Abstract
Background:
There is a scarcity of data on short-duration dual antiplatelet therapy (DAPT) followed by P2Y12 inhibitor monotherapy as compared with aspirin monotherapy after percutaneous coronary intervention (PCI).
Methods and Results:
STOPDAPT-1 is a prospective trial enrolling patients who agreed to 3-month DAPT followed by aspirin monotherapy after everolimus-eluting stent (EES) implantation. STOPDAPT-2 is a randomized trial comparing 1-month DAPT followed by clopidogrel monotherapy with 12-month DAPT after EES implantation. We compared the clinical outcomes of patients assigned to the 1-month DAPT group in STOPDAPT-2 and the 3-month DAPT group enrolled in STOPDAPT-1. The current study population consisted of 1,480 patients in STOPDAPT-2 and 1,339 patients in STOPDAPT-1. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, definite stent thrombosis and TIMI major/minor bleeding. Cumulative 1-year incidence of the primary endpoint was not significantly different between STOPDAPT-2 and STOPDAPT-1 (2.3% vs. 2.3%, P=0.98). After adjusting for confounders, there was no excess risk of STOPDAPT-2 relative to STOPDAPT-1 for the primary endpoint. Between 3 and 12 months, the cumulative incidence of primary endpoint was not significantly different between STOPDAPT-2 and STOPDAPT-1 (1.7% vs. 1.6%, P=0.77).
Conclusions:
The effect of 1-month DAPT followed by clopidogrel monotherapy on clinical outcomes was similar to that of 3-month DAPT followed by aspirin monotherapy in patients receiving PCI.
The duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) is getting shorter due to the introduction of new-generation drug-eluting stent (DES). The current American Heart Association and European Society of Cardiology (ESC) guidelines recommend 6-month DAPT after DES implantation in patients with stable coronary artery disease (CAD).1,2
Furthermore, 3-month DAPT is recommended for those with high bleeding risk (HBR) in the ECS guideline.2
Aspirin monotherapy has been the standard strategy for single antiplatelet therapy (SAPT) in patients undergoing PCI, but administration of clopidogrel to patients with atherosclerotic vascular disease is reported to be more effective than aspirin in reducing the risk of ischemic cardiovascular events.3
Recently, randomized trials demonstrated better clinical outcomes with short duration of DAPT followed by P2Y12 inhibitor monotherapy as compared with longer DAPT duration after PCI.4,5
P2Y12 inhibitors could be an important option for SAPT in place of aspirin after PCI. However, there is a scarcity of data evaluating P2Y12 inhibitor monotherapy as compared with aspirin monotherapy after short DAPT in patients with PCI. Therefore, we sought to evaluate the effect of 1-month DAPT followed by clopidogrel vs. 3-month DAPT followed by aspirin on clinical events in patients undergoing PCI.
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Methods
Study Population
The ShorT and OPtimal duration of Dual AntiPlatelet Therapy after everolimus-eluting cobalt-chromium stent (STOPDAPT)-1 trial was a prospective multicenter single-arm trial enrolling patients who agreed to follow a 3-month DAPT protocol (discontinuation of clopidogrel at 2–4 months and aspirin monotherapy thereafter) after successful cobalt-chromium everolimus-eluting stent (CoCr-EES) implantation in an all-comer population.6
Patients who underwent successful PCI using CoCr-EES were to be enrolled if the physicians in charge judged the patient to be eligible for the study. Patients who had a previous history of PCI using DES other than CoCr-EES were excluded. Between September 2012 and October 2013, 1,526 patients were enrolled in this study. Excluding 1 patient who withdrew consent for study participation, 1,525 patients were the study population for the STOPDAPT-1 trial. The research protocol was approved by the Institutional Review Board of Kyoto University and by the local ethics committees in all 58 participating medical centers (ClinicalTrials.gov: NCT 01659034). Written informed consent was given by all the study patients.
STOPDAPT-2 was a prospective, multicenter, open-label, adjudicator-blinded randomized clinical trial that was designed to compare 1-month DAPT followed by clopidogrel monotherapy with 12-month DAPT with aspirin and clopidogrel after CoCr-EES implantation.4
Patients who underwent successful PCI with CoCr-EES without concomitant use of other types of DES and without in-hospital major complications were to be enrolled. This study was basically an all-comer trial with very limited exclusion criteria, such as need for oral anticoagulation or antiplatelet therapy other than aspirin and P2Y12 receptor blockers, and history of intracranial bleeding. From December 2015 to December 2017, 3,045 patients were randomized from 90 centers in Japan. Excluding 36 patients who withdrew consent, 3,009 patients were included in the intention-to-treat population: 1,500 patients in the 1-month DAPT group, and 1,509 patients in the 12-month DAPT group. This study was conducted in accordance with the Declaration of Helsinki and the Ethical Guidelines for Medical and Health Research Involving Human Subjects in Japan. The ethical committee in each participating center approved the study protocol, and all the enrolled patients provided written informed consent. This trial was registered on Clinicaltrials.gov (ClinicalTrials.gov: NCT02619760).
We compared the clinical outcomes between patients assigned to the 1-month DAPT group in the STOPDAPT-2 and those enrolled in the STOPDAPT-1. Patients with a history of intracranial bleeding, taking oral anticoagulation or antiplatelet therapy other than aspirin and P2Y12 inhibitors were excluded to match the exclusion criteria of the 2 trials. After excluding 21 patients who had a previous history of intracranial hemorrhage and 168 patients with oral anticoagulation, 1,339 patients constituted the current study population in STOPDAPT-1. In STOPDAPT-2, 1,480 patients constituted the current study population after excluding 3 patients with a previous history of intracranial hemorrhage, 7 patients taking oral anticoagulation drugs and 11 patients taking antiplatelet therapy other than aspirin and P2Y12 inhibitors (Figure 1).
Procedures
In STOPDAPT-1, the antiplatelet regimen included aspirin (≥81 mg daily) indefinitely and thienopyridine (75 mg clopidogrel daily) for 3 months after stent implantation. Ticlopidine 200 mg/day was only allowed for those who could not tolerate clopidogrel. The acceptable time window for discontinuation of antiplatelet therapy was within ±1 month. In STOPDAPT-2, the type of DAPT within 30 days after the index PCI was left to the standard practice of each participating center (aspirin 81–200 mg/day and clopidogrel 75 mg/day or prasugrel 3.75 mg/day). At 1 month (between 30 and 59 days) after the index procedure, the patients in the 1-month DAPT group ceased aspirin and began clopidogrel monotherapy.
Persistent DAPT discontinuation was defined as discontinuation of either aspirin or P2Y12 inhibitors according to the study protocol or discontinuation lasting >60 days.
Endpoints and Definitions
The primary endpoint in this trial was a composite of cardiovascular death, myocardial infarction (MI), stroke, definite stent thrombosis (ST) and Thrombolysis in Myocardial Infarction (TIMI) major/minor bleeding at 1 year. Major secondary bleeding endpoint was TIMI major/minor bleeding and the major secondary cardiovascular endpoint was a composite of cardiovascular death, MI, stroke or definite ST at 1 year. Other secondary endpoints included death, cardiac death, cardiovascular death, non-cardiac death, non-cardiovascular death, MI, stroke, possible/probable/definite ST, bleeding events defined by TIMI or Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries (GUSTO) criteria,7,8
target lesion revascularization (TLR), coronary artery bypass grafting and any coronary revascularization.
Death was regarded as cardiac in origin unless obvious non-cardiac causes could be identified. MI and ST were defined according to the Academic Research Consortium (ARC) definitions.9
Stroke during follow-up was defined as ischemic or hemorrhagic stroke requiring hospitalization with symptoms lasting >24 h. TLR was defined as either PCI or coronary artery bypass grafting due to restenosis or thrombosis of the target lesion that included the proximal and distal edge segments as well as the ostia of the side branches. All clinical events comprising the primary endpoints were adjudicated based on source documents by the independent clinical event committee in a blinded fashion. Patients were considered to be at HBR if at least 1 major or 2 minor ARC-HBR criteria were met.10
In the present analysis, several major and minor ARC-HBR criteria were not captured. Therefore, patients with at least 1 major criterion such as severe chronic kidney disease (CKD), thrombocytopenia, severe anemia or liver cirrhosis, and those with more than 2 minor criteria such as age ≥75 years, mild anemia, previous bleeding history, prior ischemic stroke or moderate CKD were classified as HBR. We modified the ARC-HBR definitions because some criteria were not exactly captured in the trials; for example, all previous bleeding history was regarded as a minor criterion because we did not have information on the timing, requirement of hospitalization or transfusion, and recurrence for previous history of spontaneous bleeding; liver cirrhosis was considered as a major criterion regardless of the presence of portal hypertension; malignancy was excluded from the criteria for HBR because we did not have information on whether it was active or not; history of ischemic stroke was regarded as a minor criterion because we did not have information on its timing.11
In both the STOPDAPT-1 and STOPDAPT-2 trial, demographic, angiographic, and procedural data were collected from hospital charts or databases in each participating center according to the prespecified definitions by experienced clinical research coordinators in either the participating centers or the study management center. Follow-up data on the clinical events were collected from the hospital charts in the participating centers, or by mail to patients, and telephone call to referring physicians.
Statistical Analysis
Categorical variables are presented as number and percentage, and were compared with the chi-square test or Fisher’s exact test. Continuous variables are expressed as mean value±SD or median with interquartile range, and were compared using Student’s t-test or Wilcoxon rank sum test based on their distribution. Cumulative incidence was estimated by the Kaplan-Meier method and differences were assessed with the log-rank test. To evaluate the events beyond 3 months, we also conducted landmark analyses at 3 months. Patients with individual endpoint events before 3 months were excluded from the landmark analyses.12
Because of the potential for differences in the baseline characteristics of the 2 groups, we used multivariable Cox proportional hazard models to estimate the adjusted risk of patients in the STOPDAPT-2 relative to those in the STOPDAPT-1 for the primary endpoint. In the multivariable models, we chose 7 clinically relevant factors, shown in
Table 1, as the risk-adjusting variables. The continuous variables were dichotomized by clinically meaningful reference values or median values. The trial (STOPDAPT-2 or STOPDAPT-1) and the 7 risk-adjusting variables were simultaneously included in the Cox proportional hazard model. Proportional hazard assumptions for the risk-adjusting variables were assessed on the plots of log (time) vs. log [-log (survival)] stratified by the variable, and verified to be acceptable. The effect of STOPDAPT-2 relative to STOPDAPT-1 for the primary endpoint was expressed as a hazard ratio (HR) with 95% confidence interval (CI).
Table 1.
Baseline Characteristics
| |
STOPDAPT-2
(n=1,480) |
STOPDAPT-1
(n=1,339) |
P value |
| Age (years) |
68.1±10.8 |
69.7±10.7 |
<0.0001 |
| ≥75 years* |
438 (30%) |
482 (36%) |
0.0003 |
| Male sex* |
1,170 (79%) |
973 (73%) |
<0.0001 |
| Body mass index |
24.4±3.5 |
24.1±3.6 |
0.06 |
| Coexisting conditions |
| Hypertension* |
1,090 (74%) |
1,107 (83%) |
<0.0001 |
| Diabetes mellitus |
578 (39%) |
522 (39%) |
0.97 |
| Insulin-treated diabetes |
102 (6.9%) |
106 (7.9%) |
0.3 |
| Dyslipidemia |
1,102 (74%) |
1,069 (80%) |
0.0007 |
| Moderate CKD (30≤eGFR<60 mL/min/1.73 m2) |
511 (35%) |
405 (30%) |
0.02 |
| Severe CKD |
81 (5.5%) |
78 (5.8%) |
0.69 |
| ESRD (eGFR <30 mL/min/1.73 m2) not on HD |
29 (2.0%) |
31 (2.3%) |
0.51 |
| HD |
52 (3.5%) |
47 (3.5%) |
0.99 |
| AF** |
31 (2.1%) |
52 (3.9%) |
0.005 |
| Anemia* |
433 (29%) |
575 (43%) |
<0.0001 |
| Severe anemia (Hb <11.0 g/dL) |
119 (8.0%) |
214 (16%) |
<0.0001 |
| Mild anemia (Hb 11–12.9 g/dL for men and 11–11.9 g/dL for women) |
314 (21%) |
361 (27%) |
0.0004 |
| Low platelets (<100×109/L) |
15 (1.0%) |
16 (1.2%) |
0.64 |
| Prior bleeding* |
19 (1.3%) |
45 (3.4%) |
0.0002 |
| Liver cirrhosis |
6 (0.4%) |
11 (0.8%) |
0.15 |
| ARC-HBR |
475 (32%) |
568 (42%) |
<0.0001 |
| Cardiac risk factor |
| Current smoker |
397 (27%) |
283 (21%) |
0.0004 |
| Prior MI |
206 (14%) |
224 (17%) |
0.04 |
| Prior ischemic stroke* |
78 (5.3%) |
123 (9.2%) |
<0.0001 |
| Heart failure |
114 (7.7%) |
125 (10%) |
0.03 |
| Peripheral vascular disease |
93 (6.3%) |
114 (8.5%) |
0.02 |
| Prior PCI |
495 (33%) |
409 (31%) |
0.1 |
| Prior CABG |
17 (1.2%) |
30 (2.2%) |
0.02 |
| Clinical presentation |
| Stable CAD |
922 (62%) |
903 (67%) |
0.004 |
| Unstable angina |
189 (13%) |
205 (15%) |
0.052 |
| Acute MI* |
369 (25%) |
231 (17%) |
<0.0001 |
| Target vessel location |
| Left main coronary artery |
43 (2.9%) |
16 (1.2%) |
0.0010 |
| Left anterior descending coronary artery |
819 (55%) |
765 (57%) |
0.34 |
| Left circumflex coronary artery |
263 (18%) |
321 (24%) |
<0.0001 |
| Right coronary artery |
430 (29%) |
352 (26%) |
0.1 |
| Bypass graft |
3 (0.2%) |
4 (0.3%) |
0.72 |
| Complexity of CAD |
| No. of treated lesions per patient |
1.12±0.35 |
1.21±0.48 |
<0.0001 |
| Medications |
| Aspirin |
1,479 (99.9%) |
1,339 (100%) |
0.26 |
| Thienopyridines |
1,480 (100%) |
1,337 (99.9%) |
0.08 |
| Clopidogrel |
891 (60%) |
1,325 (99.0%) |
<0.0001 |
| Ticlopidine |
2 (0.1%) |
12 (0.9%) |
0.003 |
| Prasugrel |
587 (40%) |
0 (0%) |
<0.0001 |
| Statins |
1,301 (88%) |
1,077 (80%) |
<0.0001 |
| β-blockers |
664 (45%) |
506 (38%) |
0.0001 |
| ACEI/ARB |
921 (62%) |
823 (61%) |
0.68 |
| Calcium-channel blockers |
557 (38%) |
597 (45%) |
0.0002 |
| Nitrates |
176 (12%) |
192 (14%) |
0.054 |
| Lesion and procedural characteristics |
| Before index procedure |
| Chronic total occlusion |
54 (3.7%) |
61 (4.6%) |
0.22 |
| Bifurcation |
369 (25%) |
282 (21%) |
0.01 |
| After index procedure |
| No. of stents used per patient |
1.26±0.54 |
1.37±0.65 |
<0.0001 |
| Total stent length per patient (mm) |
30.3±16.7 |
33.0±20.7 |
<0.0001 |
| Multivessel treatment |
100 (6.8%) |
119 (8.9%) |
0.04 |
Values are expressed as mean±SD or n (%). *Risk-adjusting variables selected for multivariable analysis. **Patients with AF were not on oral antithrombotic therapy. We modified the ARC-HBR definitions, because some criteria of ARC-HBR were not exactly captured in the trials. ACEI, angiotensin-converting enzyme inhibitor; AF, atrial fibrillation; ARB, angiotensin II receptor blocker; ARC-HBR, Academic Research Consortium-high bleeding risk; CABG, coronary artery bypass grafting; CAD, coronary artery disease; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; Hb, hemoglobin; HD, hemodialysis; MI, myocardial infarction; PCI, percutaneous coronary intervention; STOPDAPT, ShorT and OPtimal duration of Dual AntiPlatelet Therapy after everolimus-eluting cobalt-chromium stent.
Statistical analyses were conducted by a physician (M.N.) and a statistician (T.M.) with the use of JMP 10.0 software. We considered 2-sided P-values <0.05 as statistically significant.
Results
Baseline Characteristics
Patients in the STOPDAPT-2 group were younger than those in STOPDAPT-1. The prevalence of men, moderate CKD, current smokers and acute MI was higher in STOPDAPT-2 than in STOPDAPT-1, whereas the prevalence of hypertension, dyslipidemia, atrial fibrillation, anemia, prior bleeding, ARC-HBR, prior MI, prior ischemic stroke, heart failure, peripheral vascular disease and prior coronary artery bypass grafting was higher in STOPDAPT-1 than in STOPDAPT-2. The number of treated lesions and stents used per patients were greater and total stent length was longer in STOPDAPT-1 than in STOPDAPT-2. Regarding the medications at hospital discharge, prasugrel, statins and β-blockers were more often prescribed in STOPDAPT-2 than in STOPDAPT-1 (Table 1).
Discontinuation of DAPT
DAPT was discontinued within 2 months in 1,410 patients (95.6%) in STOPDAPT-2 and was discontinued within 4 months in 1,257 patients (94.1%) in STOPDAPT-1. Cumulative 1-year incidence of persistent discontinuation of DAPT was 98.7% in the STOPDAPT-2 group and 96.6% in the STOPDAPT-1 group (P<0.0001) (Figure 2).
Clinical Outcomes Through 1-Year
Cumulative 1-year incidence of the primary endpoint was very low and not significantly different between STOPDAPT-2 and STOPDAPT-1 (2.3% vs. 2.3%, P=0.98) (Figure 3, Table 2). In the multivariable analysis, there was no excess risk of STOPDAPT-2 relative to STOPDAPT-1 for the primary endpoint (adjusted HR 1.25, 95% CI 0.75–2.08, P=0.39) (Supplementary Table). Regarding the major secondary endpoints, the cumulative incidences of TIMI major/minor bleeding and the composite of cardiovascular death, MI, stroke and definite ST were also not significantly different between STOPDAPT-2 and STOPDAPT-1.
Table 2.
Clinical Outcomes at 12 Months
| |
No. of patients with ≥1 event
(cumulative incidence) |
P value |
STOPDAPT-2
(n=1,480) |
STOPDAPT-1
(n=1,339) |
| Primary endpoint |
33 (2.3%) |
30 (2.3%) |
0.98 |
| Death |
| All-cause death |
21 (1.4%) |
22 (1.7%) |
0.66 |
| Cardiac death |
8 (0.6%) |
7 (0.5%) |
0.94 |
| Cardiovascular death |
9 (0.6%) |
8 (0.6%) |
0.96 |
| Non-cardiac death |
13 (0.9%) |
15 (1.1%) |
0.55 |
| Non-cardiovascular death |
12 (0.8%) |
14 (1.1%) |
0.55 |
| MI |
12 (0.8%) |
4 (0.3%) |
0.07 |
| Stroke |
| Any |
7 (0.5%) |
12 (0.9%) |
0.18 |
| Ischemic |
7 (0.5%) |
11 (0.8%) |
0.26 |
| Hemorrhagic |
0 (0%) |
1 (0.08%) |
0.31 |
| Bleeding |
| TIMI major |
3 (0.2%) |
5 (0.4%) |
0.41 |
| TIMI minor/major |
6 (0.4%) |
7 (0.5%) |
0.66 |
| GUSTO severe |
4 (0.3%) |
6 (0.5%) |
0.46 |
| GUSTO moderate/severe |
6 (0.4%) |
10 (0.8%) |
0.25 |
| ST |
| Definite |
1 (0.07%) |
0 (0%) |
0.34 |
| Definite or probable |
3 (0.2%) |
0 (0%) |
0.1 |
| Definite, probable or possible |
4 (0.3%) |
5 (0.4%) |
0.64 |
| Death or MI |
31 (2.1%) |
26 (2.0%) |
0.74 |
| Cardiovascular death or MI |
20 (1.4%) |
12 (0.9%) |
0.25 |
| Cardiovascular death, MI, stroke and definite ST |
27 (1.9%) |
24 (1.8%) |
0.92 |
| TLR |
34 (2.3%) |
24 (1.8%) |
0.33 |
| Coronary revascularization |
| Any |
97 (6.8%) |
95 (7.2%) |
0.66 |
| CABG |
6 (0.4%) |
3 (0.2%) |
0.38 |
Data are expressed as n (%). Cumulative incidence estimated by Kaplan-Meier method. The primary endpoint in this trial was a composite of cardiovascular death, MI, stroke, definite ST, and TIMI major/minor bleeding at 1 year. GUSTO, Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries; ST, stent thrombosis; TIMI, Thrombolysis in Myocardial Infarction; TLR, target lesion revascularization. Other abbreviations as in Table 1.
Between 3 and 12 months, the cumulative incidence of the primary endpoint was not significantly different between STOPDAPT-2 and STOPDAPT-1 (1.7% vs. 1.6%, P=0.77) (Figure 4, Table 3). Regarding the major secondary endpoints, the cumulative incidence of TIMI major/minor bleeding was not significantly different between trials (Table 3). TIMI major/minor bleeding more often occurred after discontinuation of DAPT in both groups. The cumulative incidence of the composite of cardiovascular death, MI, stroke and definite ST was also not significantly different between STOPDAPT-2 and STOPDAPT-1 (Table 3). However, the cumulative incidence of MI was significantly higher in STOPDAPT-2 than in STOPDAPT-1. There was no definite ST between 3 and 12 months after PCI in either group (Table 3).
Table 3.
Clinical Outcomes Between 3 and 12 Months
| |
No. of patients with ≥1 event
(cumulative incidence) |
P value |
| STOPDAPT2 |
STOPDAPT1 |
| Primary endpoint |
25 (1.7%) |
21 (1.6%) |
0.77 |
| Death |
| All-cause |
16 (1.1%) |
20 (1.5%) |
0.36 |
| Cardiac death |
5 (0.3%) |
7 (0.5%) |
0.46 |
| Cardiovascular death |
6 (0.4%) |
7 (0.5%) |
0.66 |
| Non-cardiac death |
11 (0.8%) |
13 (1.0%) |
0.54 |
| Non-cardiovascular death |
10 (0.7%) |
13 (1.0%) |
0.41 |
| MI |
10 (0.7%) |
2 (0.2%) |
0.03 |
| Stroke |
| Any |
5 (0.4%) |
7 (0.5%) |
0.48 |
| Ischemic |
5 (0.4%) |
6 (0.5%) |
0.67 |
| Hemorrhagic |
0 (0%) |
1 (0.08%) |
0.31 |
| Bleeding |
| TIMI major |
3 (0.2%) |
4 (0.3%) |
0.62 |
| TIMI minor/major |
5 (0.3%) |
6 (0.5%) |
0.65 |
| GUSTO severe |
2 (0.1%) |
4 (0.3%) |
0.38 |
| GUSTO moderate/severe |
4 (0.3%) |
6 (0.5%) |
0.46 |
| ST |
| Definite |
0 (0%) |
0 (0%) |
NA |
| Definite or probable |
0 (0%) |
0 (0%) |
NA |
| Definite, probable or possible |
1 (0.07%) |
5 (0.4%) |
0.08 |
| Death or MI |
24 (1.7%) |
22 (1.7%) |
0.99 |
| Cardiovascular death or MI |
15 (1.0%) |
9 (0.7%) |
0.31 |
| Cardiovascular death, MI, stroke and definite ST |
20 (1.4%) |
16 (1.2%) |
0.68 |
| TLR |
33 (2.3%) |
23 (1.7%) |
0.31 |
| Coronary revascularization |
| Any |
93 (6.5%) |
86 (6.6%) |
0.98 |
| CABG |
6 (0.4%) |
3 (0.2%) |
0.38 |
Data are expressed as n (%). Cumulative incidence estimated by Kaplan-Meier method. Abbreviations as in Tables 1,2.
Cumulative 1-year incidence of the primary endpoint was not significantly different between STOPDAPT-2 and STOPDAPT-1 in patients with and without ARC-HBR. Regarding the major secondary endpoints, the cumulative incidences of TIMI major/minor bleeding and the composite of cardiovascular death, MI, stroke and definite ST were also not significantly different between STOPDAPT-2 and STOPDAPT-1 in patients with and without ARC-HBR (Table 4).
Table 4.
Clinical Outcomes at 12 Months in Patients With and Without ARC-HBR
| |
No. of patients with ≥1 event
(cumulative incidence) |
P value |
| STOPDAPT2 |
STOPDAPT1 |
| ARC-HBR |
n=475 |
n=568 |
|
| Primary endpoint |
16 (3.4%) |
22 (3.9%) |
0.65 |
| Cardiovascular death, MI, stroke and definite ST |
14 (3.0%) |
19 (3.4%) |
0.71 |
| TIMI minor/major bleeding |
2 (0.4%) |
3 (0.5%) |
0.8 |
| No ARC-HBR |
n=1,005 |
n=771 |
|
| Primary endpoint |
17 (1.7%) |
8 (1.0%) |
0.22 |
| Cardiovascular death, MI, stroke and definite ST |
13 (1.3%) |
5 (0.7%) |
0.16 |
| TIMI minor/major bleeding |
4 (0.4%) |
4 (0.5%) |
0.73 |
Data are expressed as n (%). Cumulative incidence estimated by Kaplan-Meier method. Abbreviations as in Tables 1,2.
Cumulative 1-year incidence of the primary endpoint was not significantly different between STOPDAPT-2 and STOPDAPT-1 in patients with acute coronary syndrome (Supplementary Figure 1). Cumulative 1-year incidence of the primary endpoint was also not significantly different between STOPDAPT-2 and STOPDAPT-1 in patients with stable CAD (Supplementary Figure 2).
Discussion
The main findings of the current study were: (1) the effect of 1-month DAPT followed by clopidogrel monotherapy on clinical outcomes was similar to that of 3-month DAPT followed by aspirin monotherapy in patients undergoing PCI; and (2) there were no significant differences in clinical events between clopidogrel monotherapy and aspirin monotherapy between 3 and 12 months after PCI.
DAPT duration shorter than 3 months after PCI could be one of the important strategies in the era of new-generation DES. In the RESET13
and OPTIMIZE14
trials, 3-month DAPT followed by aspirin monotherapy was non-inferior to 12-month DAPT with respect to the occurrence of the primary composite endpoint including cardiovascular and bleeding events after zotarolimus-eluting stent implantation. In the STOPDAPT-1 trial, 3-month DAPT followed by aspirin monotherapy in patients after CoCr-EES implantation was also as safe as in those in the historical control group, where approximately 90% of patients continued 12-month DAPT.6
1-month DAPT followed by P2Y12 inhibitor monotherapy has also been reported to have equivalent cardiovascular risks as longer DAPT duration. In the Global Leaders trial, 1-month DAPT followed by ticagrelor alone tended to have lower risk of death or Q-wave MI as compared with 12-month DAPT followed by 12 months of aspirin alone through 2 years after PCI (HR, 0.87 [95% CI, 0.75–1.01], P=0.073).15
In the STOPDAPT-2 trial, 1-month DAPT followed by clopidogrel monotherapy as compared with 12-month DAPT with aspirin and clopidogrel resulted in a significantly lower rate of a composite of cardiovascular and bleeding events. The cardiovascular events were not significantly different (HR, 0.79 [95% CI, 0.49–1.29], P=0.34), but the risk of major bleeding was significantly lower in the 1-month DAPT group than in the 12-month DAPT group (HR, 0.26 [95% CI, 0.11–0.64], P=0.004).4
Therefore, both 1-month DAPT followed by P2Y12 inhibitor monotherapy and 3-month DAPT followed by aspirin could be important options in reducing bleeding events without increasing cardiovascular events. However, there are no prospective data comparing 1-month DAPT with 3-month DAPT after PCI. In this study, the effects of 1-month DAPT followed by clopidogrel on cardiovascular and bleeding events were similar to those for 3-month DAPT followed by aspirin in patients after CoCr-EES implantation. Cardiovascular and bleeding events were also similar between 1-month and 3-month DAPT in patients with ARC-HBR. Considering the higher risk for bleeding events with longer DAPT use, both 1-month DAPT followed by P2Y12 inhibitor monotherapy and 3-month DAPT followed by aspirin could be important strategies to reduce bleeding events without increasing cardiovascular events, especially in those with HBR.
In the CAPRIE trial, long-term administration of clopidogrel to patients with atherosclerotic vascular disease was more effective than aspirin in reducing the combined risk of ischemic stroke, MI, or vascular death.3
In a meta-analysis of patients with high risk of vascular disease, thienopyridines significantly reduced the risk of vascular events and gastrointestinal hemorrhage over aspirin.16
Recently, several randomized trials evaluating a short DAPT strategy leaving P2Y12 inhibitor alone as compared with long DAPT have been conducted to consider the potential benefits of P2Y12 inhibitor monotherapy in reducing cardiovascular and bleeding events over aspirin. In the SMART-CHOICE trial,17
P2Y12 inhibitor monotherapy after 3-month DAPT compared with prolonged DAPT resulted in noninferiority in terms of major adverse cardiac and cerebrovascular events. The rate of bleeding was significantly lower in the P2Y12 inhibitor monotherapy group than in the DAPT group.17
In the TWILIGHT trial, ticagrelor monotherapy was associated with a lower incidence of clinically relevant bleeding than was ticagrelor plus aspirin, with no higher risk of death, MI, or stroke among high-risk patients who underwent PCI and completed 3-month DAPT.18
In the STOPDAPT-2 trial, clopidogrel monotherapy was associated with a lower incidence of major bleeding than clopidogrel plus aspirin without increasing cardiovascular events.4
However, the effects of P2Y12 monotherapy as compared with aspirin monotherapy after PCI have not been fully evaluated. In a Korean registry, clopidogrel monotherapy as compared with aspirin monotherapy was associated with a reduced risk of recurrent ischemic events in patients receiving DES beyond 12 months after PCI; major bleeding occurred similarly in both groups.19
In a prospective single-arm registry to evaluate a safety of 3-month DAPT, P2Y12 inhibitor monotherapy was almost equivalent to aspirin monotherapy after 3 months in terms of both bleeding and thrombotic events.20
In the present study, there were also no significant differences in cardiovascular and bleeding events between clopidogrel monotherapy and aspirin monotherapy between 3 and 12 months after PCI. Direct comparison between P2Y12 inhibitor and aspirin is necessary to confirm the efficacy and safety of P2Y12 inhibitor monotherapy in a randomized fashion. The STOPDAPT-2 trial continues to follow the enrolled patients up to 5 years to compare clopidogrel monotherapy with aspirin monotherapy beyond the year after PCI using CoCr-EES (ClinicalTrials.gov: NCT02619760). A comparison of P2Y12 inhibitor monotherapy and aspirin monotherapy 1 month after PCI should also be conducted to confirm the best strategy for short DAPT after PCI.
Study Limitations
There are several important limitations to consider. First, STOPDAPT-1 compared with STOPDAPT-2 tended to more often enroll HBR patients due to its single-arm trial design to de-escalate antithrombotic therapy. Multivariable analysis might not be able to fully adjust the measured and unmeasured confounders. Second, patients received clopidogrel as a P2Y12 inhibitor monotherapy in the STOPDAPT-2 trial. Cytochrome P450 (CYP) 2C19 polymorphism is associated with reduced clopidogrel response, especially in Japanese people, which could have influenced the clinical outcomes in this study. Prasugrel or ticagrelor monotherapy was not evaluated in this study. Third, there were significantly more patients with statins and β-blockers in STOPDAPT-2 as compared with those in STOPDAPT-1, which could have a possible effect on the clinical outcomes. Fourth, as this study was conducted only in Japanese centers, the external validity to non-Asian patients would be limited. Fifth, inclusion bias should be considered. There were many patients who were not enrolled to the studies (STOPDAPT-1 and STOPDAPT-2) by physicians’ judgement, because patients who underwent complex PCI were considered to be at high risk of ischemic events by discontinuing DAPT in the early phase after PCI. Finally, the STOPDAPT-1 and STOPDAPT-2 trials are different trials conducted in different time periods.
Conclusions
The effect of 1-month DAPT followed by clopidogrel monotherapy on clinical outcomes was similar to that of 3-month DAPT followed by aspirin monotherapy in patients receiving PCI with CoCr-EES.
Acknowledgment
We appreciate the support of the co-investigators participating in the STOPDAPT and STOPDAPT-2 studies (Supplementary Appendix).
Sources of Funding
Abbott Vascular is the funding source of this study.
Conflicts of Interest
T.K., K.I.H., K. Kadota, K.T., Y.M., and K. Kozuma are advisory board members of Abbott Vascular.
Data Availability
The deidentified participant data will not be shared.
IRB Information
The research protocols of the STOPDAPT-1 and STOPDAPT-2 trials were approved by the Institutional Review Board of Kyoto University (C645, CRB5180002) and by the local ethics committees in all participating medical centers.
Disclosure
T.K., Y.M., and Y.I. are members of
Circulation Journal
’ Editorial Team
Supplementary Files
Please find supplementary file(s);
http://dx.doi.org/10.1253/circj.CJ-20-0298
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