2.1

Objectives

The aim of this observational, prospective study was to assess the potential role of PEB in the treatment of patients with DM with coronary lesions compared to a similar patient subset treated either with bare-metal stents (BMS) or DES who had been included in previous studies conducted at our institutions.

2.2

Study design

The Diabetic Argentina Registry (DEAR) was an observational, prospective, non-randomised, open-label study and enrolled patients with DM. Results were compared retrospectively with previous outcomes in patients with DM treated with DES or BMS in clinical studies conducted at our institutions, i.e. patients were treated in the same centres and by the same investigators.

2.3

Patient population

Between April 2009 and March 2011, a total of 1528 patients were screened in the catheterization laboratories from the Cardiovascular Research Centre (CECI) in three hospitals in Buenos Aires, Argentina ( Fig. 1 ).

DEAR Registry flow chart.

Out of 275 patients who had a diagnosis of DM; 92 consented for the study, were included in the study and were treated with the PEB (DIOR, Eurocor GmbH, Germany). Patients were included if they had DM type I or II; clinical indication for myocardial revascularization; age > 18 years; and lesions suitable for PCI with stent implantation in a native vessel. Major exclusion criteria were unprotected left main target vessel; acute MI during the last 48 h; contraindication for dual antiplatelet therapy; target vessel treated with DES during the same session; previous PCI with DES implantation in the target vessel during the last 6 months; malignancies; life expectancy < 1 year; inability to provide informed consent; and pregnancy.

Patient’s outcomes were compared with outcomes of patients with DM who had been included in clinical trials conducted by CECI on BMS and DES. For all of these patients, baseline characteristics and follow-up were available that allowed a retrospective head-to-head comparison with the current PEB registry. Therefore, we identified patients with DM included in ERACI III (Estudio Randomizado Argentino Angioplastia versus Cirugia Coronaria), ORAR II and ORAR III (Oral Rapamycin in Argentina), EUCATAX (paclitaxel-eluting stent with biodegradable polymer versus BMS) and Camouflage (dedicated BMS for acute coronary lesions) studies which have been previously published . We identified 225 patients with DM from 1122 patients included in these studies, 96 treated with BMS and 129 with DES. These patients were compared with 91 patients with DM who had been included and treated in the PEB registry. One patient initially selected for PEB treatment was excluded for analysis due to failure of crossing the lesion with any device ( Fig. 1 ). The final group analysis of the DEAR registry included 316 patients: 91 in the PEB group (with 87 sequential BMS implantation), 96 in the BMS only group, and 129 in DES group ( Fig. 2 and Table 1 ).

Patient population, Diabetic Argentina Registry.

2.4

Endpoints

Primary endpoints were the incidence of major adverse cardiac events (MACE) and target-vessel failure (TVF) after one and three years of follow-up in the PEB group and subsequently to compare retrospectively with the results observed in diabetics patients treated with DES and BMS in trials conducted at our institution. MACE was defined as death, MI, stroke and TVR. TVF was defined as cardiac death, MI or TVR. Comparisons were made between PEB versus BMS and PEB versus DES.

Secondary endpoints were the composite of death/MI and the incidence of stent thrombosis in the three groups. Stent thrombosis was defined according to previous definitions and in agreement with the Academic Research Consortium definition of definitive / probable.

2.5

Medication and coronary procedures

In the PEB group, an initial inflation with plain old balloon angioplasty (POBA) was attempted in all patients using a balloon/vessel ratio < 1. Thereafter, a PEB (DIOR, Eurocor GmbH, Germany) was inflated with about 10 atm. The second generation DIOR balloon was used in the study and this coronary dilation balloon with a 3 μg of paclitaxel/mm ² balloon surface paclitaxel-coating with new coating technique , where the immunosuppressive drug is dissolved in shellac, which is composed of a network of hydroxyl fatty acid esters and sesquiterpene acid esters; aleuritic acid and jalaric acid and/shelloic acid are the major constituents of shellac. Shellac is graded as food and is approved by the Food and Drug Administration. Shellac is also used as surface coating of polymer-free DES . The 1:1 mixture of paclitaxel and shellac is coated onto the microporous DIOR-balloon-surface structure.

Inflation time was scheduled to last not less than 60 s. Thereafter, a BMS was routinely deployed unless optimal balloon-angioplasty results were achieved after a few minutes of observation period after the last PEB inflation. Optimal results with PEB were defined as residual stenosis < 30% without the presence of acute recoil or minor/major dissection after 15 min of the last balloon inflation . Only BMS implantation was allowed after PEB, and the stent length should be shorter than the PEB used. Patients received any of the following BMS devices: Vision (Abbott Vascular, Santa Clara, CA) 23; Driver (Medtronic Vascular, Santa Rosa, CA) 32; Liberté (Boston Scientific, Natick, Massachusetts) 14; and Eucastsflex (Eucatech AG, Rheinfelden, Germany) 25. This group of patients received clopidogrel for three months. In the other two groups of patients, either treated with DES or BMS, PCI strategy and stent technique have been reported previously . In summary, in patients treated with a DES, clopidogrel was mandatory for one year after PCI and thereafter at the discretion of the investigator. DES designs used in this group were Taxus (Boston Scientific), Cypher (Cordis, Johnson & Johnson), Endeavor (Medtronic Vascular) and Eucatax (Eucatech AG).

2.6

Statistical analysis

According to data from our records from diabetic patients treated with DES or BMS and included in clinical trials and taking into account our hypothesis of a similar outcome with PEB and DES, we expected a 40% reduction of TVF with PEB compared with BMS, we calculated that 90 patients were needed to compare them with BMS diabetics, with a power of 80% and a significant P value of .05.

Baseline demographics, clinical and angiographic characteristics were compared using chi-square test. When we analyzed the primary end points, comparisons were made between PEB vs BMS and PEB vs DES groups.

Taking into account the nature of the study we also compared subgroups. Multivariate statistical methods were used to adjust for possible confounding factors. Comparisons were made in the entire group, in patients with multi-vessel disease and in patients with acute coronary syndromes (ACS).

Significance was expressed as a P value <.05. Continuous variables were expressed as mean ± SD and categorical variables as percentages. Continuous variables were compared using ANOVA with Bonferroni correction. Categorical variables were compared using chi-square analysis or Fisher’s exact test. Freedom-from-survival endpoints at follow-up were assessed using Kaplan–Meier curves and compared by log rank test. Logistic-regression and Cox-regression analyses were performed to determine the independent predictors of clinical outcome. In the univariate analysis we included treatment group (PEB, DES, BMS) or (PEB/DES – PEB/BMS), age, male gender, dyslipidemia, renal failure, body mass index > 30, current smoker, low left ventricular ejection fraction, multiple vessel disease, previous acute myocardial infarction, previous revascularization and acute coronary syndrome at hospital presentation. We included in the Cox regression model (enter method) treatment group and ACS according to significance and the number of patient having an event. A P value of <.05 was considered statistically significant. All analyses were performed using the SPSS v14.0 package (Chicago, IL).

2.1

Objectives

The aim of this observational, prospective study was to assess the potential role of PEB in the treatment of patients with DM with coronary lesions compared to a similar patient subset treated either with bare-metal stents (BMS) or DES who had been included in previous studies conducted at our institutions.

2.2

Study design

The Diabetic Argentina Registry (DEAR) was an observational, prospective, non-randomised, open-label study and enrolled patients with DM. Results were compared retrospectively with previous outcomes in patients with DM treated with DES or BMS in clinical studies conducted at our institutions, i.e. patients were treated in the same centres and by the same investigators.

2.3

Patient population

Between April 2009 and March 2011, a total of 1528 patients were screened in the catheterization laboratories from the Cardiovascular Research Centre (CECI) in three hospitals in Buenos Aires, Argentina ( Fig. 1 ).

DEAR Registry flow chart.

Out of 275 patients who had a diagnosis of DM; 92 consented for the study, were included in the study and were treated with the PEB (DIOR, Eurocor GmbH, Germany). Patients were included if they had DM type I or II; clinical indication for myocardial revascularization; age > 18 years; and lesions suitable for PCI with stent implantation in a native vessel. Major exclusion criteria were unprotected left main target vessel; acute MI during the last 48 h; contraindication for dual antiplatelet therapy; target vessel treated with DES during the same session; previous PCI with DES implantation in the target vessel during the last 6 months; malignancies; life expectancy < 1 year; inability to provide informed consent; and pregnancy.

Patient’s outcomes were compared with outcomes of patients with DM who had been included in clinical trials conducted by CECI on BMS and DES. For all of these patients, baseline characteristics and follow-up were available that allowed a retrospective head-to-head comparison with the current PEB registry. Therefore, we identified patients with DM included in ERACI III (Estudio Randomizado Argentino Angioplastia versus Cirugia Coronaria), ORAR II and ORAR III (Oral Rapamycin in Argentina), EUCATAX (paclitaxel-eluting stent with biodegradable polymer versus BMS) and Camouflage (dedicated BMS for acute coronary lesions) studies which have been previously published . We identified 225 patients with DM from 1122 patients included in these studies, 96 treated with BMS and 129 with DES. These patients were compared with 91 patients with DM who had been included and treated in the PEB registry. One patient initially selected for PEB treatment was excluded for analysis due to failure of crossing the lesion with any device ( Fig. 1 ). The final group analysis of the DEAR registry included 316 patients: 91 in the PEB group (with 87 sequential BMS implantation), 96 in the BMS only group, and 129 in DES group ( Fig. 2 and Table 1 ).

Patient population, Diabetic Argentina Registry.

2.4

Endpoints

Primary endpoints were the incidence of major adverse cardiac events (MACE) and target-vessel failure (TVF) after one and three years of follow-up in the PEB group and subsequently to compare retrospectively with the results observed in diabetics patients treated with DES and BMS in trials conducted at our institution. MACE was defined as death, MI, stroke and TVR. TVF was defined as cardiac death, MI or TVR. Comparisons were made between PEB versus BMS and PEB versus DES.

Secondary endpoints were the composite of death/MI and the incidence of stent thrombosis in the three groups. Stent thrombosis was defined according to previous definitions and in agreement with the Academic Research Consortium definition of definitive / probable.

2.5

Medication and coronary procedures

In the PEB group, an initial inflation with plain old balloon angioplasty (POBA) was attempted in all patients using a balloon/vessel ratio < 1. Thereafter, a PEB (DIOR, Eurocor GmbH, Germany) was inflated with about 10 atm. The second generation DIOR balloon was used in the study and this coronary dilation balloon with a 3 μg of paclitaxel/mm ² balloon surface paclitaxel-coating with new coating technique , where the immunosuppressive drug is dissolved in shellac, which is composed of a network of hydroxyl fatty acid esters and sesquiterpene acid esters; aleuritic acid and jalaric acid and/shelloic acid are the major constituents of shellac. Shellac is graded as food and is approved by the Food and Drug Administration. Shellac is also used as surface coating of polymer-free DES . The 1:1 mixture of paclitaxel and shellac is coated onto the microporous DIOR-balloon-surface structure.

Inflation time was scheduled to last not less than 60 s. Thereafter, a BMS was routinely deployed unless optimal balloon-angioplasty results were achieved after a few minutes of observation period after the last PEB inflation. Optimal results with PEB were defined as residual stenosis < 30% without the presence of acute recoil or minor/major dissection after 15 min of the last balloon inflation . Only BMS implantation was allowed after PEB, and the stent length should be shorter than the PEB used. Patients received any of the following BMS devices: Vision (Abbott Vascular, Santa Clara, CA) 23; Driver (Medtronic Vascular, Santa Rosa, CA) 32; Liberté (Boston Scientific, Natick, Massachusetts) 14; and Eucastsflex (Eucatech AG, Rheinfelden, Germany) 25. This group of patients received clopidogrel for three months. In the other two groups of patients, either treated with DES or BMS, PCI strategy and stent technique have been reported previously . In summary, in patients treated with a DES, clopidogrel was mandatory for one year after PCI and thereafter at the discretion of the investigator. DES designs used in this group were Taxus (Boston Scientific), Cypher (Cordis, Johnson & Johnson), Endeavor (Medtronic Vascular) and Eucatax (Eucatech AG).

2.6

Statistical analysis

According to data from our records from diabetic patients treated with DES or BMS and included in clinical trials and taking into account our hypothesis of a similar outcome with PEB and DES, we expected a 40% reduction of TVF with PEB compared with BMS, we calculated that 90 patients were needed to compare them with BMS diabetics, with a power of 80% and a significant P value of .05.

Baseline demographics, clinical and angiographic characteristics were compared using chi-square test. When we analyzed the primary end points, comparisons were made between PEB vs BMS and PEB vs DES groups.

Taking into account the nature of the study we also compared subgroups. Multivariate statistical methods were used to adjust for possible confounding factors. Comparisons were made in the entire group, in patients with multi-vessel disease and in patients with acute coronary syndromes (ACS).

Significance was expressed as a P value <.05. Continuous variables were expressed as mean ± SD and categorical variables as percentages. Continuous variables were compared using ANOVA with Bonferroni correction. Categorical variables were compared using chi-square analysis or Fisher’s exact test. Freedom-from-survival endpoints at follow-up were assessed using Kaplan–Meier curves and compared by log rank test. Logistic-regression and Cox-regression analyses were performed to determine the independent predictors of clinical outcome. In the univariate analysis we included treatment group (PEB, DES, BMS) or (PEB/DES – PEB/BMS), age, male gender, dyslipidemia, renal failure, body mass index > 30, current smoker, low left ventricular ejection fraction, multiple vessel disease, previous acute myocardial infarction, previous revascularization and acute coronary syndrome at hospital presentation. We included in the Cox regression model (enter method) treatment group and ACS according to significance and the number of patient having an event. A P value of <.05 was considered statistically significant. All analyses were performed using the SPSS v14.0 package (Chicago, IL).