High Bleeding Risk Patients Treated with Very Thin-Strut Biodegradable Polymer or Thin-Strut Durable Polymer Drug-Eluting Stents in the BIO-RESORT Trial

The present study is an explorative analysis of the BIO-RESORT trial (Comparison of Biodegradable Polymer and Durable Polymer Drug-Eluting Stents in an All-Comers Population) [TWENTE III]) [12]. The study design and population, as well as the main 1-year results have been published previously [12, 13]. In brief, BIO-RESORT (ClinicalTrials.​gov: NCT01674803) is an investigator-initiated, multicenter, randomized controlled trial in 3514 all-comers who were treated with PCI. The study was performed at four clinical sites in the Netherlands (Thoraxcentrum Twente, Medisch Spectrum Twente, Enschede; Rijnstate Hospital, Arnhem; Haga Hospital, The Hague; Albert Schweitzer Hospital, Dordrecht). Patients were eligible if they were 18 years or older, capable of providing informed consent, and required a PCI with DES implantation according to clinical guidelines or the operators’ judgment. All coronary syndromes were permitted and there was no limit for the number of lesions to be treated or for lesion characteristics. Only few exclusion criteria were applied [13]. Web-based computer-generated allocation sequences randomly assigned study participants in a 1:1:1 fashion to treatment with a very thin-strut, biodegradable polymer everolimus-eluting stent (Synergy; Boston Scientific, Natick, MA, USA), a very thin-strut, biodegradable polymer sirolimus-eluting stent (Orsiro; Biotronik AG, Bülach, Switzerland), or a thin-strut, durable polymer zotarolimus-eluting stent (Resolute Integrity; Medtronic, Santa Rosa, CA, USA). For the present analysis, HBR patients treated with BP-DES (i.e., Synergy and Orsiro) were compared to patients treated with DP-DES (i.e., Resolute Integrity). Dual antiplatelet therapy was generally prescribed for 6–12 months, according to international and local guidelines. The only exception was patients on oral anticoagulation therapy, in whom aspirin was usually discontinued after 1–6 months, while clopidogrel was often prescribed for 1 year. The trial complied with the CONSORT 2010 Statement and Declaration of Helsinki and was approved by the Medical Ethics Committee Twente and the institutional review boards of all participating centers. All trial participants provided written informed consent.

As there is no generally accepted definition of HBR for patients with coronary artery disease who undergo PCI, we applied the vast majority of HBR criteria applied in previous HBR studies [10, 14, 15], using data available in the BIO-RESORT study database. Patients in the present analysis were classified as HBR if they fulfilled at least one of the following criteria: (1) age ≥ 75 years; (2) current use of oral anticoagulation therapy; (3) hemoglobin < 11 g/dl; (4) platelet count < 100,000/mm³; (5) pevious gastro-intestinal bleeding within last 12 months before the index procedure; (6) previous stroke within 12 months before the index procedure; (7) previous intracranial bleeding; (8) severe renal insufficiency requiring dialysis; (9) current use of non-steroidal anti-inflammatory drugs. As (10) planned major surgery in the next 6 months after the index PCI had been an exclusion criterion of the BIO-RESORT trial, none of the BIO-RESORT patients fulfilled this criterion. In contrast to the previous HBR trials, we did not have information of previously diagnosed malignancy and severe liver disease (e.g., cirrhosis) available in our database, and therefore, we might have missed some of these HBR patients. However, if patients with severe liver disease had reduced levels of hemoglobin or platelet count, they anyway were classified as HBR.

One-year clinical follow-up data were obtained at visits to outpatient clinics or, if not feasible, by telephone or medical questionnaire. Trial coordination and data management were performed by the clinical research organization Cardiovascular Research and Education (CRE, Enschede, the Netherlands). Data monitoring and independent clinical event adjudication were performed by an independent clinical research organization (Diagram, Zwolle, the Netherlands).

All clinical endpoints were pre-specified and defined according to the Academic Research Consortium (ARC) criteria [16, 17]. The primary endpoint of this study was the 1-year rate of target vessel failure (TVF), a composite of cardiac death, target vessel-related MI, or clinically indicated target vessel revascularization. Death was considered as cardiac unless an unequivocal non-cardiac cause could be established. Secondary endpoints included any death, any MI, target lesion failure (TLF, a composite of cardiac death, target lesion-related MI, or clinically indicated target lesion revascularization), major adverse cardiac events (MACE, a composite of any death, any MI, emergent coronary bypass revascularization, or clinically indicated target lesion revascularization), the most global patient-oriented composite endpoint (POCE, a composite of any death, any MI, or any revascularization), stent thrombosis, and major bleeding. The latter was defined as any Bleeding Academic Research Consortium (BARC) type 3 or 5 and/or Thrombolysis in Myocardial Infarction (TIMI) major bleeding (i.e., including coronary artery bypass grafting-related major bleeding) [18, 19].

Continuous data are reported as mean ± standard deviation and categorical data as numbers and percentages. Student’s t test and Chi-square test (or Fisher’s exact test, as appropriate) were used to compare differences in baseline characteristics. Time to clinical endpoints was calculated using Kaplan-Meier analyses, and the log-rank test was applied for between-group comparisons. Hazard ratios were computed using Cox proportional hazard regression analyses. We used logistic regression for interaction between subgroups and treatment with regard to the primary endpoint in analogy with the BIO-RESORT trial [12]. All p values are two-sided and considered significant if being < 0.05. Data analysis was performed with SPSS, Version 22.0 (IBM Corp., Armonk, NY, USA).

HBR patients were significantly older than non-HBR and had significantly more co-morbidities (Supplementary Table 1). Proportions of all individual HBR criteria are displayed in Table 1. All 1009 HBR patients met a total of 1246 HBR criteria; 798 (79.1%) met 1 HBR criterion, 188 (18.6%) met 2 HBR criteria, and 23 (2.3%) met ≥ 3 HBR criteria. Of all HBR criteria, the most often met criteria were an age ≥ 75 years (50.6%) and the use of oral anticoagulation therapy (30.3%). HBR patients met on average 1.2 HBR criteria. Dual antiplatelet therapy containing aspirin and one of the more potent P2Y₁₂ inhibitors (i.e., ticagrelor or prasugrel) was significantly less often prescribed in HBR patients (Supplementary Table 1).

The Supplementary Table 2 presents the clinical follow-up data for HBR patients versus non-HBR patients. The rate of TVF was significantly higher in HBR patients versus non-HBR patients (6.7 vs. 4.2%, HR 1.59 [95% CI 1.17–2.17], p = 0.003). The rates of any death, cardiac death, TLF, MACE, POCE, and major bleeding were also higher in HBR patients (all p values ≤ 0.001). There was no statistically significant difference in the rates of MI, target vessel revascularization, target lesion revascularization, and stent thrombosis.

Of all 1009 HBR patients, 673 (66.7%) received BP-DES, and 336 (33.3%) received DP-DES. There were no significant between-group differences in baseline characteristics for HBR patients treated with BP-DES versus DP-DES, except for a somewhat higher body mass index in the BP-DES group (27.5 vs. 26.8, p = 0.01, Table 2). HBR criteria were similar for both stent groups (Table 1), and there was no statistically significant between-group difference in medication at discharge (Table 2). After 1 year, in both groups, similar proportions of patients were on dual antiplatelet therapy or on oral anticoagulation therapy plus P2Y₁₂ inhibitor.

Table 3 presents the clinical outcome data of HBR patients treated with BP-DES versus DP-DES. The primary clinical endpoint TVF was reached in 43/673 (6.5%) HBR patients treated with BP-DES and 24/336 (7.3%) treated with DP-DES (HR 0.88 [95% CI 0.54–1.46], p = 0.63, Fig. 2). The results for the primary endpoint were consistent in various subgroups, except for multivessel treatment (Supplementary Fig. 1). Between BP-DES and DP-DES groups, there was also no significant difference in the following secondary endpoints: any death (3.3 vs. 4.8%, p = 0.23); cardiac death (1.8 vs. 2.1%, p = 0.73); target vessel MI (2.7 vs. 3.3%, p = 0.58); TVR (2.3 vs. 3.0%, p = 0.46); TLF (6.1 vs. 5.7%, p = 0.81); TLR (2.0 vs. 0.9%, p = 0.22); MACE (7.6 vs. 8.1%, p = 0.77); POCE (9.7 vs. 10.5%, p = 0.69); definite or probable stent thrombosis (0.5 vs. 0.6%, p = 0.75); and major bleeding (3.3 vs. 3.1%, p = 0.84).

Of all HBR patients in the BP-DES group, 336/673 (49.9%) were treated with Synergy everolimus-eluting stents, and 337/673 (50.1%) were treated with Orsiro sirolimus-eluting stents. Comparison of patients treated with both individual BP-DES versus patients treated with Resolute Integrity DP-DES showed similar results for TVF and all secondary clinical endpoints (Fig. 3, Table 4). In addition, there was no significant difference in clinical outcome between patients treated with Synergy versus Orsiro BP-DES.

The results of this analysis should be considered hypothesis generating, and the study was not powered to detect differences in rare clinical events such as stent thrombosis. As there is no general HBR definition, we followed criteria applied in previous HBR trials, using data available in the database of the randomized BIO-RESORT trial. In contrast to the previous HBR trials, we had no information of previously diagnosed malignancy and severe liver disease available in our database, and therefore, we might have missed some HBR patients. However, if patients with severe liver disease had reduced levels of hemoglobin or platelet count, they anyway were classified as HBR. Furthermore, we used requirement of dialysis as parameter of severe renal insufficiency rather than a creatinine clearance < 40 cc/min/1.73 m². While this might have lowered the mean number of HBR criteria per patient, many patients with a creatinine clearance below that threshold may have been 75 years or older and, thus, anyway classified as HBR (based on their age). Nevertheless, these minor differences in HBR criteria make it somewhat difficult to compare our results with previous HBR studies. Despite high follow-up rates, and independent monitoring and event adjudication, the event rates were relatively low.