Having a higher risk of recurrent ischemic events, patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) with drug-eluting stent (DES) are recommended to receive dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor for 12 months or longer, unless contraindications, such as high bleeding risk, exist.1,2 However, prolonged DAPT led to increased mortality in several studies, rendering the optimal duration of DAPT controversial.3,4 To further investigate this issue, Dr. Hyeon-Cheol Gwon and his colleagues conducted the SMART-DATE trial, revealing that 6-month DAPT was associated with an increased risk for myocardial infarction (MI). The results were presented at the American College of Cardiology (ACC) 2018 Annual Scientific Session and simultaneously published in The Lancet.3
The largest trial to address the optimal duration of DAPT
From time to time, reducing the bleeding risk of DAPT using radial access for PCI and shorter drug duration have been the focus of many vascular interventionalists, and it is thought that perhaps with the newest generation of DES, 6 months of DAPT is enough.4
Indeed, evidence substantiating that 12 months or more is the optimal duration for DAPT was lacking, as pinpointed by Dr. Gwon of Sungkyunkwan University School of Medicine, Seoul, South Korea.5 In fact, two recently reported studies have demonstrated that the shorter 6-month DAPT might offer comparable benefits in the risk reduction for death, heart attack or stroke, bleeding, or other adverse events. Nevertheless, the small number of participants in these two studies limited the power of the evidence.5
SMART-DATE, a South Korea-based, open-label, non-inferiority trial, recruited 2,712 patients with ACS (unstable angina, non-ST-segment elevation myocardial infarction [NSTEMI], or ST-segment elevation myocardial infarction [STEMI]) who underwent PCI. “This is the largest trial to address the optimal duration of DAPT in patients with ACS,” Dr. Gwon mentioned.5
Patients were randomized to the 6-month DAPT (n=1,357) and the 12-month or longer DAPT group (n=1,355). The median age was 62 years, with approximately 75% being male. The three DES (everolimus-eluting, zotarolimus-eluting, and biolimus-eluting stents) were implanted in a third of patients each.
The primary endpoint was a composite of all-cause death, MI, or stroke (major adverse cardiac and cerebrovascular events [MACCE]) within 18 months after stent insertion, while the secondary endpoints looked into each individual component, as well as the definite or probable stent thrombosis and type 2-5 bleeding as defined by the Bleeding Academic Research Consortium (BARC). Also, clopidogrel was mainly used (80% of patients) as the DAPT component among the three P2Y12 inhibitors.3
6-month DAPT led to a higher risk of MI
At 18 months, the cumulative rate of primary composite endpoint was 4.7% for 6-month DAPT group and 4.2% for 12-month or longer DAPT group (HR=1.13; p=0.51; Figure 1), meeting the non-inferiority (pnon-inferiority=0.03, with a predefined non-inferiority margin of 2.0%).3
Although all-cause mortality did not differ significantly between the two groups (2.6% vs. 2.9%; HR=0.90; p=0.90), the risk of MI, including both non-target and target vessel MI, was 2.4-fold higher in patients taking 6-month DAPT (1.8% vs. 0.8%; HR=2.41; p=0.02; Figure 2).3
Dr. Gwon believed that “the increased risk of MI with 6-months’ treatment prevents us from concluding that short-term dual therapy is safe in patients with ACS undergoing PCI with current-generation DES.” Of note, the stent thrombosis (1.1% vs. 0.7%; p=0.32) and the rate of BARC type 2-5 bleeding (2.7% vs. 3.9%; p=0.09) also showed no statistically significant difference between the two groups.
In a post-hoc landmark analysis that studied the event incidence between 6 months and 18 months, the risk of major adverse cardiac and cerebrovascular events seemed to be higher in 6-month DAPT group (HR=1.69; p=0.07; Figure 3). Moreover, the risk of MI was even 5-fold higher in patients taking 6-month DAPT (HR=5.06; p=0.01; Figure 4).3 “Prolonged DAPT might reduce the risk of MI by prevention of non–target vessel MI rather than by reduction of stent thrombosis in patients with ACS,” Dr. Gwon noted.
Longer duration of DAPT is more optimal for ACS patients
Dr. Dipti Itchhaporia from the Hoag Memorial Hospital Presbyterian, California, US, pointed out in the ACC press conference that “this trial reinforces that the ACS patient is different from a patient with stable coronary disease. ACS patients have an increased risk of recurrent events, which is the basis of current guidelines for DAPT for at least 12 months in this population, so we have to stick to the current guidelines of giving DAPT for a minimum of 12 months or potentially longer depending on the clinical criteria.”4
Dr. Itchhaporia also applauded the study, as it “has nicely shown that this is not the case [with the newest generation of DES, 6 months of DAPT is enough], and limiting dual therapy to 6 months is associated with an increased risk of recurrent MI.”4
Dr. Daniel Simon, president and chief academic officer of the University Hospitals, Cleveland, Ohio, US, highlighted the value of SMART-DATE study. “ACS patients are at an increased risk of recurrent cardiovascular events, especially MI. SMART-DATE adds to a growing body of evidence, including the DAPT and PEGASUS trials, that prolonged DAPT reduces spontaneous or non-target lesion MI.”4
Dr. Simon also believed that SMART-DATE trial reiterated the importance of assessing the balance of ischemic and bleeding risk for individual patients, especially those presenting with ACS.4
Meanwhile, Prof. Gregg Stone, the director of cardiovascular research and education at the center for interventional vascular therapy at New York-Presbyterian Hospital/Columbia University Medical Center, US, likewise explained the limitations of the study, in particular the high crossover rate (~20%) from 6-month to 12-month or longer of DAPT.6,7 Dr. Gwon also added that “the absence of blinding —that is, both patients and doctors knew whether a patient was in the DAPT-6 or the DAPT-12 group— and the absence of a group that was randomly assigned to receive a placebo” may impact the results as well.5
In a commentary published together with the main study in The Lancet, Dr. Zuzana Motovska from the University Hospital Kralovske Vinohrady, Srobarova, Czech Republic and Dr. Deepak Bhatt from the Brigham and Women’s Hospital Heart and Vascular Center, Boston, US, concluded that “nevertheless, for the time being, a minimum of 12 months of DAPT after ACS should be considered as the standard of care, while 6 months of DAPT is likely to be reasonable in patients at high baseline bleeding risk or with bleeding while on DAPT.”4,8
1. 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;68:1082–1115.
2. 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.
3. Hahn JY, Song YB, Oh JH, 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 randomised, open-label, non-inferiority trial. Lancet. 2018. [Epub ahead of print].
4. Shortening Dual Antiplatelet Therapy Ups MI Risk in ACS. Medscape. 2018. (Accessed April 2 2018, at https://www.medscape.com/viewarticle/893925).
5. Heart Attack Risk Increases with Six-Month Dual Antiplatelet Therapy. American College of Cardiology. 2018. (Accessed April 2 2018, at http://www.acc.org/about-acc/press-releases/2018/03/10/12/18/mon-1045am-heart-attack-risk-increases-with-six-month-dual-antiplatelet-therapy).
6. SMART-DATE: Shorter DAPT duration noninferior to longer duration, but increases MI risk. Healio. 2018. (Accessed April 2 2018, at https://www.healio.com/cardiac-vascular-intervention/percutaneous-coronary-intervention/news/online/%7Bf95bf1ec-0eb8-4d4e-8848-3d0c53aede70%7D/smart-date-shorter-dapt-duration-noninferior-to-longer-duration-but-increases-mi-risk).
7. Safety of 6-Month Duration of Dual Antiplatelet Therapy After Percutaneous Coronary Intervention in Patients With Acute Coronary Syndromes – SMART-DATE. American College of Cardiology. 2018. (Accessed April 2 2018, at http://www.acc.org/latest-in-cardiology/clinical-trials/2018/03/11/14/21/smart-date).
8. Motovska Z, Bhatt DL. 12 months of DAPT after acute coronary syndrome still beats 6 months. Lancet. 2018. [Epub ahead of print].