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Clinical Outcomes in Patients Treated With Biodegradable-Polymer Biolimus-Eluting Stents and 6 Months of Dual-Antiplatelet Therapy: The French eBiomatrix 6-Month DAPT Registry
Abstract
Background. Dual-antiplatelet treatment (DAPT) has conventionally been prescribed for 1 year after percutaneous coronary intervention (PCI) with drug-eluting stent (DES) implantation. Recent evidence suggests that a duration of only 6 months may be equally safe and effective when using contemporary DES options. Objective. The aim of this study was to assess clinical outcomes in patients treated with the BioMatrix biodegradable-polymer coated biolimus-eluting stent (BP-BES; Biosensors International) who received only 6 months of DAPT. Methods. This prospective “all-comers” registry enrolled 2038 patients in France. Following PCI, DAPT was started for a recommended period of 6 months. Patients were followed up at 6 and 24 months. The primary endpoint of major adverse cardiac and cerebrovascular event (MACCE) was a composite of all-cause death, cerebrovascular accidents, non-fatal myocardial infarction, or clinically driven target-vessel revascularization. Secondary endpoints included stent thrombosis (ST) and major bleeding (MB). Results. The mean age of the study population was 67 ± 10.5 years and 77% of patients were male. Follow-up data were available in 96.9% and 95.3% of patients at 6 and 24 months, respectively. At 6 months, the incidences of MACCE, ST, and MB were 3.1%, 0.3%, and 0.4%, respectively. At 24 months, 21.2% of patients were still on DAPT and the cumulative incidences of MACCE, ST, and MB were 9.7%, 0.54%, and 0.79%, respectively. Conclusions. In this unselected population of patients undergoing PCI with a BP-BES, a 6-month duration of DAPT after implantation is safe and effective.
J INVASIVE CARDIOL 2022;34(5):E363-E368. Epub 2022 April 22.
Key words: dual-antiplatelet treatment, percutaneous coronary intervention, stent thrombosis
Percutaneous coronary intervention (PCI) is widely regarded as the preferred method of revascularization in most patients with coronary artery disease. However, stents can be associated with the potentially catastrophic complication of stent thrombosis (ST). In order to mitigate this risk, treatment with 2 antiplatelet agents after PCI is recommended. However, the optimal duration of dual-antiplatelet treatment (DAPT) is less clear. Earlier studies with first-generation drug-eluting stent (DES) implantation suggested that a prolonged duration of DAPT was required to reduce the risk of ST.1 However, prolonged DAPT is associated with a higher risk of bleeding. There is increasing evidence that newer-generation stents along with optimal implantation technique may allow the DAPT course to be curtailed without necessarily incurring an additional risk of ST.2 One of these is the BioMatrix biodegradable-polymer biolimus-eluting stent (BP-BES; Biosensors International). The outcome of patients receiving DAPT for 12 months after implantation of this DES has previously been published.3 The purpose of the current registry study was to provide outcome data in patients who received a 6-month course of DAPT after PCI with this device.
Methods
Patients were prospectively enrolled from an “all-comers” population at 30 centers in France. Patients were eligible if they had coronary stenosis in native arteries ranging from 2.25-4.0 mm in diameter suitable for treatment with PCI and DAPT after DES implantation. There was no limit to the number of lesions or vessels that could be treated.
All patients received either the BioMatrix Flex or BioMatrix NeoFlex DES. These stents consist of a stainless-steel backbone that is coated on the abluminal surface with a biodegradable polymer made of polylactic acid (PLA) containing the active pharmaceutical agent Biolimus A9. The NeoFlex version of the stent is the latest iteration in design, offering improved flexibility, trackability, and side-branch access compared with its predecessor.
Following stent implantation, the recommendation was for a maximum of 6 months of DAPT with aspirin and 1 of the following 4 agents: clopidogrel, ticagrelor, prasugrel, or ticlopidine. Patients in whom a DAPT duration >6 months was mandated from the outset were excluded. However, patients presenting with acute coronary syndrome (ACS) were eligible for recruitment.
Follow-up protocol. All patients were followed at 6 months and 2 years via telephone contact. Assessments of anginal status, medications, and the occurrence of adverse events were recorded. Information regarding length, type, duration of DAPT, and reason for discontinuation was also collected.
Ethics. The study was performed in accordance with Good Clinical Practice guidelines and conformed to the principles set forth in the Declaration of Helsinki. All patients provided written consent in order to participate in this registry.
Endpoints and definitions. The primary endpoint was the incidence of major adverse cardiac and cerebrovascular event (MACCE), defined as a composite of all-cause death, myocardial infarction (MI), cerebrovascular accidents, or clinically driven target-vessel revascularization at 6 months.
The secondary endpoints included ST at 6 and 24 months as well as major bleeding (Blood Academic Research Consortium [BARC] 3, 4, or 5) at those timepoints. Stent thrombosis was defined as definite or probable according to the previously published definition from the Academic Research Consortium (ARC).4Bleeding events were classified in line with BARC recommendations.5Myocardial infarction was defined as a rise of cardiac biomarker levels with at least 1 value above the 99th percentile upper reference limit and at least 1 of the following: ischemic symptoms; evidence of new ischemic changes on electrocardiogram or echocardiogram; or identification of intracoronary thrombus at angiography.
The European Cardiovascular Research Center (CERC) was the independent institute in charge of data collection, monitoring, and clinical events committee (CEC) organization. All endpoint-related adverse events were independently adjudicated by the CEC, which was composed of cardiologists not involved in the study.
Statistical analysis. Continuous variables are presented as mean with standard deviation or median with interquartile ranges. Categorical variables include the frequency and percentage of patients in each group. Where appropriate, 95% confidence intervals have been calculated for each variable. Chi-square test was used to calculate the P-value for equality of proportions. Multivariate analysis was performed to identify factors that predicted MACCE, stent thrombosis, and bleeding.
Results
A total of 2098 patients were recruited between March 2014 and January 2017. Sixty patients were excluded from statistical analysis due to deviation from the protocol (absence of consent [n = 1], implantation of a non-study stent [n = 45], and no PCI undertaken [n = 14]). The study population was therefore composed of 2038 patients. Patient demographics are presented in Table 1.
The lesion characteristics and procedural details are shown in Table 2. Bifurcation disease was present in 12.4% of cases while 9.2% of patients received treatment for a chronic total occlusion. Procedural success was obtained in 99.2% of cases and 99.2% of patients were discharged on DAPT.
Follow-up data were available in 96.9% and 95.3% of patients at 6 and 24 months, respectively (Table 3). The primary endpoint of MACCE occurred in 3.1% and 9.7% of cases at 6 and 24 months, respectively. At 6 months, definite/probable ST had occurred in 0.3% and major bleeding had occurred in 0.41% of patients. Between 6 and 24 months, definite/probable ST occurred in an additional 0.24% and major bleeding occurred in an additional 0.38% of patients.
At 6 months, 65.1% of patients were on DAPT and by 24 months, 21.2% of patients remained on DAPT. This provided the opportunity to compare the primary and secondary outcomes at 24 months between the cohort in which DAPT was stopped at 6 months and the cohort with extended treatment (Table 4). There was no difference in MACCE (8.6% vs 9.4%; P=.55) or ST (0.31% vs 0.63%; P=.04). The short DAPT group had a higher rate of major bleeding than the extended DAPT group (1.6% vs 0.6%; P=.04).
Multivariate analysis showed that male gender and advanced age were independent predictors of MACCE. There was no correlation between any of the parameters collected in the study and either ST or bleeding risk (Table 5).
Discussion
In this registry, the cessation of DAPT after 6 months did not increase the risk of ST over the intervening 18-month period. The outcomes of our study are comparable to those of a previous French registry with this DES in which the duration of DAPT was 12 months.3 The incidence of ST (definite and probable) at 2 years was similar at 0.6% with 12 months of DAPT and 0.5% in this registry. The major bleeding event rate was 0.2% with 12 months of DAPT compared with 0.8% in this registry. Furthermore, both studies had similar incidences of MI (1.4% vs 1.8% with 6 and 12 months of DAPT, respectively) and target-vessel revascularization (5.5% vs 6.3%), implying that prolonged DAPT does not confer an additional protection against thrombotic events. Our paradoxical observation of higher bleeding rate in the 6-month DAPT group is likely due to premature discontinuation of DAPT for bleeding, although it has to be noted that the number of events in both arms was small.
The current registry adds to the growing body of evidence that a 6-month course of DAPT following the implantation of a third-generation DES is safe. The recommendation of 12 months of DAPT as the standard of care after PCI originates from trials performed in the era of bare-metal stents.6,7 The CREDO trial7 showed that 1 year of DAPT was superior to 1 month of therapy by conferring a 27% relative risk reduction in the composite endpoint of death, MI, and stroke, and this set the 12-month DAPT benchmark. The introduction of DES options led to a significant improvement in cardiovascular outcomes.8 However, it also raised the specter of late ST, presumably due to delayed arterial healing induced by the antimitotic agents present in those stents.9 In order to mitigate the risk of ST, the recommendation for 12 months of DAPT was maintained. However, more recent trials have called this practice into question. The EXCELLENT trial compared 6 months vs 1 year of DAPT with aspirin and clopidogrel after DES implantation.10 There was no statistical difference in the primary outcome of target-vessel failure (defined as a composite of cardiac death, MI, and target-vessel revascularization) between the 2 groups. These results were replicated in the larger (n = 4000 patients) ISAR-SAFE trial.11 This study showed no significant difference in the composite of death, MI, ST, stroke, and major bleeding at 15 months after DES implantation between groups receiving 6 and 12 months of DAPT. A meta-analysis of 10 trials addressing the duration of DAPT showed that 6 months of DAPT had similar rates of mortality, MI, and ST, but lower rates of major bleeding compared with 1 year of DAPT.12 The results of all these trials were endorsed in the European Society of Cardiology guidelines, which recommend a 6-month course of DAPT after elective implantation of DES for stable angina.13 There is evidence that a prolonged and intensified antiplatelet course of DAPT may be beneficial in patients presenting with ACS.14 Our registry had a lower proportion of ACS patients compared with previous registries3,15 and trials.10,11 The recommendation of a 6-month course of treatment from the outset may have deterred recruitment of this subgroup and thus caution should be exercised when generalizing our results to the entirety of the ACS population. Furthermore, a comparatively high proportion of patients were treated for silent ischemia in our cohort compared with other published studies.16,17 Percutaneous treatment of such a “low-risk” group is associated not only with a lower incidence of ST but also of MACCE and thus may have masked any potential benefit of prolonged DAPT in our study.
Our study confirmed the traditional cardiovascular risk factors of old age and male gender to be associated with a higher rate of adverse events. However, we were unable to identify any factor that influenced either ST or major bleeding. Stent thrombosis has traditionally been attributed to the type of stent used (earlier-generation DES devices), patient characteristics (diabetes, chronic renal insufficiency, clopidogrel resistance), and procedural factors (stent length, lesion complexity, stent undersizing or underexpansion).18-20 While it remains a feared complication of PCI, its incidence has been decreasing with the evolution of PCI over the years. Improper stent implantation techniques, including under-expansion and strut malapposition, appear to be more significant than delayed endothelialization in the development of ST.21 Moreover, the natural atherosclerotic process in an individual may play an important role, as evidenced by the observation of neoatherosclerosis and in-stent plaque rupture, particularly in cases of very late ST.22
The GLOBAL LEADERS trial compared 1-month treatment with ticagrelor and aspirin followed by 23 months of ticagrelor only with 12 months of DAPT followed by aspirin monotherapy.23 Although the study did not show the experimental interventional arm to be superior, it is interesting to note that the incidence of ST was the same in both groups, suggesting that an even shorter DAPT treatment might be safe at least in elective cases.
Study limitations. As a registry, our study has the limitations inherent to this type of study, notably, lack of randomization, possible observer bias, self-reporting, and limited monitoring. Despite the original aim of the trial, a significant proportion of patients (21%) were still on DAPT at 24-month follow-up, which may have influenced our results. Our registry included patients presenting with both ACS and stable angina. The underlying pathophysiological processes are different in these 2 clinical presentations and may consequently mandate different lengths of DAPT.
Conclusion
Treatment with 6 months of DAPT after implantation of the BioMatrix DES is safe and is not associated with a higher risk of ST. Further work should be directed toward investigating DAPT duration in specific subgroups with high bleeding risk to evaluate the efficacy and safety of even shorter DAPT treatment.
Affiliations and Disclosures
From 1Pôle Santé République, Clermont-Ferrand, France; 2CERC, Massy, France ; 3Clinique du Millénaire, Montpellier, France; 4Ramsay Générale de Santé, Institut Cardiovasculaire Paris Sud, Massy, France; 5Clinique des Cèdres, Cornebarrieu, France; 6Hôpital Ambroise Paré, Boulogne-Billancourt, France; 7Hôpital Cochin, Paris, France; 8Polyclinique de Bois Bernard, Bois-Bernard, France; 9Clinique de la Sauvegarde, Lyon, France; 10Hôpital Trousseau, CHRU de Tours, France; 11Biosensors, Boulogne-Billancourt, France; 12Hôpital Européen Georges Pompidou, Paris, France.
Funding: Biosensors France SAS, Boulogne-Billancourt, France.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Varenne reports consulting and research grants from Boston Scientific, Abbott Vascular, AstraZeneca, and Servier; Dr Angoulvant reports personal fees from AstraZeneca, Bayer, Bristol-Myers-Squibb/Pfizer, Sanofi, Amgen, Novartis, Novo-Nordisk, Servier, and MSD, outside the submitted work. Prof Spaulding reports consultant income from Medtronic, Edwards, Techwald, and Stentys; fees for presentations from Astra Zeneca, Boehringer Ingelheim, Abbott, and BMS. Clauset Cruchon and Keith Oldroyd are employees of Biosensors. The remaining authors report no conflicts of interest regarding the content herein.
Manuscript accepted September 1, 2021.
Address for correspondence: Prof Christian Spaulding, Département de Cardiologie, Hôpital Européen Georges Pompidou, 20 rue Leblanc 75015 Paris. Email: christian.spaulding@aphp.fr
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