Adult patients were prospectively enrolled in seven Malaysian centers (ClinicalTrials.gov Identifiers NCT02629575, NCT02905214) [7, 13], treated with a first-generation PF-SES and compared to a Malaysian all-comers cohort receiving the second-generation PF-SES. All of these studies were based on the same protocol and used the same data capture system (studiesportal.com). A follow-up window of 12 ± 3 months was allowed to accommodate for the all-comers nature of this observational study.
Prior to commencing this study, two lead ethics votes were obtained to cover all participating centers (IJN Research Ethics Committee, Kuala Lumpur, nos. IJNREC/142/2016 and IJNREC/04/2016; Medical Ethics Committee University of Malaya Medical Center, no. 20166–2540). The Declaration of Helsinki in its most recent form was the basis for this trial. Patients were informed and consented prior to enrollment. No patient was included without prior consent.
Endpoints and Definitions
The primary endpoint was the accumulated target lesion revascularization rate (TLR, coronary artery bypass grafting and repeat percutaneous coronary intervention [Re-PCI]). The secondary endpoints were the rates of myocardial infarction (MI), all-cause death and major adverse cardiac events (MACE) consisting of TLR, myocardial infarction (MI) and all-cause death . MI was based on the available definition at the time the studies were conducted . The all-cause death rate was used to define the accumulated MACE rate, while cardiac death was only defined during hospitalization. Acute/subacute ST was defined by the Academic Research Consortium (ARC) criteria . Minor bleeding was defined as Bleeding Academic Research Consortium (BARC) types 1 and 2, whereas major bleeding episodes were categorized as BARC 3a–5 . The criterion for renal insufficiency was an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2 and a cutoff eGFR rate for mandatory dialysis of < 15 mL/min/1.73 m2. Severe vessel tortuosity was defined by the angulation criterion of > 45° .
Two ultrathin strut PF-SES’s (Coroflex© ISAR and Coroflex© ISAR NEO, B. Braun Melsungen AG, Germany) were used in this comparative study. Their coating technology, which consists of a probucol-sirolimus matrix on the abluminal side only, was previously described by Krackhardt et al. . The PF-SES’s were implanted following each institution’s guidelines and preferences. The differences between these two devices were primarily in the slightly modified stent architecture, i.e. ring connectors and slightly widened connector base as shown in Fig. 2, which shows the BMS backbones of the PF-SES’s. This stent architecture modification was beneficial for enhancing the radiopacity of the second-generation PF-SES. Moreover, it resulted in a 50% increase in radial strength.
The two PF-SES’s have an identical polymer-free stent coating, which was intensively studied in the ISAR-TEST 5 trial with a 10-year clinical follow-up . The devices were studied in different ethnic subpopulations , in lesion morphological subgroups  and dialyzed patients , and were investigated with a focus on real-world dual-antiplatelet therapy (DAPT) .
Inclusion and Exclusion Criteria
Adult patients had to meet the requirements for PCI at the time the study was conducted . Patients with stable angina and/or objective proof of ischemia or patients with acute coronary syndrome (ACS) were included. De novo lesions or in-stent restenosis (ISR) in single or multiple vessel disease with reference diameters from 2.0 to 4.0 mm could be treated.
Radial or femoral vascular access was recommended with an introducer sheath of at least 5 French in diameter. The operators could pre-dilate lesions with a balloon catheter of their preference. Alternatively, the direct stenting approach could also be chosen. All patients received intravenous administration of heparin (70 IU/kg), which was supplemented as needed. Preloading with platelet aggregation inhibitor was recommended but not mandatory.
The choice of the P2Y12 receptor antagonists (clopidogrel, prasugrel, ticagrelor) was left to the discretion of the treating physician. Various post-procedural anti-platelet therapy regimens, including clopidogrel 75 mg/day, prasugrel 10 mg/day or ticagrelor 2 × 90 mg/day, were allowed, with lifetime administration of acetylsalicylic acid 100–325 mg/day .
An electronic data capture system [22, 23] with a proven track record was used for both cohorts. The system enabled built-in plausibility checks during each stage of the data entry. In the case of discrepancies, as detected by remote monitoring, a data verification process was initiated to ensure the accuracy of the collected data.
To evaluate dichotomous and categorical variables, the two-sided Fisher’s exact test or the chi-square statistic were used whenever applicable. Means and standard deviations were used to describe continuous variables, which were compared with the unpaired t test or the Mann–Whitney U test in cases where the Shapiro–Wilk test revealed a strong deviation from a normal distribution. The significance level α was 0.05 for all tests. SPSS version 24.0 software (IBM Corp., Armonk, NY) was used for all statistical analyses.
In the entire cohort, 643 patients (Table 1) were treated with either the first-generation PF-SES (413 patients) or the second-generation PF-SES (230 patients). Recruitment of the individual studies occurred from November 2014 to December 2018. Patient demographics were quite similar overall in terms of age (59.7 ± 10.9 years vs. 60.0 ± 11.3, p = 0.744), male gender (81.6% vs. 81.3%, p = 0.987), diabetes mellitus (51.3% vs. 55.7%, p = 0.293), hypertension (63.4% vs. 63.9%, p = 0.905) and ACS rates (44.8% vs. 46.1, p = 0.752).
Regarding the lesion morphological baseline data, there were no differences between treatment groups in terms of lesion length (20.8 ± 7.3 mm vs. 22.9 ± 7.9, p = 0.111) or vessel diameter (2.87 ± 0.39 vs. 2.93 ± 0.40, p = 0.052) despite numerically smaller diameters in the first-generation PF-SES group (Table 1). Patients treated with second-generation PF-SES tended to have more complex lesions as characterized by calcification (10.3% vs. 16.2%, p = 0.022), severe tortuosity (3.5% vs. 6.9%, p = 0.041) and B2/C lesions (49.2% vs. 62.8%, p < 0.001).
Pre-dilatation was carried out in 87.8% of the overall cohort (Table 2), whereas post-dilatation was conducted in 72.2%. All pre- and post-dilatation was done with non-compliant balloons at the discretion of the operator. Cutting/scoring balloons was not recommended or used to prepare the lesions. Rotablation devices were permitted but not used. Stent diameters were slightly larger in the second-generation PF-SES group (2.92 ± 0.39 mm vs. 2.86 ± 0.39 mm, p = 0.046), while stent lengths were comparable (23.7 ± 7.2 mm vs. 24.0 ± 7.4 mm, p = 0.633). Inflation pressures were higher in the first-generation PF-SES group (13.9 ± 2.9 atm vs. 13.1 ± 2.8 atm, p < 0.001). There were no differences in terms of the overall technical success rate per stent implantation despite a numerically higher rate in the second-generation PF-SES group (98.8% vs. 100.0%, p = 0.079).
Clopidogrel was preferred (Table 2) for preloading and post-procedural anti-platelet therapy. There were significant differences in terms of DAPT regimens between the two treatment groups. The decreasing use of ticagrelor in ACS patients with second-generation PF-SES is noteworthy.
As previously reported by Krackhardt et al. , independent of the patients’ presentation at baseline, the DAPT duration in Malaysia is close to 12 months, with 11.6 ± 1.7 months for first-generation PF-SES versus 11.9 ± 1.0 months (p = 0.045) for the second-generation PF-SES.
At the 12-month follow-up, 643 patients were available for analysis (96.1%). The overall rates for accumulated TLR were not significantly different between first- and second-generation PF-SES (0.8% vs. 0.9%, p = 0.891). The accumulated MACE rates were not different (p = 0.561), with 1.5% (6/413) and 2.2% (5/230), respectively. The rates for accumulated definite/probable ST were not significantly different (p = 0.065), and bleeding complications were also not different between the treatment groups (0.5% vs. 0.4%, p = 0.894). Subgroup analyses in B2/C and ACS patients were conducted for comparison. In ACS patients there were no differences in terms of 12-month MACE (3.0% vs. 1.9%, p = 0.591). Likewise in patients with B2/C lesions, the accumulated MACE rates did not differ (2.7% vs. 2.1%, p = 0.699).