Title: Duration of Dual Antiplatelet Therapy After Implantation of Drug-Eluting Stents (DES-LATE)
Trial Sponsor: Grants from the Cardiovascular Research Foundation (Korea), and a grant from the Korean Ministry of Health & Welfare as part of the Korea Health 21 Research & Development Project
Year Presented: 2010
Year Published 2010
Topic(s): General Cardiology, Interventional Cardiology
Summary Posted: 3/15/2010 11:00:00 AM
Writer: Dharam J. Kumbhani, M.D., S.M.
Author Disclosure: This author has nothing to disclose.
Reviewer: Deepak L. Bhatt, M.D., M.P.H., F.A.C.C.
Author Disclosure: Research/Research Grants: Astra Zeneca; Consultant Fees/Honoraria: Duke Clinical Research Institute; Research/Research Grants: Heartscape; Research/Research Grants: PLx Pharma; Research/Research Grants: Cogentus; Research/Research Grants: Sanofi Aventis; Data Safety Monitoring Board (Gov’t/Nonprofit): Duke Clinical Research Institute; Research/Research Grants: Bristol Myers Squibb; Research/Research Grants: Eisai; Research/Research Grants: Takeda; Research/Research Grants: The Medicines Company; Research/Research Grants: Ethicon
Related Resources
Presentation Slides: DES-LATE
Related Trial: Comparison of Sirolimus and Paclitaxel-Eluting Stents Versus Zotarolimus-Eluting Stents in Real World Practice (ZEST — Presented at ACC.09/i2)
Description
Drug-eluting stents (DES) are associated with decreased restenosis and need for target lesion revascularization, as compared with bare-metal stents, in patients undergoing percutaneous coronary intervention (PCI). However, there is a higher risk of late stent thrombosis with DES, especially after clopidogrel is stopped.
Current guidelines mandate dual antiplatelet therapy (DAT) with aspirin and clopidogrel for at least 12 months after DES PCI, and it is sometimes continued as long as possible. The optimal long-term duration of DAT is thus unknown. DES-LATE is a composite of two separate clinical trials (REAL-LATE and ZEST-LATE), which were both designed to study the optimal duration of DAT following DES PCI.
Hypothesis
DAT with aspirin and clopidogrel would be superior to aspirin alone in patients who had undergone PCI at least 12 months earlier.
Drugs/Procedures Used
Patients in both trials received either clopidogrel 75 mg daily with low-dose aspirin (100-200 mg), or low-dose aspirin alone in an open-label fashion.
Concomitant Medications
Statins (79%), beta-blockers (66%), and angiotensin-converting enzyme inhibitors (46%)
Principal Findings
A total of 2,701 patients were randomized (1,625 in REAL-LATE and 1,076 in ZEST-LATE), of which 1,357 received DAT, whereas 1,344 received aspirin monotherapy. The two trials were merged due to slow enrollment. All patients were enrolled in South Korea. Baseline characteristics were fairly similar between the two arms. About 26% had diabetes, 3.5% had prior myocardial infarction (MI), and 12.5% had prior angioplasty. About 37.5% of patients underwent PCI for stable PCI, whereas the rest had acute coronary syndromes, including unstable angina (40.8%), ST-elevation MI (11%) and non-ST-elevation MI (10.7%). Multivessel disease was noted in about 48% of the patients, whereas the left anterior descending artery was revascularized in about 49% of the patients. The mean number of stents per lesion was 1.3, with a mean stented length of 31.4 mm. The majority of DES were sirolimus-eluting stents (SES; 57%); others included paclitaxel-eluting stents (PES; 24%), and zotarolimus-eluting stents (ZES; 19%).
The median time from index procedure to randomization was 12.8 months, and only 12% of patients were on DAT beyond 18 months prior to randomization. Although about 98.3% of the patients were still taking aspirin at the end of 2 years of follow-up, only 83% of patients in the DAT arm and 4.4% of the patients in the aspirin arm were taking clopidogrel at the end of 2 years of follow-up.
The incidence of the primary endpoint (MI or cardiovascular death) at 2 years was similar between the DAT and aspirin monotherapy arms (1.8% vs. 1.2%, hazard ratio 1.65, 95% confidence interval 0.80-3.36, p = 0.17). No difference was noted when the analysis was conducted separately for each trial. There was also no difference between the two arms in the incidence of all-cause mortality (1.6% vs. 1.4%, p = 0.24), MI (0.8% vs. 0.7%, p = 0.49), stroke (1.0% vs. 0.3%, p = 0.19), definite stent thrombosis (0.4% vs. 0.4%, p = 0.76), or need for repeat revascularization (3.1% vs. 2.4%, p = 0.22). The composite endpoint of MI, stroke, or all-cause mortality showed a trend towards being higher in the DAT arm compared with the aspirin arm at the end of 2 years (3.2% vs. 1.8%, p = 0.051); the rates at the end of 1 year were identical (1.1% vs. 1.1%, p=NS). TIMI major bleeding was similar between the two arms (0.2% vs. 0.1%, p = 0.35).
Interpretation
Although the risks of late stent thrombosis with DES, especially after cessation of DAT, are well known, the optimal duration of DAT following DES PCI is unknown. Data from observational studies have been conflicting, and no randomized trial has been conducted on this topic yet. This trial thus seeks to answer a very important question. In this trial, patients who had been on DAT for at least 12 months following DES PCI were randomized to continuing DAT for another 2 years, or stopping clopidogrel, and continuing aspirin only. The investigators found no difference in the incidence of any of the endpoints studied, including stent thrombosis. They did note a trend towards harm for the composite endpoint of death, MI, or stroke with DAT.
One limitation of this trial is that it represents the combination of two separate trials, which were merged due to slow enrollment. ZEST-LATE was a continuation of the ZEST trial, which compared ZES to SES, and had slightly different enrollment criteria as compared with REAL-LATE, which included a broader patient population. Thus, there may be some heterogeneity between the patients in the two trials. Further, despite the merger, the overall trial was still underpowered to detect differences in clinical outcomes between the two trials, since the event rates were <25% of anticipated. Moreover, the results of this trial suggest that continuation of DAT beyond 12-24 months after DES PCI is not associated with superior clinical outcomes, as compared with discontinuation of clopidogrel after this period.
Most patients in this trial received first-generation DES. It is thus unknown if these results will be applicable to second- and third-generation DES as well. Further, it is unclear whether the results of this trial can be applied to non-Asian populations. Individual variability in response to clopidogrel can be as high as 30% among different ethnic groups, and this has a bearing on ischemic and thrombotic outcomes. Future larger trials, confirming the above results in a more diverse patient population, are thus necessary.
Finally, it should be noted that patients who had experienced a major adverse cardiac event (MACE) or bleeding since implantation were excluded from this trial. The optimal duration of DAT in such patients, as well as high-risk patients, such as those with left main stents, is likely to be longer.
Conditions
• Coronary heart disease
Therapies
• Antiplatelet agent / Clopidogrel
• Antiplatelet agent / Aspirin
Study Design
Randomized. Parallel.
Patients Enrolled: 2,701
Mean Follow-Up: 19.2 months
Mean Patient Age: 62 years
% Female: 30
Mean Ejection Fraction: 59.5%
Primary Endpoints
Cardiovascular death or MI
Secondary Endpoints
All-cause mortality
Stroke
MI
Stent thrombosis
Repeat revascularization
Death, MI, or stroke
Cardiovascular death, MI, or stroke
TIMI major bleeding
Patient Population
DES implantation at least 12 months before enrollment
No MACE or major bleeding since stent implantation
On DAT at the time of enrollment
Exclusions:
Contraindication to antiplatelet therapy
Established indication for continuing clopidogrel, such as peripheral arterial disease
Life-expectancy <1 year
Anticipated noncompliance
Participation in another drug or coronary device study
References: Park SJ, Park DW, Kim YH, et al. Duration of dual antiplatelet therapy after implantation of drug-eluting stents. N Engl J Med 2010;Mar 15:[Epub ahead of print].