Original paper
Taxcor for the prevention of restenosis. Polish multicentre observational study to assess the efficacy and safety of the Genius TAXCOR I stent

Introduction

Percutaneous coronary intervention (PCI) is a routine method of treatment used to restore normal blood flow through the coronary arteries in patients with ischaemic heart disease. Main factors limiting the effectiveness of this method include restenosis and in-stent thrombosis. Introduction of the antiproliferative drug-eluting stents (drug-eluting stents, DES) reduced, but did not eliminate the restenosis phenomenon. The symptoms of recurrent stenosis or coronary artery occlusion typically occur 6-9 months after PCI. The frequency of restenosis is 20-50% and it depends on the number of clinical risk factors and specific characteristics of the atherosclerotic lesion [1]. Various substances were assessed clinically for their ability to reduce restenosis. Only in the case of DES has there been a reduction of the restenosis risk by over 75% in comparison to the uncoated, bare-metal stents [2]. Stents have been covered with immunosuppressive drugs (sirolimus and its analogues, tacrolimus), cell proliferation inhibitors (sirolimus, paclitaxel, actinomycin), anti-inflammatory drugs (dexamethasone), extracellular matrix modulators (batimastat) or endothelium regenerating drugs (17β-oestradiol). Described drugs are frequently combined with synthetic polymers acting as reservoirs releasing the drug over a period of several weeks or months. The problem of in-stent thrombosis in patients with implanted bare-metal stent (BMS) was initially reduced by the introduction of dual antiplatelet therapy. It returned in the form of a more frequent late in-stent thrombosis caused by more widespread use of DES. This phenomenon regards antiproliferative drug-eluting stents and is probably related to slower endothelialization and therefore to a longer period of contact between the circulating blood and the stent uncoated by endothelium. The first studies comparing the safety profile of BMS and DES demonstrated a higher risk of in-stent thrombosis in DES [3]. Since then the introduction of new technologies of DES production and new drugs used for stent coating have led to a better and better safety profile [4] and a significant reduction of the frequency of in-stent thrombosis. In view of many advantages of DES in comparison to other therapeutic options in ischaemic heart disease constant refinement of these stents seems an important issue. It leads to an increase of safety and efficacy of treatment and justifies efforts to find new technologies and to test their effectiveness in clinical studies. The use of DES has advantages over systemic drug administration. Local action of the drug released from a stent yields higher local concentration of the active compound and their precise release during a requested time. With this route of administration the systemic effect is minimal and usually free from toxicity. Drugs released from stents belong to the group of immunosuppressive and cytostatic substances characterized by specific pharmacokinesis and clinical action.

Aim

The aim of the study was to assess the safety and efficacy of the Genius TAXCOR I stent (Eurocor GmbH, Germany) eluting 1 µg/mm² of paclitaxel implanted during elective or emergency PCI.

The procedure of stent implantation had to conform with current clinical practice and standards of care of the participating centre.

Material and methods

Study plan

Taxcor PL registry was a multicentre, open-label phase IV clinical trial. The registry was conducted in 10 university centres in Poland.

Collected data included information on PCI procedures and laboratory results of the studied patients. According to the protocol all patients were obliged to report data regarding their health status during a telephone contact with the attending physician (after 1, 3 and 6 months of observation) and to return for examinations after 12 months of observation. The study included 102 patients. Two patients were excluded from the final analysis due to large proportion of missing data.

All data were collected with the use of electronic case report forms (e-CRF) accessed online (ww.taxcor.pl). Each investigator had a personal authentication login and password, the connection was secured with SSL protocol and the system met the standards required for EDC devices.

Studied population

The study included consecutive patients meeting clinical and angiographic criteria of the Genius TAXCOR I stent use and qualified for percutaneous coronary intervention. The main inclusion criterion was the presence of angina or other obvious signs of myocardial ischaemia and patient’s eligibility for PCI or coronary artery bypass grafting (CABG). Therefore the group included in the study consisted of patients qualified for PCI based on the clinical symptoms and/or results of the stress tests in whom coronary angiography confirmed the presence of significant coronary artery stenosis. Angiographic inclusion criteria were: de novo stenosis or restenosis of the coronary artery with lumen reduction over 70% (assessed according to the centre defined protocols – visually or with the use of quantitative coronary angiography (QCA)) and with angiographically confirmed diameter > 2.25 mm and < 4.0 mm (appropriate to the available stent sizes). The length of stenosis could not exceed 25 mm; it was important to cover the whole stenosis with a stent. In case of the need to place several stents (for example due to edge dissection, displacement of the stent during implantation or miscalculation of the stent length) they had to overlap. Only two stenoses could be treated during one PCI procedure, but they had to be located in two different coronary arteries (left anterior descending of the left coronary artery (LAD) or circumflex artery of the left coronary artery (Cx) or right coronary artery (RCA)).

Before initiation of any study procedures patients included in the study had to sign an informed consent form. The study received approval from the Bioethical Committee (Committee for Ethics and Supervision of Studies on Humans and Animals of the Central Clinical Hospital of the Ministry of Interior and Administration in Warsaw).

A full list of the inclusion and exclusion criteria is presented in Table 1.

Stent implantation procedure. Peri- and post-procedural treatment

The stent implantation procedure as well as peri- and post-procedural treatment conformed with the current guidelines and with the local practice of the centre. The study protocol did not interfere with the standards of care in patients with ischaemic heart disease.

Follow-up period and study end-points

Data were collected using an electronic CRF. According to the protocol a telephone contact with the patient was required after 1, 3 and 6 months of follow-up. There was also a control visit with the attending physician after 12 months of follow-up which included collection of data on the incidents considered as MACE, classification of the angina symptoms and ascertainment of compliance to prescribed pharmacotherapy.

Study end-points

The primary end-point of the study was a target vessel failure (TVF) defined as coronary death, myocardial infarction (ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI)) or target vessel revascularization (repeated PCI or surgery with bypasses of the stented vessel) during 12 months of follow-up. In case of inability in assignment of death or myocardial infarction to the treated vessel these incidents were considered as such.

Secondary end-points of the study included:

• MACE (major adverse cardiac event) incidents defined as death, myocardial infarction (STEMI, NSTEMI), target vessel revascularization during 30 days and 12 months of follow-up;

• 1-month and 12-month mortality;

• 1-month and 12-month coronary mortality, classified as such in dubious cases;

• 1-month and 12-month myocardial infarction defined as pathological ST-segment elevation with increase of CK-MB above the upper reference limit (STEMI) or lack of ST-segment elevation with increase of CK-MB above the upper reference limit (NSTEMI); at least 5-fold increase of CK-MB above the upper reference limit was necessary to diagnose myocardial infarction related to CABG, and at least 2-fold increase of CK-MB above the upper reference limit was necessary to diagnose a peri-procedural myocardial infarction (related to PCI);

• target lesion revascularization (TLR) defined as any revascularization of the stented vessel segment ± 5 mm proximally or distally to the stented segment during 1-month and 12-months follow-up;

• target vessel revascularization (TVR) defined as any revascularization of the treated vessel during 1-month and 12-months follow-up;

• in-stent thrombosis during 1-month (early) and 12-month (late) follow-up defined as an acute coronary syndrome with angiographically documented vessel occlusion caused by thrombus located in the proximity of the previously implanted stent or any myocardial infarction or coronary death related to the treated vessel in case of lack of angiographic confirmation;

• success of the studied device defined as achievement of final stenosis diameter < 30% assessed by a physician performing PCI;

• successful procedure defined as achievement of final stenosis diameter < 30% without MACE related to the treated lesion during hospitalization.

Statistical analysis

Because of the observational character of the study, no formal study sample calculation was performed. Descriptive statistics were presented for all analysed variables including division into pre-defined subgroups. In the case of non-parametric variables data were presented as numbers and percentages. Continuous variables were presented as mean, standard deviation, median, minimum, maximum and the number of observations.

Results

The total number of patients analysed in the Taxcor PL registry was 100 recruited in 10 centres in Poland. Baseline demographic and clinical data of the studied patients are presented in Table 2.

Percutaneous coronary interventions – detailed data

Analysis of the studied group demonstrated that in 90% of cases PCI involved one coronary artery with one critical stenosis. Localization of the treated lesions is presented in the Table 3.

Data obtained during the study include 100 PCI procedures involving 110 atherosclerotic lesions. The mean time of the PCI procedure was 43 min (SD 24). The mean diameter of the implanted stent was 3.17 mm (SD 0.36) and its mean diameter was 20.5 mm (SD 5.82). Characteristics of the treated lesions by visual assessment of the operator are presented in Table 4.

Ten patients received a 600 mg loading dose of clopidogrel before the procedure, 6 patients received a 300 mg loading dose and 56 patients were on chronic clopidogrel treatment before the procedure and did not require a loading dose. Mean dose of unfractionated heparin used during percutaneous coronary intervention was 7600 IU (SD 1900 IU).

In-hospital follow-up (during index hospitalization)

The mean time of hospitalization of patients included in the study was 2.5 days (SD 3.4). Two PCI procedures during index hospitalization were complicated by a branch occlusion with a consequent myocardial infarction. Three patients suffered from a haematoma of the puncture site which did not require surgery or blood transfusion. There were 3 cases of distal dissection (type B, C and D) reported during PCI procedures. No other adverse events were reported (Table 5).

Long-term follow-up of patients

During 1-month follow-up one patient underwent repeated PCI procedure of the previously untreated vessel (next step of coronary revascularization).

During 3 months follow-up (1st-3rd month) one patient discontinued clopidogrel treatment due to gastro-intestinal tract bleeding. He was admitted to the general surgery ward, diagnosed with an abdominal tumour and qualified for the surgical procedure – hemicolectomy. One patient underwent repeated PCI of the previously untreated vessel.

During 6 months follow-up (3rd-6th month) 1 patient died – he was hospitalized and underwent surgery (hemicolectomy) on the surgical ward due to diagnosed gastro-intestinal tumour (a malignant process was found in histopathological examination) and died from multiorgan failure after 2 months of hospitalization. Five patients underwent repeated PCI of the previously untreated vessels.

During 12 months follow-up (6th-12th month) 2 patients underwent repeated PCI including one PCI of the previously treated vessel (TVR). Sixteen patients discontinued thienopyridine treatment 12 months after the procedure as recommended.

Data of patients included in the TAXCOR PL study in various periods of follow-up are presented in Figure 1. Summary of adverse events during 1-year follow-up is presented in Table 6.

Analysis of study end-points

The primary end-point of the study defined by the study protocol was a TVF. According to the definition this complication occurred in 3 patients (coronary death – 0, myocardial infarction [STEMI, NSTEMI] – 2, target vessel revascularization [repeated PCI or surgery with bypasses of the previously treated vessel] during 12 months follow-up – 1).

The frequency of secondary end-points is presented in Table 7.

Discussion

Results of the study procedure, in-hospital follow-up and long-term follow-up of patients who underwent implantation of the Genius Taxcor I stent show high safety and efficacy of this method of treatment in patients with ischaemic heart disease as demonstrated during 6-month follow-up.

The presented results undoubtedly show that the use of the Genius Taxcor I stent was safe in a large proportion of patients and led to perfect long-term results of clinical follow-up. Achievement of 98% success of the studied device and 96% of the successful procedures is comparable with the results of other registries on drug-eluting stents.

Similarly, the frequency of MACE in 1-year follow-up is comparable with that reported in other registries on the efficacy and safety of DES [5], such as the one presented in the study on 2633 patients with implanted DES published in the CCI journal by Ran Kornowski’s group, who reported a 3% frequency of death and over 4% frequency of TVR during 1-year follow-up. Frequency of the same adverse events in the Taxcor PL registry did not exceed 2% [6]. Analysis of the frequency of in-stent thrombosis reported in the published studies ranging between one and several percent in 1-year follow-up [7] shows that the studied stent is characterized by a comparable safety profile regarding this complication.

Currently reported data on efficacy and safety of the ‘limus’ coated stents (such as everolimus) and publications comparing the efficacy of paclitaxel with this new group of drugs show the advantage of the ‘limus’ group concerning mainly the reduction of major adverse events or target vessel failure requiring repeated interventions [8]. Analysis of the obtained results demonstrates that the frequency of end-points in which ‘limus’ stents show an advantage over paclitaxel coated stents presented in the Taxcor PL registry is similar to the one reported for the everolimus coated stents.

There are some limitations of the Taxcor PL study including the lack of angiographic assessment of the results by an independent core laboratory, the observational character of the study and the lack of angiographic control or full monitoring of the reported data.

Conclusions

The results of the Taxcor PL registry demonstrate that the Genius Taxcor I stent is safe in use and leads to satisfactory results in the short-term and long-term follow-up, which is comparable to other commercially available coronary stenting systems.

References

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