Abstract
Background:
The benefits and risks of prolonged dual antiplatelet therapy (DAPT) have not been studied extensively across a broad spectrum of acute coronary syndromes. In this study we investigated whether treatment effects of prolonged DAPT were consistent in patients presenting with ST-segment elevation myocardial infarction (STEMI) vs. non-STEMI (NSTEMI).
Methods and Results:
As a post hoc analysis of the SMART-DATE trial, effects of ≥12 vs. 6 months DAPT were compared among 1,023 patients presenting with STEMI and 853 NSTEMI patients. The primary outcome was a composite of recurrent myocardial infarction (MI) or stent thrombosis at 18 months after the index procedure. Compared with the 6-month DAPT group, the rate of the composite endpoint was significantly lower in the ≥12-month DAPT group (1.2% vs. 3.8%; hazard ratio [HR] 0.31, 95% confidence interval [CI] 0.12–0.77; P=0.012). The treatment effect of ≥12- vs. 6-month DAPT on the composite endpoint was consistent among NSTEMI patients (0.2% vs. 1.2%, respectively; HR 0.20, 95% CI 0.02–1.70; P=0.140; Pinteraction=0.718). In addition, ≥12-month DAPT increased Bleeding Academic Research Consortium (BARC) Type 2–5 bleeding among both STEMI (4.4% vs. 2.0%; HR 2.18, 95% CI 1.03–4.60; P=0.041) and NSTEMI (5.1% vs. 2.2%; HR 2.37, 95% CI 1.08–5.17; P=0.031; Pinteraction=0.885) patients.
Conclusions:
Compared with 6-month DAPT, ≥12-month DAPT reduced recurrent MI or stent thrombosis regardless of the type of MI at presentation.
Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12
receptor antagonist is the cornerstone of treatment in patients with acute coronary syndrome (ACS).1
In the Smart Angioplasty Research Team: Safety of 6-month duration of Dual Antiplatelet Therapy after Percutaneous Coronary Intervention in Patients with Acute Coronary Syndromes (SMART-DATE) trial (Clinicaltrials.gov ID: NCT01701453), ≥12-month DAPT, compared with 6-month DAPT, significantly reduced recurrent myocardial infarction (MI) after percutaneous coronary intervention (PCI) with drug-eluting stents in patients with ACS.2
However, given the different prognoses across the broad spectrum of ACS,3,4
it is clinical importance that the treatment effect of prolonged DAPT be assessed according to initial presentation. To date, there are limited data on the benefits and risks of prolonged DAPT according to the type of MI at initial presentation. Therefore, in the present study we sought to investigate whether treatment effects of prolonged DAPT would be consistent in patients presenting with ST-segment elevation MI (STEMI) vs. non-STEMI (NSTEMI) after PCI with current-generation drug-eluting stents.
Methods
Study Design
The design and main findings of the SMART-DATE trial have been reported elsewhere.2,5
Briefly, the SMART-DATE trial was a multicenter, prospective, open-label, non-inferiority randomized study testing the non-inferiority of 6- vs.≥12-month DAPT following PCI with current-generation drug-eluting stents for ACS. The SMART-DATE trial was approved by the Institutional Review Board (IRB) of Samsung Medical Center, as well as IRBs at each participating center. The study was designed by the SMART-DATE Trial Steering Committee and coordinated by the Academic Clinical Research Organization of Samsung Medical Center.
The aim of the present study was to examine whether the ischemic benefits and bleeding risks associated with ≥12- vs. 6-month DAPT are consistent according to type of MI at initial presentation. These analyses were not prespecified in the original trial protocol.
Study Population and Procedures
Patients who had ACS and at least 1 lesion in a native coronary vessel with a reference diameter of 2.25–4.25 mm and stenosis >50% by visual estimation that was amenable to PCI with current-generation drug-eluting stents were eligible for inclusion criteria in the SMART-DATE trial. Major exclusion criteria were: (1) a known hypersensitivity or contraindication to aspirin, clopidogrel, heparin, biolimus, everolimus, zotarolimus, or contrast media; (2) active pathological bleeding, major bleeding within the previous 3 months, or major surgery within the previous 2 months; (3) a history of bleeding diathesis or known coagulopathy; (4) life expectancy <2 years; (5) an elective surgical procedure planned within <12 months; and (6) active participation in another drug or device investigational study. All patients provided written informed consent to participate.
Patients were randomly assigned to either to the 6- or ≥12-month DAPT group at the time of the index procedure in a ratio of 1 : 1. Randomization was stratified by the site of enrollment, diabetes, the type of P2Y12
inhibitor (clopidogrel, prasugrel, or ticagrelor), and clinical presentation (unstable angina, NSTEMI, or STEMI). STEMI was defined as the presence of an ST-segment elevation >0.1 mV in 2 or more contiguous electrocardiogram leads or new left bundle branch block with elevated biomarkers of myocardial necrosis (myocardial band fraction of creatine kinase or troponin T or I greater than the upper limit of normal). NSTEMI was defined as the presence of elevated biomarkers of myocardial necrosis with 1 of the following: (1) transient ST-segment elevation or depression, or T-wave changes consistent with myocardial ischemia; or (2) identification of a culprit lesion at coronary angiography. Patients were randomly assigned to receive either an zotarolimus-eluting stent (Resolute Integrity; Medtronic Vascular, Santa Rosa, CA, USA), an everolimus-eluting stent (XIENCE Prime; Abbott Vascular, Santa Clara, CA, USA), or a biolimus A9-eluting stent (BioMatrix Flex; Biosensors Inc., Newport Beach, CA, USA) in a ratio of 1 : 1 : 1. PCI was performed according to standard techniques. After the procedure, all patients received aspirin (100 mg daily indefinitely) and a P2Y12
inhibitor (clopidogrel 75 mg daily, prasugrel 10 mg daily, or ticagrelor 90 mg twice daily), which was maintained according to the randomization scheme (6 vs. ≤12 months). Prasugrel and ticagrelor became available in South Korea during the study. Clinical follow-up was performed at 1, 6, 12, and 18 months after the index PCI. An independent clinical event adjudication committee, whose members were unaware of study group assignments, assessed all clinical events.
Study Outcomes
The primary endpoint of the present analysis was a composite of recurrent MI or definite or probable stent thrombosis at 18 months after the index procedure. Secondary endpoints included major adverse cardiac and cerebrovascular events (MACCE; a composite of death, recurrent MI, or stroke), the individual components of MACCE, cardiac death, cardiac death or MI, definite or probable stent thrombosis defined by the Academic Research Consortium (ARC),6
Bleeding Academic Research Consortium (BARC) Type 2–5 bleeding, major bleeding (BARC Type 3–5 bleeding),7
and net adverse clinical events (NACE; a composite of MACCE plus BARC Type 2–5 bleeding).
All deaths were considered cardiac unless a definite non-cardiac cause could be established. Recurrent MI was defined as elevated cardiac enzymes (cardiac troponin or myocardial band fraction of creatine kinase) above the upper reference limit with ischemic symptoms or electrocardiography findings indicative of ischemia that was not related to the index procedure.6
Procedure-related MIs were not considered a clinical outcome. Stroke was defined as any non-convulsive focal or global neurological deficit of abrupt onset lasting for more than 24 h or leading to death, which was caused by ischemia or hemorrhage within the brain. Stent thrombosis was defined as definite or probable stent thrombosis according to the ARC classification.6
Major bleeding was defined as BARC Type 3–5 bleeding.7
Statistical Analysis
In this post hoc analysis of the SMART-DATE trial based on initial type of MI, categorical variables are presented as counts and percentages and were compared using the Chi-squared test or Fisher’s exact test, as appropriate. Continuous variables are presented as the mean±SD and were compared using Student’s t-test. Cumulative event rates were estimated with the Kaplan-Meier method and compared using log-rank tests. Time from randomization to the occurrence of the first event was used in the survival analysis. For the study endpoints, patients who were lost to follow-up were censored at the time of the last known contact. For analyses of the primary and secondary endpoints, hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using the Cox proportional hazards method. An interaction between the 2 the DAPT regimens and type of MI at initial presentation was estimated by Cox regression analysis. The analysis was further adjusted for clinical variables and medications that showed differences with P<0.1 between STEMI and NSTEMI patients (age, diabetes, hypertension, dyslipidemia, current smoking, left ventricular ejection fraction [LVEF], type of P2Y12
inhibitor, and glycoprotein IIb/IIIa inhibitors). As a sensitivity analysis, landmark analysis at 6 months from the index MI was conducted. All analyses were conducted according to an intention-to-treat principle. Two-sided P<0.05 was considered significant. All analyses were performed using SAS version 9.2 (SAS Institute, Cary, NC, USA) and R version 3.4.3 (R Foundation for Statistical Computing).
Results
Study Population
Of 1,876 patients with MI who were enrolled in the SMART-DATE trial, 1,023 (54.5%) presented with STEMI and 853 (45.5%) presented with NSTEMI at the index procedure (Figure 1). Patients with STEMI were younger and had lower rates of cardiovascular comorbidities and lower LVEF compared with NSTEMI patients (Supplementary Table 1). The rate of ticagrelor or prasugrel use was higher among STEMI than NSTEMI patients (26.3% vs. 19.3%; P<0.001). Patients with STEMI had higher rates of thrombotic lesions, the use of glycoprotein IIb/IIIa inhibitors, and the left main or left anterior descending artery as a treated lesion, but lower rates of multivessel disease and calcified and bifurcation lesions compared with NSTEMI patients.
Baseline clinical, lesion, and procedural characteristics were well balanced between randomized arms among patients with STEMI and NSTEMI (Table 1). The rate of ticagrelor or prasugrel use was not significantly different between the ≥12- and 6-month DAPT groups regardless of type of MI.
Table 1.
Baseline Clinical Characteristics of Patients Receiving DAPT for ≥12 or 6 Months According to the Type of MI
| |
STEMI (n=1,023) |
NSTEMI (n=853) |
≥12-month
DAPT (n=514) |
6-month
DAPT (n=509) |
P value |
≥12-month D
APT (n=425) |
6-month
DAPT (n=428) |
P value |
| Clinical characteristics |
| Age (years) |
60.4±12.8 |
60.6±11.8 |
0.864 |
62.6±11.5 |
62.0±11.8 |
0.471 |
| Male sex |
402 (78.2) |
405 (79.6) |
0.595 |
331 (77.9) |
318 (74.3) |
0.221 |
| BMI (kg/m2) |
24.4±3.1 |
24.1±3.4 |
0.173 |
24.2±3.1 |
24.2±3.1 |
0.828 |
| Diabetes |
125 (24.3) |
120 (23.6) |
0.781 |
123 (28.9) |
111 (25.9) |
0.326 |
| Hypertension |
223 (43.9) |
217 (43.3) |
0.852 |
200 (47.6) |
217 (51.1) |
0.318 |
| Dyslipidemia |
111 (21.9) |
90 (18.1) |
0.139 |
102 (24.7) |
117 (27.7) |
0.321 |
| Current smoker |
245 (48.4) |
234 (47.2) |
0.694 |
167 (40.1) |
161 (37.9) |
0.502 |
| Previous MI |
11 (2.2) |
12 (2.4) |
0.803 |
4 (1.0) |
12 (2.8) |
0.083 |
| Previous revascularization |
17 (3.4) |
17 (3.4) |
0.929 |
12 (2.9) |
24 (5.7) |
0.068 |
| Cerebrovascular disease |
13 (2.6) |
17 (3.4) |
0.429 |
20 (4.8) |
16 (3.8) |
0.464 |
| Chronic renal failure |
1 (0.2) |
2 (0.4) |
0.556 |
2 (0.5) |
1 (0.2) |
0.554 |
| LVEF (%) |
51.0±10.0 |
51.2±10.6 |
0.756 |
55.4±10.1 |
55.1±10.6 |
0.766 |
| P2Y12 inhibitor at randomization |
|
|
0.075 |
|
|
0.552 |
| Clopidogrel |
388 (75.5) |
366 (71.9) |
|
349 (82.1) |
339 (79.2) |
|
| Ticagrelor |
91 (17.7) |
117 (23.0) |
|
52 (12.2) |
62 (14.5) |
|
| Prasugrel |
35 (6.8) |
26 (5.1) |
|
24 (5.6) |
27 (6.3) |
|
| Lesion characteristics |
| Transradial approach |
181 (35.2) |
183 (36.0) |
0.787 |
226 (53.3) |
227 (53.3) |
0.996 |
| Multiple vessels disease |
219 (42.6) |
203 (39.9) |
0.377 |
212 (49.9) |
211 (49.4) |
0.891 |
| Location of lesion treated |
| LM or LAD |
317 (61.7) |
302 (59.3) |
0.444 |
238 (56.0) |
216 (50.6) |
0.114 |
| LCX |
71 (13.8) |
73 (14.3) |
0.808 |
165 (38.8) |
160 (37.5) |
0.685 |
| RCA |
214 (41.6) |
200 (39.3) |
0.446 |
137 (32.2) |
157 (36.8) |
0.165 |
| Calcified lesion |
55 (10.7) |
41 (8.1) |
0.145 |
72 (17.0) |
60 (14.1) |
0.244 |
| Bifurcated lesion |
31 (6.0) |
31 (6.1) |
0.975 |
48 (11.3) |
42 (9.9) |
0.489 |
| Thrombotic lesion |
220 (42.9) |
213 (41.8) |
0.737 |
84 (19.8) |
88 (20.7) |
0.759 |
| Glycoprotein IIb/IIIa inhibitors |
61 (11.9) |
42 (8.3) |
0.060 |
16 (3.8) |
16 (3.8) |
0.989 |
| Use of intravascular ultrasound |
101 (19.6) |
98 (19.3) |
0.873 |
105 (24.8) |
92 (21.6) |
0.266 |
| Multilesion intervention |
109 (21.2) |
96 (18.9) |
0.349 |
135 (31.8) |
126 (29.5) |
0.475 |
| Multivessel intervention |
77 (15.0) |
70 (13.8) |
0.576 |
108 (25.4) |
105 (24.6) |
0.782 |
| No. stents per patient |
1.3±0.6 |
1.4±0.7 |
0.192 |
1.5±0.8 |
1.5±0.8 |
0.198 |
| No. lesions treated per patient |
1.2±0.5 |
1.3±0.6 |
0.228 |
1.4±0.6 |
1.4±0.6 |
0.398 |
| Type of drug-eluting stent |
|
|
0.849 |
|
|
0.397 |
| No stent |
5 (1.0) |
3 (0.6) |
|
1 (0.2) |
4 (0.9) |
|
| Everolimus-eluting stents |
178 (35.0) |
175 (34.0) |
|
140 (32.9) |
161 (37.6) |
|
| Zotarolimus-eluting stents |
171 (33.6) |
171 (33.3) |
|
147 (34.6) |
137 (32.0) |
|
| Biolimus-eluting stents |
153 (30.1) |
161 (31.3) |
|
135 (31.8) |
124 (29.0) |
|
| Other stents |
2 (0.4) |
4 (0.8) |
|
2 (0.5) |
2 (0.5) |
|
Unless indicated otherwise, data are given as n (%) or the mean±SD. BMI, body mass index; DAPT, dual antiplatelet therapy; LAD, left anterior descending; LCX, left circumflex; LM, left main; LVEF, left ventricle ejection fraction; MI, myocardial infarction; NSTEMI, non-ST-segment elevation myocardial infarction; RCA, right coronary artery; STEMI, ST-segment elevation myocardial infarction.
Adherence to study protocol did not different according to type of MI (in the 6-month DAPT group, 71.5% and 75.9% among STEMI and NSTEMI patients, respectively [P=0.14]; in the ≥12-month DAPT group, 96.1% and 95.5% among STEMI and NSTEMI patients, respectively [P=0.780]).
Outcomes in STEMI vs. NSTEMI Patients
The rate of recurrent MI or stent thrombosis was significantly higher among patients with STEMI than NSTEMI (2.5% vs. 0.7%; adjusted [a] HR 2.59, 95% CI 1.01–6.63, P=0.048;
Supplementary Table 2). Cardiac death was more frequent in patients with STEMI than NSTEMI (2.6% vs. 1.0%; aHR 2.53, 95% CI 1.01–6.33, P=0.048). There was no significant difference between STEMI and NSTEMI patients in the rate of BARC Type 2–5 bleeding (3.2% vs. 3.7%; aHR 0.93, 95% CI 0.54–1.60, P=0.795) or NACE (8.7% vs. 6.3%; aHR 1.29, 95% CI 0.89–1.87, P=0.183).
Treatment Effect of Prolonged DAPT in STEMI vs. NSTEMI Patients
At 18 months after the index procedure, recurrent MI or stent thrombosis was significantly lower in the ≥12- than 6-month DAPT group for patients initially presenting with STEMI (1.2% vs. 3.8%; HR 0.31, 95% CI 0.12–0.77, P=0.012;
Table 2; Figure 2). The treatment effect of ≥12-month DAPT for recurrent MI or stent thrombosis was similar among patients with NSTEMI (0.2% vs. 1.2%; HR 0.20, 95% CI 0.02–1.70, P=0.140; Pinteraction=0.718;
Tables 2,3). The risk of BARC Type 2–5 bleeding was significantly higher with ≥12- than 6-month DAPT among patients with STEMI (4.4% vs. 2.0%; HR 2.18, 95% CI 1.03–4.60, P=0.041) and NSTEMI (5.1% vs. 2.2%; HR 2.37, 95% CI 1.08–5.17, P=0.031; Pinteraction=0.885;
Figure 3). However, the rates of major bleeding and NACE (Figure 4) did not differ significantly between the 2 DAPT regimens in either the STEMI or NSTEMI groups.
Table 2.
Clinical Outcomes at 18 Months in Patients Receiving ≥12- or 6-Month DAPT According to Type of MI
| |
≥12-month
DAPT |
6-month
DAPT |
HR (95% CI) |
P value |
| STEMI |
| No. patients |
514 |
509 |
|
|
| MI or stent thrombosis |
6 (1.2) |
19 (3.8) |
0.31 (0.12–0.77) |
0.012 |
| MACCE |
25 (4.9) |
34 (6.8) |
0.72 (0.43–1.20) |
0.205 |
| Death |
20 (3.9) |
16 (3.2) |
1.23 (0.64–2.37) |
0.537 |
| MI |
4 (0.8) |
16 (3.2) |
0.24 (0.08–0.73) |
0.012 |
| Target vessel MI |
3 (0.6) |
11 (2.2) |
0.27 (0.07–0.96) |
0.042 |
| Non-target vessel MI |
1 (0.2) |
5 (1.0) |
0.20 (0.02–1.68) |
0.137 |
| Cerebrovascular accident (stroke) |
4 (0.8) |
4 (0.8) |
0.99 (0.25–3.95) |
0.987 |
| Cardiac death |
15 (2.9) |
11 (2.2) |
1.34 (0.62–2.93) |
0.456 |
| Cardiac death or MI |
17 (3.3) |
25 (5.0) |
0.66 (0.36–1.23) |
0.192 |
| Stent thrombosis |
6 (1.2) |
13 (2.6) |
0.45 (0.17–1.19) |
0.108 |
| Early (≤30 days) |
5 (1.0) |
8 (1.6) |
0.62 (0.20–1.88) |
0.396 |
| Late (30–365 days) |
1 (0.2) |
3 (0.6) |
0.32 (0.03–3.10) |
0.327 |
| Very late (>365 days) |
0 (0.0) |
2 (0.4) |
NA |
0.2A |
| BARC Type 2–5 bleeding |
22 (4.4) |
10 (2.0) |
2.18 (1.03–4.60) |
0.041 |
| Major bleeding |
3 (0.6) |
1 (0.2) |
2.95 (0.31–28.39) |
0.348 |
| Net adverse clinical events |
44 (8.6) |
44 (8.8) |
0.98 (0.65–1.49) |
0.930 |
| NSTEMI |
| No. patients |
425 |
428 |
|
|
| MI or stent thrombosis |
1 (0.2) |
5 (1.2) |
0.20 (0.02–1.70) |
0.140 |
| MACCE |
14 (3.3) |
14 (3.3) |
1.00 (0.48–2.10) |
>0.999 |
| Death |
9 (2.1) |
10 (2.4) |
0.90 (0.37–2.23) |
0.828 |
| MI |
1 (0.2) |
5 (1.2) |
0.20 (0.02–1.70) |
0.140 |
| Target vessel MI |
1 (0.2) |
2 (0.5) |
0.50 (0.05–5.50) |
0.570 |
| Non-target vessel MI |
0 (0.0) |
3 (0.7) |
NA |
0.08A |
| Cerebrovascular accident (stroke) |
4 (1.0) |
0 (0.0) |
NA |
0.05A |
| Cardiac death |
3 (0.7) |
5 (1.2) |
0.60 (0.14–2.52) |
0.486 |
| Cardiac death or MI |
4 (1.0) |
9 (2.2) |
0.44 (0.14–1.44) |
0.175 |
| Stent thrombosis |
1 (0.2) |
1 (0.2) |
0.99 (0.06–15.83) |
0.994 |
| Early (≤30 days) |
0 (0.0) |
0 (0.0) |
NA |
NA |
| Late (30–365 days) |
1 (0.2) |
0 (0.0) |
NA |
0.3A |
| Very late (>365 days) |
0 (0.0) |
1 (0.2) |
NA |
0.3A |
| BARC Type 2–5 bleeding |
21 (5.1) |
9 (2.2) |
2.37 (1.08–5.17) |
0.031 |
| Major bleeding |
5 (1.3) |
1 (0.2) |
4.97 (0.58–42.55) |
0.143 |
| Net adverse clinical events |
31 (7.4) |
22 (5.2) |
1.43 (0.82–2.46) |
0.204 |
Unless indicated otherwise, data are given as n (%), with the percentages of event rates being Kaplan-Meier estimates. Hazard ratios (HRs) are presented with 95% confidence intervals (CIs). Major adverse cardiac and cerebrovascular events (MACCE) were defined as a composite of all-cause mortality, MI, and stroke. Net adverse clinical events are all ischemic and bleeding events. AP values derived from log-rank tests. BARC, Bleeding Academic Research Consortium; NA, not applicable. Other abbreviations as in Table 1.
Table 3.
Interaction Between MI at Initial Presentation (STEMI vs. NSTEMI) and the Duration of DAPT (≥12 vs. 6 Months) for Clinical Outcomes
| Outcomes |
Interaction P value
(intention-to-treat) |
Interaction P value
(per-protocol) |
| Unadjusted |
Multivariable CoxA |
Unadjusted |
Multivariable CoxA |
| MI or stent thrombosis |
0.718 |
0.668 |
0.898 |
0.781 |
| MACCE |
0.467 |
0.501 |
0.565 |
0.736 |
| Death |
0.586 |
0.446 |
0.532 |
0.342 |
| MI |
0.873 |
0.874 |
0.999 |
0.954 |
| Target vessel MI |
0.649 |
0.620 |
0.790 |
0.849 |
| Non-target vessel MI |
0.998 |
0.999 |
0.999 |
0.999 |
| Cerebrovascular accident (stroke) |
0.997 |
0.998 |
0.998 |
>0.999 |
| Cardiac death |
0.335 |
0.212 |
0.536 |
0.294 |
| Cardiac death or MI |
0.557 |
0.478 |
0.846 |
0.698 |
| Stent thrombosis |
0.595 |
0.653 |
0.645 |
0.770 |
| BARC Type 2–5 bleeding |
0.885 |
0.978 |
0.474 |
0.432 |
| Major bleeding |
0.742 |
0.853 |
0.998 |
0.999 |
| Net adverse clinical events |
0.290 |
0.438 |
0.267 |
0.439 |
MACCE were defined as a composite of all-cause mortality, MI, and stroke. Net adverse clinical events are all ischemic and bleeding events. AAdjusted for clinical variables and medications that showed differences with P<0.1 between STEMI and NSTEMI patients (age, diabetes, hypertension, dyslipidemia, current smoking, LVEF, type of P2Y12 inhibitor, and glycoprotein IIb/IIIa inhibitors). Abbreviations as in Tables 1,2.
Results from the per-protocol analysis and 6-month landmark analysis were similar to those from the intention-to-treat analysis (Table 3; Supplementary Tables 3–5). There were no significant interactions between the 2 DAPT regimens and presentation of MI at the time of the index procedure.
Discussion
In the present analysis from the SMART-DATE trial, patients initially presenting with STEMI had a higher rate of recurrent MI or stent thrombosis than those presenting with NSTEMI. The rate of recurrent MI or stent thrombosis was significantly lower with ≥12- than 6-month DAPT among patients with STEMI, and the treatment effect of ≥12-month DAPT for recurrent MI or stent thrombosis was consistent among patients with NSTEMI. Compared with 6-month DAPT, the rate of BARC Type 2–5 bleeding was significantly higher with ≥12-month DAPT in both STEMI and NSTEMI patients, but the rates of major bleeding and NACE were not. There were no significant interactions for clinical outcomes between the 2 DAPT regimens and the initial MI presentation.
Current major guidelines universally recommend prolonged DAPT for at least 12 months in patients with STEMI and non-ST-segment elevation (NSTE) ACS.8,9
However, data are limited regarding the optimal or minimum duration of DAPT according to clinical presentation. Although there are conflicting results, previous studies reported that patients with STEMI had a higher risk of adverse events than those with NSTEMI.3,10–12
Therefore, the optimal or minimum duration of DAPT may differ according to the presence of ST-segment elevation in patients with MI undergoing PCI. The SMART-DATE trial investigated whether a reduced 6-month duration of DAPT is non-inferior to conventional ≥12-month DAPT at 18 months after implantation of current-generation drug-eluting stents in patients with ACS.2
Because both STEMI and NSTEMI patients were included in the SMART-DATE trial, the present post hoc analysis was performed according to type of MI. To the best of our knowledge, this analysis is the first to systematically compare a short vs. prolonged duration of DAPT according to the presence of ST-segment elevation in patients with MI.
In the present analysis, the difference in recurrent MI or stent thrombosis between the ≥12- and 6-month DAPT groups was statistically significant only for patients with STEMI. This finding may be explained by the higher incidence of ischemic events in patients with STEMI than NSTEMI. However, a numerical decrease in recurrent MI or stent thrombosis with ≥12-month DAPT was also found among patients with NSTEMI, and there was no interaction for recurrent MI or stent thrombosis between the duration of DAPT and type of MI at initial presentation. Therefore, our interpretation for this study is that the treatment effect of ≥12-month DAPT for recurrent MI or stent thrombosis is consistent among patients with NSTEMI. Two decades ago, the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial demonstrated that clopidogrel on top of aspirin decreased recurrent ischemic events compared with aspirin alone in patients with NSTE-ACS.1
Despite advances in devices and techniques for PCI and medical treatment other than antiplatelet therapy, the results of the present study show that prolonged DAPT is beneficial in reducing the rate of recurrent ischemic events in contemporary practice among both STEMI and NSTEMI patients. It has been reported that the risk of stent thrombosis is higher in patients with ACS than in those with stable ischemic heart disease.13
Moreover, an intravascular ultrasound imaging study showed that multiple plaque ruptures and culprit lesion plaque rupture were more common in patients with MI than in those with stable ischemic heart disease,14
supporting our findings of a benefit of prolonged DAPT for the prevention of recurrent MI or stent thrombosis. Interestingly, the risk of recurrent ischemic events was significantly higher in patients with STEMI than NSTEMI, and the rate of bleeding was similar between the 2 types of MI. Compared with 6-month DAPT, BARC Type 2–5 bleeding was significantly and consistently increased with ≥12-month DAPT among STEMI and NSTEMI patients. Although not statistically significant, most of the major bleeding occurred with ≥12-month DAPT regardless of the type of MI. Therefore, decisions regarding the duration of DAPT after MI should be individualized based on ischemic and bleeding risks (e.g., Predicting Bleeding Complication in Patients Undergoing Stent Implantation and Subsequent Dual Antiplatelet Therapy (PRECISE-DAPT) score15).
In the Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin – Thrombolysis in Myocardial Infarction 54 (PEGASUS-TIMI 54) trial, treatment with ticagrelor significantly reduced the risk of cardiovascular death, MI, or stroke in patients with spontaneous MI occurring 1–3 years prior.16
Therefore, the present study provides important evidence to justify long-term use of DAPT in the subset of patients at high ischemic risk, such as those with prior MI. Conversely, the results of the present study are not in accordance with the Randomized Open Label Trial of 6 Months Versus 12 Months DAPT After Drug-Eluting Stent in STEMI (DAPT-STEMI), in which 6-month DAPT was non-inferior to 12-month DAPT for a composite of death, MI, any revascularization, stroke, or bleeding in 870 patients with STEMI.17
In addition, the risk of recurrent MI was similar between the 6- and 12-month DAPT groups in DAPT-STEMI. Differences in the timing of randomization, DAPT regimens, and risk profiles of the enrolled patients may explain the apparent discrepancies between the SMART-DATE trial and DAPT-STEMI. Recent large trials, including the Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention (TWILIGHT),18
Comparison Between P2Y12 Antagonist Monotherapy and Dual Antiplatelet Therapy After DES (SMART-CHOICE),19
and the ShorT and OPtimal Duration of Dual AntiPlatelet Therapy-2 Study (STOPDAPT-2),20
reported that shorter DAPT was non-inferior to longer DAPT for ischemic events with lower bleeding risks. However, there are significant differences between those studies and the SMART-DATE trial. Above all, in the TWILIGHT, SMART-CHOICE, and STOPDAPT-2 trials, the single antiplatelet therapy after DAPT in the experimental arm (shorter DAPT group) consisted of a P2Y12
inhibitor, compared with aspirin in the SMART-DATE trial. Moreover, a broad range of patients, including low-risk patients, were enrolled in the former 3 trials, whereas patients with ACS were exclusively enrolled in the SMART-DATE trial. As a result, the rates of all-cause death, cardiac death, and stent thrombosis were all numerically higher in the SMART-DATE trial than in the other 3 trials, although a comparison of MI is difficult because of the different definitions used in each trial. Thus, different antiplatelet regimens and study populations may explain the inconsistent findings across these studies.
Study Limitations
The present study has several limitations. First, the results of this study should be interpreted cautiously and only considered as hypothesis generating because these analyses were not prespecified and specifically powered to assess interactions. Although there was no significant interaction between the 2 DAPT regimens and the type of MI, statistical significance of different outcome between ≥12- and 6-month DAPT was not reached in patients with NSTEMI. This could be explained by the relatively lower incidence of clinical events in patients with NSTEMI than STEMI. Second, the SMART-DATE trial included only ACS patients undergoing PCI using current-generation drug-eluting stents. Therefore, the findings of this study may not apply to patients who undergo bypass surgery and receive medical treatment. Third, randomization was done at the time of the index procedure, not 6 months after the index procedure. Although randomization at 6 months after the index procedure when treatment in each group actually differs may be desirable, randomization at 6 months could have resulted in selection bias because of the selective enrollment patients with low-risk profiles in whom 6-month DAPT seemed adequate. Nevertheless, the 6-month landmark analysis showed consistent results in the present study. Fourth, unblinded treatment may have affected the clinical course despite well-balanced baseline characteristics between the ≥12- and 6-month DAPT groups, because the SMART-DATE trial was open-label randomized study. Finally, a considerable proportion of patients in the 6-month DAPT group received a P2Y12
inhibitor after 6 months. However, results from the per-protocol analyses were consistent with those from intention-to-treat analyses.
Conclusions
In patients with MI, compared with 6-month DAPT, ≥12-month DAPT reduced recurrent MI or stent thrombosis with increased bleeding risk regardless of the type of MI at the initial presentation. However, because the present study was not prespecified and specifically powered to assess interactions between types of MI, a future large study is needed.
Sources of Funding
This work was supported by Abbott Vascular Korea, Medtronic Vascular Korea, Biosensors Inc., and Dong-A ST. The study sponsors had no role in study design, data accrual, data analysis, or manuscript preparation.
Disclosures
H.-C.G. has received research grants from Abbott Vascular, Boston Scientific, and Medtronic and speaker’s fees from Abbott Vascular, Boston Scientific, and Medtronic. J.-Y.H. has received grants from Abbott Vascular, Biotronik, Boston Scientific, Daiichi Sankyo, and Medtronic and speaker’s fees from AstraZeneca, Daiichi Sankyo, and Sanofi-Aventis. All other authors have no conflicts of interest to declare.
IRB Information
This study was approved by the Institutional Review Board (IRB) of Samsung Medical Center (2011-12-070), as well as IRBs at each participating center.
Data Availability
The authors will provide original data when required.
Supplementary Files
Please find supplementary file(s);
http://dx.doi.org/10.1253/circj.CJ-20-0704
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