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Duration of Dual Antiplatelet Therapy After Implantation of Drug-Eluting Stents - DES-LATE
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 (DAPT) 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 DAPT 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 DAPT following DES PCI.
Hypothesis:
DAPT with aspirin and clopidogrel would be superior to aspirin alone in patients who had undergone PCI at least 12 months earlier.
Study Design
- Parallel
Patients Enrolled: 2,701 (initially)
Mean Follow Up: 42 months
Mean Patient Age: 62 years
Female: 30%
Mean Ejection Fraction: 59.5%
Patient Populations:
- DES implantation at least 12 months before enrollment
- No MACE or major bleeding since stent implantation
- On DAPT 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
Primary Endpoints:
- Cardiovascular death/MI/stroke
Secondary Endpoints:
- All-cause mortality
- Stroke
- MI
- Stent thrombosis
- Repeat revascularization
- Death, MI, or stroke
- Cardiovascular death, MI, or stroke
- TIMI major bleeding
Drug/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 5,045 patients were randomized, 2,514 to DAPT and 2,531 to aspirin monotherapy. The trial was recruited in successive cohorts. Initially, a total of 2,701 patients were randomized (these itself were from two smaller trials: 1,625 in REAL-LATE and 1,076 in ZEST-LATE. The two trials had been merged due to slow enrollment.). Finally, in a second phase, another 2,344 patients were enrolled. All patients were enrolled in South Korea.
Baseline characteristics were fairly similar between the two arms. Approximately 28% had diabetes, 4% had prior myocardial infarction (MI), and 12% had prior angioplasty. Approximately 38.5% of patients underwent PCI for stable PCI, whereas the remainder had acute coronary syndromes, including unstable angina (37%), ST-segment elevation MI (STEMI) (12.5%), and non-STEMI (10.6%). Multivessel disease was noted in approximately 49% of the patients, whereas the left anterior descending artery was revascularized in approximately 50% of the patients. The mean number of stents per lesion was 1.3, with a mean stented length of 30 mm. The majority of DES were sirolimus-eluting stents (SES; 44%); others included paclitaxel-eluting stents (PES; 20%), zotarolimus-eluting stents (ZES; 19%), and everolimus-eluting stents (EES; 11%).
The median time from index procedure to randomization was 13.3 months, and only 12% of patients were on DAPT beyond 18 months prior to randomization. Although approximately 96% of the patients were still taking aspirin at the end of 2 years of follow-up, only 79.4% of patients in the DAPT arm and 8.1% 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 (cardiovascular death/MI/stroke) at 2 years (2.6% vs. 2.4%, p = 0.75) and at 4 years was similar between the DAPT and aspirin monotherapy arms (4.4% vs. 5.1%, p > 0.05). No difference was noted when the analysis was conducted separately for each trial. At 24 months, there was also no difference between the two arms in the incidence of all-cause mortality (2.0% vs. 1.4%, p = 0.12), MI (0.8% vs. 1.2%, p = 0.23), stroke (0.9% vs. 0.9%, p = 0.98), definite stent thrombosis (0.3% vs. 0.5%, p = 0.34), or need for repeat revascularization (3.5% vs. 2.8%, p = 0.20) between the DAPT and aspirin monotherapy arms, respectively. TIMI major bleeding was similar between the two arms (1.4% vs. 1.1%, p = 0.20).
Interpretation:
Although the risks of late stent thrombosis with DES, especially after cessation of DAPT, are well known, the optimal duration of DAPT 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 DAPT for at least 12 months following DES PCI were randomized to continuing DAPT 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.
One major limitation of this trial is that it represents the combination of two separate phases (the second phase was enrolled after presentation of the first phase). Moreover, the first phase included two trials that 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.
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.
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 DAPT in such patients, as well as high-risk patients, such as those with left main stents, also remains unknown.
References:
Lee CW, Ahn JM, Park DW, et al. Optimal duration of dual antiplatelet therapy after drug-eluting stent implantation: a randomized controlled trial. Circulation 2014;129:304-12.
Presented by Dr. Seung-Jung Park at ACC.13, San Francisco, March 10, 2013.
Park SJ, Park DW, Kim YH, et al. Duration of dual antiplatelet therapy after implantation of drug-eluting stents. N Engl J Med 2010;362:1374-82.
Keywords: Ethnic Groups, Myocardial Infarction, Stroke, Follow-Up Studies, Platelet Aggregation Inhibitors, Pyridinolcarbamate, Drug-Eluting Stents, Ticlopidine, Sirolimus, Angioplasty, Purinergic P2Y Receptor Antagonists, Percutaneous Coronary Intervention, Stents, Paclitaxel, Metals, Thrombosis, Diabetes Mellitus
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