.043). Figure 2 shows the cumulative frequency distribution of minimal lumen diameter (MLD) (re-pci, ost-pci and at control angiograhy). All 57 atients of the study underwent 9 months clinical follow-u (table 4). The number of atients who suffered a MACE was not statistically different across study grous, but a strong trend towards better clinical outcome was discovered in the Taxus grou (13.8% vs 35.7%, ¼0.054). This result was mainly driven by the increased rate of TLR in the grou (32.1% vs 10.3%, ¼0.15). Two deaths were registered in the study oulation (¼0.98): one atient in the grou died from intracranial haemorrhage and one in the PES grou due to liver malignancy. No Table 1 Baseline clinical and angiograhic characteristics Men 22 (78.6%) 22 (75.9%) 0.81 Age6SD (years) Hyertension 21 (75.0%) 20 (70.8%) 0.61 Diabetes mellitus 13 (37.9%) 11 (46.4%) 0.51 Dysliidemia 17 (60.7%) 13 (54.2%) 0.23 Previous revascularisation with CABG 3 (10.7%) 4 (13.8%) 0.72 Previous revascularisation with PCI 3 (10.7%) 4 (13.8%) 0.72 Previous myocardial infarction 5 (17.9%) 6 (20.7%) 0.78 Stable angina 13 (46.4%) 13 (44.8%) 0.90 Tye B2/C lesions* 17 (60.7%) 20 (69.0%) 0.51 Bifurcation lesion 6 (21.4%) 7 (24.1%) 0.81 Lesion length6sd (mm) Reference vessel diameter6sd (mm) MLD6SD (mm) Lesion stenosis6sd (% LD) *According to ACC/AHA classification, SG Ellis et al, Circulation 1990; 82(4): CABG, coronary artery byass intervention; LD, lumen diameter; MLD, minimal lumen diameter;, aclitaxel-coated balloon; PCI, ercutaneous coronary intervention. cardiac death was observed across study grous, nor any stent thrombosis/abrut vessel closure. Only one atient in the grou suffered an acute Q-wave myocardial infarction in a vessel not treated during index rocedure (¼0.30). Figure 3 shows KalaneMeier curves for MACE, showing early failure of the, mainly driven by increased TLR. DISCUSSION The PICCOLETO study failed to demonstrate any equivalence between Dior and for the treatment of small coronary artery disease in terms of angiograhic restenosis; if atients in the grou showed a higher er cent diameter stenosis, atients treated with the exerienced an incidence of er cent diameter stenosis lower than exected. Moreover, a strong trend towards better clinical outcome with the has been observed, mainly driven by a higher revascularisation rate in the oulation treated with. The resent findings do not suort the original hyothesis of using a for PCI of small coronary artery disease. A simlistic exlanation would resolve with the axiom that a stent is always better than a balloon. However, it is believed that before drawing such conclusions, some considerations should be made. First of all, PCI of small coronary arteries has always brought little satisfaction to interventional cardiologists. If there is a clear sueriority of stenting over balloon angiolasty for coronary vessels with diameter $3.0 mm, 15 this argumentation is controversial for smaller calibre arteries. 16 Drug-eluting stent use has changed this scenario, dramatically reducing in-stent restenosis rate and TLR in this setting However, the increased risk of stent thrombosis at any time after DES imlantation has cooled down the initial enthusiasm. Stent thrombosis risk seems indeendent from vessel calibre, but is Table 3 Six months angiograhic outcome Reference vessel diameter6sd (mm) MLD6SD (mm) Per cent diameter stenosis6sd Angiograhic binary restenosis 9 (32.1%) 3 (10.3%) MLD, minimal lumen diameter;, aclitaxel-coated balloon. Heart 2010;96:1291e1296. doi: /hrt

4 Table 4 Nine months clinical outcome Death 1 (3.6%) 1 (3.5%) 0.98 Cardiac death Myocardial infarction 1 (3.6%) Target lesion revascularisation 9 (32.1%) 3 (10.3%) 0.15 Target vessel revascularisation 9 (32.1%) 4 (13.8%) 0.10 Stent thrombosis*/abrut vessel closure MACE 10 (35.7%) 4 (13.8%) *Definite/robable stent thrombosis according to Academic Research Consortium classification, L Mauri et al, NEJM 2007;356:1020e9. MACE, major adverse cardiovascular events;, aclitaxel-coated balloon. Figure 2 Cumulative frequency distribution of minimal lumen diameter (MLD): re-ercutaneous coronary intervention (PCI), ost-pci and follow-u, in the two study grous. DES, drug-eluting stent; MLD, minimal lumen diameter;, aclitaxel-coated balloon; PES, aclitaxeleluting stent. increased in longer lesions and in atients with diabetes mellitus, tyical features associated with small vessel disease (in the resent oulation, more than 40% were diabetic) The risk of stent thrombosis continues for 5 years after DES imlantation, 21 whereas the ossibility of undergoing major surgery increases with ageing in Western oulations. Moreover, sustained drug release after DES imlantation and an imutable inflammatory effect of the olymer have been advocated as ossible causes of delayed re-endothelialisation over stent struts, that has been found to be a common feature of this comlication. 22 On the contrary, the drug-coated balloon, in addition to the absence of a ermanent metal rosthesis, allows a raid dilution of the drug after inflation, that is increased by aclitaxel high tissue enetration and ersistence, due to its liohilic roerties. 23 Drug distribution is also higher, because in the case of DES imlantation only about 15% of the stented vessel wall is covered by struts, whereas a drug-coated balloon allows drug distribution hyothetically all around the vessel wall. Second, the Dior balloon is the only device of this kind to be marketed in Euroe. In the recently ublished Pecad II study, the SeQuent Please (B Braun, Melsungen, DE, Germany) achieved better in-segment late lumen loss when comared to the in an in-stent restenosis oulation. 7 Moreover, the not yet ublished Pecad I SVD (small vessel disease) study 24 was a multicentre, rosective, one-arm registry that showed a very intriguing 0.32 mm late lumen loss and an 11.7% target lesion revascularisation rate at 6 month follow-u. The Dior utilises a eculiar coating technology, where adherence of aclitaxel is mediated by a roughened surface of the balloon, whereas in the SeQuent Please aclitaxel is stuck to a water-soluble matrix, that warrants comlete release of aclitaxel after first balloon exansion, with high bioavailability Figure 3 KalaneMeier curves for MACEs, showing early failure of, due to increased rates of TLR. MACE, major adverse coronary event;, aclitaxel-coated balloon; PES, aclitaxel-eluting stent; TLR, target lesion revascularisation Heart 2010;96:1291e1296. doi: /hrt

5 of the drug on the target site; the two technologies have already been comared in a orcine model, where the latter warranted significantly better inhibition of neointimal roliferation. 25 A recent study in which the Dior was tested in a orcine model, showed a 48 h tissue aclitaxel concentration of 0.3 mg/g, 26 a quantity of drug that has already been shown to be enough to achieve a comlete inhibition of smooth muscle cell roliferation. 27 If it is true that different technologies used for DES have already been shown to translate into different clinical outcomes, the same could be argued for. Another oint that deserves mention is the choice of the for the control grou. Direct comarisons between Taxus and Ciher (Cordis Cororation, Johnson & Johnson, New Brunswick, New Jersey, USA) stents has shown the sueriority of the latter in terms of late lumen loss, TLR and MACEs in atients treated for small vessel disease and in atients with diabetes Therefore, it is argued that the difference observed in the resent study between and Taxus stent could be even higher if a different DES was used. Finally, an interesting issue to address in future studies is routine imlantation of a BMS after use. In the resent study only 36% of atients in the grou received a stent. The analysis of this small subgrou showed a binary restenosis rate of 28.9% of atients, a finding similar to that of atients treated with the lone. On the contrary, in the abovementioned Pecad I SVD registry, 24 atients not undergoing stent imlantation after achieved an extraordinary low late lumen loss and TLR rate (0.16 mm and 4.9% resectively). However, due to the small oulation of the resent study subgrou, and the non-randomised nature of the Pecad I SVD study, no conclusion can be drawn about this secific issue, and further secific studies are needed. A number of limitations about this ilot study should be ointed out. First of all, the nature of the study itself is questionable: comaring a stent to a balloon in small vessels subordinates the second grou to acute vessel recoil, an imortant comonent of restenosis, indeendent from the effect of aclitaxel. The oulation enrolled was small and not sufficient to allow for drawing any clinical conclusions. Due to the different treatment allocations (randomisation to lone balloon or stent), the study could not be blinded to oerators; investigators that analysed the study endoints were blinded, but about two-thirds of atients in the grou did not receive a stent, a difference easily observed by investigators. The articular clinical setting of the study oulation (small vessel disease, high ercentage of atients with diabetes, the exclusion of atients with recent myocardial infarction) renders this study unique, and its results should not be extraolated to different clinical characteristics. In conclusion, the technology tested in this study during PCI of small vessel disease was inferior to the gold standard treatment with DES. However, the oortunity for treating coronary lesions without lacing a (drug-eluting) stent is too attractive to be left out of further exeriments. Cometing interests None. Ethics aroval This study was conducted with the aroval of the Ethics Committee, Osedale della Misericordia, Groseto, Italy, 5 July Provenance and eer review Not commissioned; externally eer reviewed. REFERENCES 1. Elezi S, Kastrati A, Neumann FJ, et al. Vessel size and long-term outcome after coronary stent lacement. Circulation 1998;98:1875e Pfisterer M, Brunner-La Rocca HP, Rickenbacher P, et al. 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