SMART-DATE
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Clinical Question
Among patients with acute coronary syndrome undergoing percutaneous coronary intervention (PCI) with drug-eluting stents (DES), how does 6-month duration of dual antiplatelet therapy (DAPT) compare to 12-month or longer duration DAPT in terms of rates of death, myocardial infarction (MI), or stroke?
Bottom Line
6-month duration of DAPT was found non-inferior in the primary composite endpoint of all-cause death, myocardial infarction, or stroke at 18 months following PCI in the studied patient population. However, the 6-month DAPT group resulted in a higher rate of MI, a secondary endpoint, than in the 12-month or longer duration DAPT group.
Major Points
For patients with acute coronary syndrome, the current ACC/AHA and ESC guidelines recommend a P2Y12 inhibitor with aspirin as dual antiplatelet therapy for ≥ 12 months. There is limited and controversial data concerning the optimal DAPT duration in the subset of acute coronary syndrome patients specifically undergoing percutaneous coronary intervention with drug-eluting stents, however.
The SMART-DATE Trial enrolled 2,712 patients with acute coronary syndrome undergoing PCI intervention with DES. The patients were randomized to either 6-month DAPT (n=1357) or 12-month or longer DAPT (n=1355). DAPT consisted of a P2Y12 inhibitor and aspirin for both groups. Six-month duration of DAPT was found non-inferior to 12-month or longer DAPT in the composite outcome of all-cause death, myocardial infarction, or stroke at 18 months post-PCI (4.7% vs. 4.2%); the non-inferiority margin was pre-defined at 2.0%. The 6-month DAPT therapy group was associated with a higher rate of myocardial infarction (1.8% vs 0.8%; p=0.02; NNH=100), however neither all-cause death nor stroke differed significantly among groups. Less patients, though statistically insignificant, experienced BARC type 2-5 bleeding in the 6-month DAPT groups vs the 12-month or longer DAPT group (2.7% vs. 3.9%; HR 0.69; 95% CI 0.45-1.05; p=0.09, NNT = 83).
Given these conflicting outcomes, the optimal duration of DAPT for patients with acute coronary syndrome undergoing PCI with DES remains uncertain. There may be a role for shorter duration of DAPT in patients at high risk of bleeding, but that conclusion cannot be met based on this study. The subgroup analyses are not suggestive of benefit of shorter duration of DAPT in all studied groups as data was found insignificant.
Guidelines
- 2016 ACC/AHA Guideline Focused Update on Duration of DAPT in Patients with CAD
- If ACS is being treated with PCI:
- After DES implantation, DAPT with a P2Y12 inhibitor is recommended for at least 12 months (COR I, LOE B-R)
- Recommend aspirin at a daily dose of 81 mg in patients treated with DAPT (COR I, LOE B-NR)
- If patient is at a high risk of bleeding or develops a high risk of bleeding (started on oral anticoagulant therapy), may consider discontinuation of P2Y12 inhibitor therapy after 6 months (COR IIIb, LOE C-LD)
- 2017 ESC focused update on DAPT in CAD
- If ACS is being treated with PCI:
- DAPT with a P2Y12 inhibitor and aspirin is recommended for 12 months unless there are contraindications such as excessive risk of bleeding (Class I, Level A)
- If patient is at high risk of bleeding, consider discontinuation of P2Y12 inhibitor therapy after 6 months (Class IIa, Level B)
- In patients with ACS who have tolerated DAPT without a bleeding complication, continuation of DAPT for longer than 12 months may be considered (Class IIb, Level A)
Design
- Prospective, randomized, open-label, non-inferiority, multicenter, single-nation trial
- N= 2712
- 6-month DAPT (n= 1357)
- 12-month or longer DAPT (n=1355)
- Setting: 31 centers in South Korea
- Enrollment: 2012-2015
- Follow-up: 1, 6, 12, and 18 months post-PCI intervention
- Analysis: Intention-to-treat and non-inferiority
- Primary outcome: composite major adverse cardiac and cerebrovascular events including all-cause mortality, MI, or stroke at 18 months post-PCI intervention
Population
Inclusion Criteria
- Acute coronary syndrome, including:
- Unstable angina
- Non-ST-segment elevation myocardial infarction (NSTEMI)
- ST-elevation myocardial infarction (STEMI)
- ≥ 1 lesion in a native coronary vessel
- Reference diameter of 2.25-4.25 mm
- Stenosis ≥ 50%, amenable by PCI intervention with stents
Exclusion Criteria
- Known hypersensitivity or contraindication to aspirin, clopidogrel, heparin, biolimus, everolimus, zotarolimus, or contrast media
- Active pathological bleeding
- Major bleeding within the previous 3 months
- Major surgery within the previous 2 months
- History of bleeding diathesis or known coagulopathy
- Life expectancy < 2 years
- Elective surgical procedure planned within < 12 months
- Active participation in another investigational study
Baseline Characteristics
Derived from the 6-month DAPT group, which was similar to the 12-month or longer DAPT group. Mean (SD) or median (IQR).
- Demographics
- Age (mean): 62.0 years (IQR 11.5)
- Male: 74.9%
- BMI (mean): 24.3 kg/m2 (3.2)
- Current smokers: 38.0%
- Past Medical History
- Diabetes: 26.9%
- Hypertension: 49.9%
- Dyslipidemia: 24.2%
- Previous myocardial infarction: 2.3%
- Previous revascularization: 4.9%
- Cerebrovascular disease: 3.9%
- Chronic renal failure: 1.0%
- Mean left ventricular ejection fraction: 55.5% (11.0%)
- Clinical presentation
- ST-elevation myocardial infarction: 37.5%
- Non-ST-elevation myocardial infarction: 31.5%
- Unstable angina: 31.0%
Interventions
- Random (1:1) to either 6 month DAPT group or at least 12 months DAPT group
- Computer-generated block randomization
- Stratification by:
- Enrollment site
- Clinical presentation- unstable angina, NSTEMI, or STEMI
- Diabetes
- Type of P2Y12 inhibitor
- Patients also randomly assigned (1:1:1) to a stent type
- Zotarolimus-eluting stent
- Everolimus-eluting stent
- Biolimus A9-eluting stent
- Both groups received conventional therapy consisting of:
- Pre-PCI: aspirin 300 mg/day PO and clopidogrel 300 mg or 600 mg PO loading dose at least 12 hours before procedure or as early as possible
- During PCI: UFH or LMWH as anticoagulation
- Post-PCI: aspirin 100 mg/day PO indefinitely and clopidogrel 75 mg/day PO, duration according to randomization (6 months vs 12 months or longer)
- After December 2014 (once prasugrel and ticagrelor became available), patients may have received prasugrel 60 mg PO daily followed by 10 mg PO daily or ticagrelor 180 mg PO daily followed by 90 mg twice daily instead of clopidogrel
- All patients recommended to follow standard ACC/AHA and ESC guidelines for post-procedure pharmacological therapy, if indicated, including statins, beta blockers, or renin-angiotensin system blockers
Outcomes
Comparisons are intensive therapy vs. standard therapy.
Primary Outcomes
- Composite of all-cause death, myocardial infarction, or stroke at 18 months
- 4.7% vs. 4.2% (HR 1.13; 95% CI 0.79-1.62; p=0.51; ARI: 0.5%; NNH= 200)
Secondary Outcomes
- All-cause death
- 2.6% vs. 2.9% (HR 0.90; 95% CI 0.57-1.42; p=0.90; NNT= 333.3)
- MI
- 1.8% vs. 0.8% (HR 2.41; 95% CI 1.15-5.05; p=0.02; NNH=100)
- Stroke
- 0.8% vs. 0.9% (HR 0.92; 95% CI 0.41-2.08; p=0.84; NNT=1000)
- Cardiac death
- 1.4% vs. 1.8% (HR 0.75; 95% CI 0.41-1.38; p=0.36; NNT=250)
- Cardiac death or MI
- 2.9% vs. 2.4% (HR 1.22; 95% CI 0.77-1.95; p=0.40; NNH=200)
- Stent thrombosis
- 1.1% vs. 0.7% (HR 1.50; 95% CI 0.68-3.35; p=0.32; NNH=250)
- Bleeding Academic Research Consortium (BARC) type 2-5 bleeding
- 2.7% vs. 3.9% (HR 0.59; 95% CI 0.45-1.05; p=0.09; NNT=83.3)
Subgroup Analysis
Full subgroup analyses are presented in the supplementary appendix. Only subgroups with a P-value for interaction <0.05 are presented here.
- Myocardial Infarction
- Acute Myocardial Infarction (p=0.025)
- Acute MI: 2.3% vs. 0.5% (HR 4.27; 95% CI 1.61-11.32; NNH=55.6)
- Non-acute MI: 0.7% vs 1.2% (HR 1.32; 95% CI 0.14-2.46)
- Major adverse cardiac and cerebrovascular events
- Left main (LM) or left anterior descending (LAD) treated (p=0.014)
- LM or LAD treated: 4.4% vs 5.3% (HR 0.82; 95% CI 0.52-1.28)
- LM or LAD not treated: 5.2% vs 2.3% (HR 2.26; 95% CI 1.15-4.43)
Adverse Events
- Major adverse cardiac and cerebrovascular events
- 4.7% vs 4.2% (HR 1.13; 95% CI 0.79-1.62; P=0.51; NNH=200)
- Major bleeding
- 0.5% vs 0.8% (HR 0.97; 95% CI 0.22-1.65; P=0.33; NNT=333.3)
Criticisms
- Study was open label
- Study chose a wide non-inferiority margin
- Adherence to the study protocol was much lower in the 6-month DAPT group (73.7% vs. 95.7%)
- Patient nationalities not reported, potentially lacking external validation
- The study did not report adherence to the discharge medications, possibly affecting internal validity
- The patients were not randomized to type of P2Y12 inhibitor they received; a majority (81%) of patients received clopidogrel
Funding
This trial was funded by Abbott Vascular Korea, Medtronic Vascular Korea, Biosensors Inc, and Dong-A ST. Medtronic Vascular and Biosensors Inc are manufacturers of two of the types of stents patients were randomized to. The authors disclosed that the sponsors of this trial had no role in study design, data collection, site monitoring, data analysis, data interpretation, or writing of the report.
Further Reading
Hahn JY, Song YB, Oh JH, Cho DK, et al. 6-month versus 12-month or longer dual antiplatelet therapy after percutaneous coronary intervention in patients with acute coronary syndrome (SMART-DATE): a randomized, open-label, non-inferiority trial. Lancet 2018; 391: 1274-1284.
Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2016; 68: 1082–115.
Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the task force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2018; 39: 213–60.