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Efficacy and Safety of 3 Versus 6 Months of Dual-Antiplatelet Therapy in Patients Implanted With Coroflex ISAR Stents: A Prospective, Multicenter, Randomized Clinical Trial
Abstract
Background. The optimal duration of dual-antiplatelet therapy (DAPT) after implantation of a drug-eluting stent (DES), especially recently developed polymer-free DESs, is unknown. This study examined the efficacy and safety of 3- versus 6-month DAPT in patients implanted with Coroflex ISAR polymer-free DESs. Methods. Between May 2015 and August 2020, 488 patients who underwent Coroflex ISAR stent implantation were enrolled in the study and randomly assigned to the 3-month (n=244) or 6-month (n=244) DAPT group. Results. At 1 year, the primary endpoint (composite of cardiovascular death, myocardial infarction, target vessel revascularization, and Bleeding Academic Research Consortium [BARC] type 2-5 bleeding) occurred in 9 (3.7%) patients in the 3-month DAPT group and in 7 (2.9%) patients in the 6-month DAPT group (hazard ratio 1.31; P=.60). There was no difference between the 3- and 6-month DAPT groups in either BARC type 2-5 bleeding (1.6% vs 0.8%; hazard ratio 2.00; P=.42) or any bleeding (2.9% vs 3.3%; hazard ratio 0.87; P=.80). Conclusion. Compared with 6 months of DAPT, 3 months of DAPT did not increase the risk of primary endpoint 1 year after Coroflex ISAR stent implantation, although it should be noted that the trial has limited power to see differences due to low event rate and low recruitment rate.
J INVASIVE CARDIOL 2022;34(9):E653-E659. Epub 2022 July 22.
Key words: coronary artery disease, drug-eluting stents, dual-antiplatelet therapy, duration of therapy, randomized controlled trial
Drug-eluting stents (DESs) are generally more thrombogenic than bare metal stents such that all patients implanted with these stents receive dual-antiplatelet therapy (DAPT) for 6-12 months, regardless of their clinical condition.1-4 However, based on studies evaluating the optimal duration of DAPT in DES patients, the current European Society of Cardiology and American College of Cardiology(ACC)/American Heart Association(AHA) guidelines recommend 6 months of DAPT for patients with stable coronary artery disease (SCAD) and 12 months of DAPT for those with acute coronary syndrome (ACS).5,6 For SCAD and ACS patients with a high risk of bleeding, the duration of DAPT after DES implantation is 1-3 and 6 months, respectively.5,6 Nonetheless, the optimal duration of DAPT is unclear, including whether 1-3 months of treatment is effective in patients without a high risk of bleeding.7,8
In the stents used to treat diseased coronary artery segments, the polymeric coatings, applied to facilitate drug release, may trigger an inflammatory reaction and thus delay arterial healing and promote thrombosis.9,10 New-generation DESs were designed to overcome this problem via the use of either more biocompatible polymer coatings or polymer-free DESs.11,12 However, whether a very short course of DAPT is sufficient in patients treated with a polymer-free DES remains unclear. The aim of the ISAR-DAPT (A Comparative Evaluation of Efficacy and Safety in the 3-Month DAPT Group vs the 6-Months DAPT Group of Patients Treated with the Coroflex ISAR Stent) study was to investigate the safety of 3 months, rather than 6 months, of DAPT in patients implanted with a polymer-free DES.
Methods
Study design. The ISAR-DAPT trial is an investigator-initiated, prospective, multicenter, randomized, open-label study performed at 17 sites in Korea (Figure 1). The trial compared aspirin monotherapy after 3 versus 6 months of DAPT in patients implanted with a polymer-free, ultrathin strut, sirolimus- and probucol-coated drug-eluting stent (PF-SES) (Coroflex ISAR, B. Braun Melsungen AG).
Patients eligible for enrollment were ≥ 19 years of age and had chronic SCAD or ACS, excluding myocardial infarction (MI). Further eligibility criteria were at least one lesion in a native coronary vessel with a diameter stenosis ≥ 50% that was suitable for coronary stent implantation in a vessel with a reference vessel diameter ≥ 2.25 mm. Details of study design are provided in Supplemental Material.
Based on previous data involving a similar patient population profile, a primary endpoint rate of 10% was assumed for both groups.7 Originally, with 80% power and a 1-sided type I error of 3%, a sample size of 906 patients in each group would be able to demonstrate noninferiority between both groups for the primary endpoint with a noninferiority fixed margin of 2.7%, which is in accordance with noninferiority margins used in contemporary trials of drug-eluting stents.
Study procedures and clinical follow-up. The study was conducted in accordance with the principles of the Declaration of Helsinki, revised in 2013. The ethics committees of the seventeen participating centers independently approved the protocol, and all participants provided written informed consent.
Patients were allocated to the study groups by the treating physician immediately after confirmation they met the eligibility criteria. Randomization was achieved using a computer-generated random sequence. Patients were randomly assigned at a 1:1 ratio to either the 3-month DAPT group (100 mg aspirin/day plus 75 mg clopidogrel/day or 180 mg ticagrelor/day for 3 months and aspirin alone thereafter) or the 6-month DAPT group (100 mg aspirin/day plus 75 mg clopidogrel/day or 180 mg ticagrelor/day for 6 months and aspirin alone thereafter).
Percutaneous coronary intervention (PCI) was performed according to standard techniques. Details of study procedures and quantitative coronary angiographic analyses are provided in Supplemental Material. After stent implantation, a daily dose of 100 mg aspirin was prescribed indefinitely, together with 75 mg clopidogrel daily or 180 mg ticagrelor daily for 3 or 6 months depending on the randomization scheme. Thus, clopidogrel or ticagrelor therapy was stopped at 3 months after the index procedure in the 3‐month DAPT group but at 6 months after the index procedure in the 6‐month DAPT group. Daily aspirin was prescribed continuously for patients in both groups.
The follow-up examinations were performed in hospital and then via clinic visits or telephone interviews at 1, 3, 6 and 12 months. At follow-up, patient data, including clinical status, all interventions, outcomes, and adverse events, were recorded. Detailed information on the use of aspirin and clopidogrel or ticagrelor was obtained as well.
Study endpoints. The primary analysis was a noninferiority comparison of 3- and 6-month DAPT for the primary endpoint of major adverse cardiac events (MACE) (cardiac death, recurrent myocardial infarction, target-lesion revascularization) at 12 months from the time of the procedure. Due to slower than expected enrollment, it was clear that enrollment of 906 patients could not be achieved. To improve statistical power, the primary hypothesis was changed to a hypothesis that compared with 6 months of DAPT, 3 months of DAPT would be noninferior in the risk of the composite of cardiovascular death, non-fatal MI, target-vessel revascularization, and Bleeding Academic Research Consortium (BARC) type 2-5 bleeding.13 The primary endpoint of the ISAR-DAPT trial was the composite of cardiovascular death, non-fatal MI, target-vessel revascularization, and BARC type 2-5 bleeding.13 Secondary endpoints included the individual components of the primary endpoint, MACE (composite of cardiovascular death, non-fatal MI, and target-vessel revascularization per patient), death of any cause, target-lesion revascularization, non-target-vessel revascularization, stent thrombosis, any bleeding, and cerebrovascular accidents. Detailed definitions of study endpoints, clinical diseases, and procedural findings are provided in Supplemental Material.
Statistical analysis. All analyses were performed according to the intention-to-treat principle, with the inclusion of all randomized patients according to their original group allocation and without imputation. The detailed methods of statistical analysis are provided in Supplemental Material.
Results
Baseline and procedural characteristics. The ISAR-DAPT study became a longer-lasting RCT than anticipated. Our study was originally scheduled to be completed by June 2019 but lasted until August 2020. Recruitment was much more challenging than expected, and from May 2015 until August 2020, 523 patients underwent screening, with 488 patients finally recruited into the study. The study design and the detailed enrollment of patients are provided in Figure 1. The mean age of the patients was 64.5 ± 9.6 years, and 363 (74.4%) of them were men. Stable angina was the clinical presentation in 196 patients (40.2%) and unstable angina in 292 patients (59.8%). The baseline demographic and clinical characteristics of the study population were well balanced between the 3- and 6-month DAPT groups (Table 1).
The angiographic and procedural characteristics of the patients are presented in Table 2. Among the 609 lesions treated in 488 patients, 317 lesions were in left anterior descending artery (52.1%), 468 lesions were ACC/AHA class B2 or type C (76.8%), 242 lesions were long lesion (≥20 mm), the mean stent diameter was 3.03 ± 1.02 mm and the mean stent length per lesion was 23.2 ± 9.1 mm.
Study outcomes. Clinical follow-up data were available for 488 patients (244 patients in the 3-month DAPT group and 244 patients in the 6-month DAPT group). The clinical events at 1 year are summarized in Table 3. The cumulative 1-year incidence of the primary endpoint, defined as a composite of cardiovascular death, non-fatal MI, target-vessel revascularization, and BARC type 2-5 bleeding, was low and not significantly different between the 3-month and the 6-month DAPT groups (Figure 2A). At 1 year, the primary endpoint occurred in 9 patients (3.7%) in the 3-month DAPT group and 7 patients (2.9%) in the 6-month DAPT group (hazard ratio [HR] of the 3-month DAPT group, 1.31; 95% confidence interval [CI], 0.49-3.51; P=.60). Among the major secondary endpoints, the cumulative incidences of MACE and BARC type 2-5 bleeding also did not significantly differ between the two groups. The cumulative 1-year incidence of the MACE was not significantly different between the 3-month and the 6-month DAPT groups (2.0% vs 2.0%, HR, 1.00; 95% CI, 0.30-3.55; P=.97) (Figure 2B). The cumulative 1-year incidence of the target-vessel revascularization per patient and the target-lesion revascularization were not significantly different between the 3-month and the 6-month DAPT groups (Figure 2C, 2D). The rates of BARC type 2-5 bleeding were 1.6% for the 3-month DAPT group and 0.8% for the 6-month DAPT group (HR, 2.00; 95% CI, 0.37-10.91; P=.42). No significant differences were observed between the 2 groups in other secondary endpoints. Stent thrombosis did not occur in both groups.
In prespecified subgroup analysis, the results of comparison between the 2 groups were consistent across various subgroups. The results of the subgroup analysis of the primary endpoint are shown in Figure 3. There was no statistically significant association between the duration of DAPT and the primary endpoint in patients with diabetes (HR, 2.67; 95% CI, 0.49-14.60; P=.13 for interaction), ACS (HR, 0.95; 95% CI, 0.27-3.27; P=.68 for interaction) or multi-stent implantation (HR, 0.66; 95% CI, 0.15-3.00; P=.19 for interaction).
Discussion
The major finding of this study was the absence of a difference in the incidence of net adverse cardiovascular and clinical events (cardiovascular death, MI, target-vessel revascularization, or BARC type 2-5 bleeding) at 1 year after PF-SES implantation among patients treated with 3 months or 6 months of DAPT.
The risk of bleeding is higher with DAPT than with aspirin alone, and the cost of treatment is higher as well.14,15 The increased risk of bleeding can affect patient compliance and result in premature discontinuation of DAPT. Endoscopic, dental, and surgical procedures are often delayed because of prolonged DAPT, which may affect patient quality of life.16 Therefore, determining the minimum required duration of DAPT would benefit patients undergoing stent implantation.
Regardless of the DES type, the current recommendations call for a minimum of 6 months of DAPT after DES implantation to prevent late stent thrombosis.5,6 However, several studies have recently challenged this practice, instead suggesting that 1-3 months of DAPT may be just as effective as well as safer.17-20 In fact, in some studies, patients treated for 1-3 months had less bleeding than did those treated for 6 months or longer, while the rates of ischemic events were similar in both ACS and SCAD patients.19,21 Consistent with those studies, we found no difference in either the therapeutic effect or the safety of 3-month DAPT compared with 6-month DAPT.
Early-generation DESs were associated with a significantly higher risk of very late stent thrombosis compared with bare-metal stents.22 The underlying pathogenic mechanisms appeared to be a polymer-related inflammatory reaction and endothelial cell dysfunction, both of which predispose to thrombus formation on uncovered struts.23 In response to these concerns, polymer-free stent technology has long been an area of interest. Recent studies reported that the long-term outcomes of patients treated with a PF-SES versus a new-generation durable polymer DES do not differ significantly.24,25
The advances in stent development, including non-polymer coatings and bioabsorbable polymers, are also likely to reduce the duration of DAPT. Studies of biodegradable polymer DESs have shown that in patients receiving these stents, 6-month DAPT was just as or even more effective than longer-term DAPT.26-28 In the recent SMART-CHOICE trial, there was no difference between 3- and 12-month DAPT in patients implanted with a biodegradable polymer DES.20 Nonetheless, few studies have investigated the optimal duration of DAPT after polymer-free DES treatment, although an observational study reported that 6 months or less of DAPT yielded results similar to those achieved with 12 months of DAPT.29 To the best of our knowledge, this is the first prospective, randomized study to demonstrate that neither the efficacy nor safety differs between 3- and 6-month DAPT in patients undergoing polymer-free stent implantation.
Study limitations. This study had several limitations. First, the total number of events was relatively low, weakening the support for the conclusions, although estimates of the event rates were based on data from previous studies. Second, our study was an open-label trial and was not placebo controlled. This can affect study outcomes, including target-vessel revascularization, a component of the primary composite endpoint. Third, aspirin is usually recommended as antiplatelet monotherapy following DAPT. Whether the more potent antiplatelet agents prasugrel and ticagrelor affect the risk–benefit balance of prolonged DAPT remains to be determined. Fourth, 1 year of clinical follow-up may not be sufficient to assess late outcomes, especially the occurrence of very late stent thrombosis.
Conclusion
Among patients undergoing PCI and PF-SES implantation, the risk of the occurrence of cardiovascular death, MI, target-vessel revascularization, or BARC type 2-5 bleeding did not differ significantly in patients treated with 3 versus 6 months of DAPT. However, it should be noted that the trial was not statistically powered to detect a difference between the groups due to low event rate and low recruitment rate.
Affiliations and Disclosures
*Joint first authors.
From the 1Department of Cardiology, Ajou University School of Medicine, Suwon, Korea; 2Division of Cardiology, Department of Internal Medicine, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Korea; 3Cardiovascular Center, Korea University Guro Hospital, Seoul, Korea; 4Department of Internal Medicine, Seoul National University Boramae Medical Center and College of Medicine, Seoul National University, Seoul, Korea; 5Sejong General Hospital, Sejong Heart Institute, Bucheon, Korea; 6Department of Cardiology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea; 7Division of Cardiology, Department of Internal Medicine, Ewha Womans University Medical Center, Seoul, Korea; 8Division of Cardiology, Department of Internal Medicine, Inje University Busan Paik Hospital, Busan, Korea; 9Division of Cardiology, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Goyang, Korea; 10Division of Cardiology, Department of Internal Medicine, Chonnam National University Hospital, Gwangju, Korea; 11Department of Cardiology, Dong-A University Hospital, Busan, Korea; 12Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea; 13Division of Cardiology, Department of Internal Medicine, Youido St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea; 14Department of Cardiology, College of Medicine, Bucheon St. Mary’s Hospital, The Catholic University of Korea, Bucheon, Korea; 15Division of Cardiology, Cardiovascular Center, Mediplex Sejong Hospital, Incheon, Korea; and 16Department of Cardiology, Gachon University Gil Medical Center, Incheon, Korea.
Funding: This study was funded by B. Braun Korea.
Trial Registration: clinicaltrials.gov Identifier: NCT02609698
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Manuscript accepted October 1, 2021.
Address for correspondence: Myeong-Ho Yoon, MD, PhD, Department of Cardiology, Ajou University School of Medicine, 164, Worldcup-Ro, Yeongtong-Gu, Suwon, 16499, Republic of Korea. Email: yoonmh65@hanmail.net
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Supplemental Materials
Study design. The ISAR-DAPT trial is an investigator-initiated, prospective, multicenter, randomized, open-label study performed at 19 sites in Korea. The trial compared aspirin monotherapy after 3 versus 6 months of DAPT in patients implanted with a polymer-free, ultrathin strut, sirolimus- and probucol-coated drug-eluting stent (PF-SES) (Coroflex ISAR, B. Braun Melsungen, Melsungen AG).
Patients. Patients eligible for enrolment were ≥19 years of age and had chronic SCAD or ACS, excluding myocardial infarction (MI). Further eligibility criteria were at least one lesion in a native coronary vessel with a diameter stenosis ≥50% that was suitable for coronary stent implantation in a vessel with a reference vessel diameter ≥2.25 mm. The criteria for patient selection were otherwise broad, reflecting routine clinical practice. No limit was set for the number of treated lesions or vessels or for the lesion length. Exclusion criteria were acute MI, scheduled elective surgery within 12 months after the index procedure unless antiplatelet therapy was maintained throughout the perisurgical period, chronic total occlusion or in-stent restenosis, cardiogenic shock, pregnancy, active pathologic bleeding or a history of bleeding diathesis, life expectancy <24 months, previous treatment with any DES within 6 months, and intolerance or known hypersensitivity to aspirin, clopidogrel, or both.
Study procedures. The study was conducted in accordance with the principles of the Declaration of Helsinki, revised in 2013. The ethics committees of the seventeen participating centers independently approved the protocol, and all participants provided written informed consent. Patients were allocated to the study groups by the treating physician immediately after confirmation they met the eligibility criteria. Randomization was achieved using a computer-generated random sequence. Patients were randomly assigned at a 1:1 ratio to either the 3-month DAPT group (100 mg aspirin/day plus 75 mg clopidogrel/day or 180 mg ticagrelor/day for 3 months and aspirin alone thereafter) or the 6-month DAPT group (100 mg aspirin/day plus 75 mg clopidogrel/day or 180 mg ticagrelor/day for 6 months and aspirin alone thereafter).
Treatment protocol. Percutaneous coronary intervention (PCI) was performed according to standard techniques. Before the index procedure, all patients received DAPT with 100 mg aspirin once daily plus either 75 mg clopidogrel once daily or 180 mg ticagrelor once daily for 5 days; otherwise, a 300-mg loading dose of aspirin and either a 600-mg loading dose of clopidogrel or a 180-mg loading dose of ticagrelor were administered at least 24 hours prior to the procedure. All interventions were performed according to current standard guidelines, and the final interventional strategy, including the administration of glycoprotein IIb/IIIa antagonists, pre-/postdilation, and the use of intravascular imaging techniques, was left entirely to the discretion of the operator, with the exception of stent utilisation. Unfractionated heparin was administered throughout the procedure to maintain an activated clotting time of ≥250 seconds. Angiographic success was defined as residual stenosis <30% as determined by visual analysis in the presence of TIMI (Thrombolysis in Myocardial Infarction) 3 grade flow. After the procedure, all patients received optimal pharmacological therapy, including statins, beta-blockers, angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers at the discretion of the responsible clinician. Additionally, the importance of cardiovascular risk factor modification was discussed with the patients. After stent implantation, a daily dose of 100 mg aspirin was prescribed indefinitely, together with 75 mg clopidogrel daily or 180 mg ticagrelor daily for 3 or 6 months depending on the randomization scheme. Thus, clopidogrel or ticagrelor therapy was stopped at 3 months after the index procedure in the 3‐month DAPT group but at 6 months after the index procedure in the 6‐month DAPT group. Daily aspirin was prescribed continuously for patients in both groups.
Follow-up. The follow-up examinations were performed in hospital and then via clinic visits or telephone interviews at 1, 3, 6, and 12 months. At follow-up, patient data, including clinical status, all interventions, outcomes, and adverse events, were recorded. Detailed information on the use of aspirin and clopidogrel or ticagrelor was obtained as well.
Study endpoints. The primary endpoint of the ISAR-DAPT trial was the composite of cardiovascular death, non-fatal MI, target-vessel revascularization, and Bleeding Academic Research Consortium (BARC) type 2-5 bleeding.1 Secondary endpoints included the individual components of the primary endpoint, death of any cause, non-target-vessel revascularization, stent thrombosis, any bleeding and cerebrovascular accidents.
Clinical events were defined based on the recommendations of the Academic Research Consortium.2 All deaths were considered cardiac unless a definite noncardiac cause could be established. MI occurring during the first 48 hours after PCI was defined as an increase in cardiac enzyme (creatine kinase-MB fraction or troponin T/troponin I) levels to 3 times higher than the upper limit of normal in a stable patient.2 In patients with elevated baseline levels of cardiac enzymes, MI was defined as a subsequent greater than 2-fold increase in enzyme levels.3 After the first 48 hours, MI was defined as the presence of clinical signs of MI combined with an increase in the creatine kinase-MB fraction or troponin T/troponin I level greater than the upper limit of normal.2 Target-vessel revascularization was defined as repeat revascularization of the treated vessel by PCI.2 Target-lesion revascularization was defined as either a repeat PCI of the lesion within 5 mm of the deployed stent of the target vessel.2 Stent thrombosis was defined as definite or probable according to the Academic Research Consortium classification.2 Cerebrovascular accident was defined as any non-convulsive focal or global neurologic deficit of abrupt onset lasting for >24 hours or leading to death from ischaemia or haemorrhage within the brain.
Statistical analysis. All analyses were performed according to the intention-to-treat principle, with the inclusion of all randomized patients according to their original group allocation and without imputation. Categorical variables are reported as counts and percentages; significant differences were assessed using the Chi-squared test or, in cases of low counts, Fisher’s exact test. Continuous variables are presented as the mean (standard deviation [SD]) and were compared using the 2-sample t test. The rates of cumulative major adverse cardiovascular events were estimated using the Kaplan–Meier method and compared by log-rank test. Hazard ratios (HRs) with 95% confidence intervals (95% CIs) were estimated according to the Cox proportional hazards method. All analyses were accompanied by tests of the interaction between DAPT allocation and subgroup. All P-values are 2-sided and a P-value <.05 was considered to indicate statistical significance. All analyses were performed using SPSS, version 18.0 (SPSS, Inc).
Supplemental References
1. Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation. 2011;123(23):2736-2747. doi:10.1161/CIRCULATIONAHA.110.009449
2. Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation. 2007;115(17):2344-2351. doi:10.1161/CIRCULATIONAHA.106.685313
3. Fox KA, Poole-Wilson PA, Henderson RA, et al. Interventional versus conservative treatment for patients with unstable angina or non-ST-elevation myocardial infarction: the British Heart Foundation RITA 3 randomised trial. Randomized Intervention Trial of unstable Angina. Lancet. 2002;360(9335):743-751. doi:10.1016/s0140-6736(02)09894-x
