One-year clinical outcomes of patients with versus without acute coronary syndrome with 3-month duration of dual antiplatelet therapy after everolimus-eluting stent implantation.

There has been no previous prospective study evaluating 3-month dual antiplatelet therapy (DAPT) after cobalt-chromium everolimus-eluting stent (CoCr-EES) implantation in patients with acute coronary syndrome (ACS). The STOPDAPT trial is a prospective multi-center single-arm study evaluating 3-month DAPT duration in all-comer population after CoCr-EES implantation. Among 1525 study patients enrolled from 58 Japanese centers, the present study compared the 1-year clinical outcomes between ACS patients (N = 487) and stable coronary artery disease (CAD) patients (N = 1038). In the ACS group, 228 patients (47%) had unstable angina and 259 patients (53%) had myocardial infarction. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, definite stent thrombosis (ST) and TIMI major/minor bleeding. Thienopyridine was discontinued within 4-month in 455 patients (94.0%) in the ACS group and 977 patients (94.3%) in the stable CAD group. Cumulative 1-year incidence of and the adjusted risk for the primary endpoint were not significantly different between the ACS and stable CAD groups (2.3% vs. 3.0%, P = 0.42, and HR 0.94, 95%CI 0.44-1.87, P = 0.87). In the 3-month landmark analysis, cumulative incidence of the primary endpoint was also not significantly different between the ACS and stable CAD groups (1.3% vs. 2.4%, P = 0.16). There was no definite/probable ST through 1-year in both groups. In the propensity matched analysis, the cumulative 1-year incidence of the primary endpoint were similar between the ACS and stable CAD groups (2.3% versus 2.1%, P = 0.82). In conclusion, stopping DAPT at 3 months after CoCr-EES implantation in patients with ACS including 47% of unstable angina was as safe as that in patients with stable CAD.

Introduction

The current American Heart Association (AHA) and European Society of Cardiology (ESC) guidelines recommend 6-month dual antiplatelet therapy (DAPT) after drug-eluting stent (DES) implantation in patients with stable coronary artery disease (CAD).[1,2] On the other hand, DAPT has been recommended for at least 1 year in patients with acute coronary syndrome (ACS), irrespective of the revascularization strategies and stent types. However, due to the paucity of dedicated randomized trials or prospective trial evaluating short DAPT in patients with ACS, the optimal duration of DAPT after DES implantation in ACS is still a matter of debate.

We previously reported the favorable outcomes of those patients treated with 3-month DAPT after cobalt-chromium everolimus-eluting stent (CoCr-EES) in the STOPDAPT (ShorT and OPtimal duration of Dual AntiPlatelet Therapy after everolimus-eluting cobalt-chromium stent) trial as compared with those enrolled in the historical control of RESET (Randomized Evaluation of Sirolimus-eluting versus Everolimus-eluting stent Trial) study, in which nearly 90% of patients had continued DAPT at 1-year. [3,4] The STOPDAPT trial included a substantial proportion of patients with ACS. Therefore, we sought to evaluate the safety of 3-month DAPT duration after CoCr-EES implantation in those with ACS as compared with those with stable CAD.

Methods

Study population

STOPDAPT trial is a prospective multi-center single-arm trial enrolling patients who agreed to follow the 3-month DAPT protocol (discontinuation of clopidogrel at 2- to 4-month and aspirin monotherapy thereafter) after successful CoCr-EES implantation in all-comer population.[3] Patients who underwent successful percutaneous coronary intervention (PCI) using CoCr-EES were to be enrolled, if the physicians in charge judged the patient to be eligible for the study evaluating 3-month DAPT duration. Patients who had previous history of PCI using DES other than CoCr-EES were excluded.

Between September 2012 and October 2013, 6070 patients underwent PCI using CoCr-EES in 58 Japanese centers (List A in S1 Appendix). We excluded 2490 patients who were previously treated with DES other than CoCr-EES. Among 3580 eligible patients, 1526 patients (43%) were enrolled in this study. Excluding 1 patient who withdrew consent for study participation, 1525 patients constituted the current study population. Among 1525 patients, 487 patients presented as ACS and 1038 patients had stable CAD (Fig 1). Complete 1-year clinical follow-up was achieved in 1519 patients (99.6%). We compared the clinical outcomes between ACS and stable CAD patients.

Fig 1

Study flow chart.

CoCr-EES, Cobalt-chromium everolimus-eluting stent; DES, drug-eluting stent; ACS, acute coronary syndrome; CAD, coronary artery disease.

As a historical control group, we selected the CoCr-EES group in the RESET trial (a randomized controlled trial comparing CoCr-EES with sirolimus-eluting stent conducted by the same study group in 2010), where nearly 90% of patients had continued DAPT at 1-year.[4] The eligibility criteria of the RESET was comparable to that of the STOPDAPT except for the inclusion of patients with previous DES implantation in the RESET. Among 1597 patients in the CoCr-EES group in the RESET, 38 patients with in-hospital primary endpoint events were excluded from the historical control group in this study, because patients in the STOPDAPT were enrolled after completion of successful PCI. A total of 1559 patients were selected as a historical control group.[3]

Ethics

The research protocol of the STOPDAPT trial (S1 Protocol) was approved by the Institutional Review Board in Kyoto University and by the local ethics committees in all of 58 participating medical centers (List A in S1 Appendix) (ClinicalTrials.gov: NCT 01659034). Written informed consent was obtained from all the study patients.

Procedures

Antiplatelet regimen included aspirin (≥81mg daily) indefinitely and thienopyridine (75mg clopidogrel daily) for 3-month after stent implantation. Ticlopidine 200 mg/day was only allowed for those who did not tolerate clopidogrel. Patients were instructed to discontinue thienopyridine at 3-month hospital visit. Acceptable time window for the discontinuation of thienopyridine therapy was within ±1 month. DAPT duration in patients with oral anticoagulants was the same as the rest of the population. Status of antiplatelet therapy was evaluated throughout the follow-up period as previously described.[5] Persistent discontinuation of thienopyridine was defined as withdrawal lasting for at least 2 months.[5]

Endpoints and definitions

ACS included those patients who presented as ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI), and unstable angina (UA) at the time of index PCI. The remaining study patients other than ACS were regarded as having stable CAD. STEMI was defined as those with an increase of cardiac biomarker with persistent ST-segment elevation or new Q-wave in electrocardiogram. NSTEMI was defined as those with an increase of cardiac biomarker without electrocardiogram changes of STEMI. High-sensitivity troponin or CK-MB value > upper reference limit were diagnosed as MI in the all participating centers. UA was defined as those with anginal pain of Braunwald class I-III with no increase of a cardiac biomarker.[6] The Global Registry of Acute Coronary Events (GRACE) score was calculated in patients with ACS.[7] 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. Primary endpoint events were adjudicated by the independent clinical event committee (List B in S1 Appendix). Major secondary endpoints were TIMI major/minor bleeding and a composite of cardiovascular death, MI, stroke or definite ST at 1 year. Other secondary endpoints included 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,[8,9] target-lesion revascularization (TLR), target-vessel revascularization (TVR), 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 definitions.[10] Stroke during follow-up was defined as ischemic or hemorrhagic stroke requiring hospitalization with symptoms lasting >24 hours. 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 ostium of the side branches. Patients with planned staged PCI were enrolled in this study after the completion of all the planned coronary revascularization procedures. Therefore, scheduled staged PCI procedures were not included in any coronary revascularization during follow-up.

Data collection and follow-up

Demographic, angiographic, and procedural data were collected from hospital charts or databases in each participating center according to the pre-specified definitions by experienced clinical research coordinators in the participating centers (List B in S1 Appendix) or in the study management center (List B in S1 Appendix). Follow-up data on the clinical events were collected from the hospital charts in the participating centers (74%), letters to patients (20%), and telephone call to referring physicians (8.4%).

Statistical analysis

Categorical variables were presented as number and percentage, and were compared with the chi-square test or the Fisher’s exact test. Continuous variables were expressed as mean value ± SD or median with inter-quartile range, and were compared using the Student’s t test or Wilcoxon rank sum test based on their distributions. As the main analysis in the present study, clinical outcomes were compared between the ACS patients and the stable CAD patients in the STOPDAPT trial. Cumulative incidence was estimated by the Kaplan-Meier method and differences were assessed with the log-rank test. To evaluate the events beyond 3-month, we also conducted the landmark analyses at 3-month. Those patients who had the individual endpoint events before 3-month were excluded in the landmark analyses. Due to the presence of differences in baseline characteristics between the 2 groups, we used multivariable Cox proportional hazard models to estimate the risk of patients with ACS relative to those with stable CAD for the primary endpoint. In the multivariable analysis, we chose 7 clinically relevant factors indicated in Table 1 as the risk adjusting variables (age > = 75 years, diabetes, hemodialysis, atrial fibrillation, prior MI, peripheral vascular disease, and statins use). The continuous variables were dichotomized by clinically meaningful reference values or median values. The presentation (ACS or stable CAD), the 7 risk-adjusting variables and random effect of center 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) versus log [-log (survival)] stratified by the variable. The assumptions were verified to be acceptable for all the variables. The effect of ACS relative to stable CAD for the primary endpoint was expressed as hazard ratios (HR) and their 95% confidence intervals (CI). As the sensitivity analyses, we conducted propensity matched analysis. The propensity score was calculated from the 7 risk-adjusting variables. Using the propensity score, patients in the stable CAD group were randomly matched to ACS patients using a greedy matching strategy. Sample size calculation for the main analysis of this study was previously described. [3]

Table 1

Baseline characteristics: ACS versus stable CAD.

	ACS	Stable CAD	P Value
	487 patients	1038 patients
	555 lesions	1283 lesions
Clinical characteristics
Age–years	69.0±12.3	70.5±9.7	0.009
Age > = 75 years *	176 (36%)	394 (38%)	0.49
Men	361 (74%)	756 (73%)	0.59
Body mass index	24.0±3.6	24.2±3.5	0.21
Coexisting condition
Hypertension	406 (83%)	855 (82%)	0.63
Diabetes mellitus *	162 (33%)	442 (43%)	0.0005
Insulin-treated diabetes	18 (3.7%)	101 (9.7%)	<0.0001
Treated with oral medication only	91 (19%)	269 (26%)	0.002
Treated with diet therapy only	53 (11%)	72 (6.9%)	0.01
Dyslipidemia	386 (79%)	823 (79%)	0.99
ESRD (eGFR<30 mL/min/1.73m2) not on HD	16 (3.3%)	19/1034 (1.8%)	0.09
HD *	8 (1.6%)	48 (4.6%)	0.002
Atrial fibrillation *	39 (8.0%)	133 (13%)	0.005
Anemia (Hemoglobin <11.0 g/dL)	76 (16%)	165 (16%)	0.88
Cardiac risk factor
Current smoker	142 (29%)	173 (17%)	<0.0001
Family history of coronary artery disease	58 (12%)	134 (13%)	0.58
Prior myocardial infarction *	38 (7.8%)	229 (22%)	<0.0001
Prior Stroke	49 (10%)	119 (11%)	0.41
Heart failure	58 (12%)	147 (14%)	0.23
Peripheral vascular disease *	19 (3.9%)	123 (12%)	<0.0001
Prior percutaneous coronary intervention	80 (16%)	388 (37%)	<0.0001
Prior coronary-artery bypass grafting	6 (1.2%)	35 (3.4%)	0.01
Clinical characteristics
Clinical presentation
Unstable angina	228 (47%)
Acute myocardial infarction	259 (53%)
STEMI	215 (44%)
NSTEMI	44 (9.0%)
GRACE score
Unstable angina	109.4±27.0
STEMI	159.6±32.1
NSTEMI	123.8±32.5
Left ventricular ejection fraction <30%	4/419 (1.0%)	13/896 (1.5%)	0.45
Multivessel disease	141 (29%)	437 (42%)	<0.0001
Target vessel location
Left main coronary artery	4 (0.8%)	13 (1.3%)	0.44
Left anterior descending coronary artery	299 (61%)	567 (55%)	0.01
Left circumflex coronary artery	85 (17%)	276 (27%)	<0.0001
Right coronary artery	125 (26%)	280 (27%)	0.59
Bypass graft	1 (0.2%)	3 (0.3%)	0.76
Complexity of coronary artery disease
No. of treated lesions per patient	1.14±0.42	1.24±0.5	<0.0001
Medications
Aspirin	487 (100%)	1037 (99.9%)	0.38
Thienopyridines	487 (100%)	1035 (99.7%)	0.13
Clopidogrel	485 (99.6%)	1023 (98.8%)	0.13
Ticlopidine	2 (0.4%)	12 (1.2%)
Statins *	438 (90%)	785 (76%)	<0.0001
Strong statins**	407 (84%)	706 (68%)	<0.0001
Maximum approved doses of strong statin	7 (1.4%)	20 (1.9%)	0.49
B-blockers	256 (53%)	364 (35%)	<0.0001
ACE-I/ARB	334 (69%)	605 (58%)	0.0001
Calcium-channel blockers	164 (34%)	511 (49%)	<0.0001
Nitrates	65 (13%)	154 (15%)	0.44
Anticoaglants	45 (9.2%)	123 (12%)	0.12
Warfarin	38 (7.8%)	87 (8.4%)	0.7
Dabigatran	5 (1.0%)	29 (2.8%)	0.02
Rivaroxaban	2 (0.4%)	7 (0.7%)	0.52
Lesion and procedural characteristics
Before index procedure
Chronic total occlusion	7 (1.4%)	65 (6.3%)	<0.0001
Culprit for STEMI	202 (41%)
Bifurcation	105 (22%)	212 (20%)	0.61
After index procedure
No. of stents used per patient	1.27±0.56	1.42±0.68	<0.0001
Total stent length per patient—mm	30.7±18.0	33.9±22.1	0.09
Multivessel treatment	28 (5.8%)	102 (9.8%)	0.006

Values are expressed as mean ± SD or number (%).

* Risk-adjusting variables selected for multivariable analysis.

** Atorvastatin, pitavastatin and rosuvastatin were considered to be strong statins.

ACS = acute coronary syndrome; CAD = coronary artery disease; ESRD = end stage renal disease; eGFR = estimated glomerular filtration rate; HD = hemodialysis; STEMI = ST-segment elevation myocardial infarction; NSTEMI = non-ST-segment elevation myocardial infarction; The Global Registry of Acute Coronary Events (GRACE); ACE-I = angiotensin converting enzyme inhibitors; ARB = angiotensin II receptor blockers.

Statistical analyses were conducted by a physician (Natsuaki M) and a statistician (Morimoto T) with the use of JMP 10.0 software. We used 2-sided P values <0.05 as statistically significant.

Results

Baseline characteristics: Enrolled versus non-enrolled patients in the STOPDAPT

Baseline characteristics were significantly different in several aspects between the enrolled and non-enrolled patients (S1 Table). AMI presentation were more prevalent in the non-enrolled group, while stable CAD were more often found in the enrolled group.

Baseline characteristics: ACS versus stable CAD

In ACS group, 44% of patients presented as STEMI, 9% of patients presented as NSTEMI and 47% of patients had UA. Baseline characteristics were significantly different in several aspects between the ACS and stable CAD groups (Table 1). Patients in the ACS group were significantly younger than those in the stable CAD group. The ACS group more often had current smoker, while the stable CAD group more often had diabetes, hemodialysis, atrial fibrillation, prior MI, peripheral vascular disease, prior PCI, prior coronary artery bypass grafting and multi-vessel disease. The ACS group more often included treatment of left anterior descending artery, while the stable CAD group more often included treatment of left circumflex artery and chronic total occlusion. The stable CAD group had greater number of stents per patient, and longer total stent length per patient than the ACS group. Multi-vessel treatment was more often performed in the stable CAD group than in the ACS group. Regarding the medications at hospital discharge, statins, β-blockers and angiotensin converting enzyme inhibitors/angiotensin II receptor blockers were more often prescribed in the ACS group than in the non-ACS group. Maximum approved doses of strong statins were very infrequently implemented (Table 1).

Discontinuation of thienopyridine

Thienopyridine was discontinued within 4-month in 455 patients (94.0%) in the ACS group and 977 patients (94.3%) in the stable CAD group. Cumulative 1-year incidence of persistent discontinuation of thienopyridine was 96.7% in the ACS group and 96.8% in the stable CAD group (P = 0.34) (Fig 2).

Fig 2

Cumulative incidence of persistent discontinuation of thienopyridine.

ACS, acute coronary syndrome; CAD, coronary artery disease; PCI, percutaneous coronary intervention.

Clinical outcomes through 1-year

Cumulative 1-year incidence of the primary endpoint was very low and not significantly different between the ACS and stable CAD groups (2.3% versus 3.0%, P = 0.42) (Fig 3 and Table 2). In the multivariable analysis, there was no excess risk of the ACS group relative to the stable CAD group for the primary endpoint (adjusted HR 0.94, 95% CI 0.44–1.87, P = 0.87) (Table 3). Regarding the major secondary endpoints, the cumulative incidences of TIMI major/minor bleeding and a composite of cardiovascular death, MI, stroke and definite ST were also not significantly different between the ACS and stable CAD groups. There was no definite/probable ST through 1-year after PCI in both groups (Fig 4).

Fig 3

Cumulative incidence of the primary endpoint.

Primary endpoint was defined as a composite of cardiovascular death, MI, stroke, definite ST and TIMI major/minor bleeding. MI, myocardial infarction; ST, stent thrombosis; TIMI, Thrombolysis in Myocardial Infarction; ACS, acute coronary syndrome; CAD, coronary artery disease; PCI, percutaneous coronary intervention.

Table 2

Clinical outcomes at 12-month.

	No. of patients with at least one event		P Value
	(Cumulative incidence)
	ACS	Stable CAD
	N = 487	N = 1038
Primary Endpoint	11 (2.3%)	31 (3.0%)	0.42
Death
All-cause	5 (1.0%)	25 (2.4%)	0.07
Cardiac death	2 (0.4%)	7 (0.7%)	0.53
Cardiovascular death	2 (0.4%)	8 (0.8%)	0.42
Non-cardiac death	3 (0.6%)	18 (1.7%)	0.08
Myocardial infarction	1 (0.2%)	3 (0.3%)	0.76
Stroke
Any	4 (0.8%)	13 (1.3%)	0.45
Ischemic	3 (0.6%)	11 (1.1%)	0.4
Hemorrhagic	2 (0.4%)	2 (0.2%)	0.44
Bleeding
TIMI major	4 (0.8%)	8 (0.8%)	0.92
TIMI minor/major	6 (1.2%)	9 (0.9%)	0.5
TIMI minimal/minor/major	14 (2.9%)	23 (2.2%)	0.44
GUSTO severe	4 (0.8%)	6 (0.6%)	0.59
GUSTO moderate/severe	4 (0.8%)	12 (1.2%)	0.55
Definite stent thrombosis	0 (0%)	0 (0%)
Stent thrombosis
Possible	0 (0%)	6 (0.6%)	0.09
Probable	0 (0%)	0 (0%)
Definite or probable	0 (0%)	0 (0%)
Definite, probable or possible	0 (0%)	6 (0.6%)	0.09
Death or myocardial infarction	6 (1.2%)	28 (2.7%)	0.07
Cardiovascular death or myocardial infarction	3 (0.6%)	11 (1.1%)	0.4
Cardiovascular death, MI or stroke	7 (1.4%)	24 (2.3%)	0.26
Cardiovascular death, MI, stroke or definite ST	7 (1.4%)	24 (2.3%)	0.26
Target-lesion revascularization	8 (1.7%)	22 (2.2%)	0.52
Target-vessel revascularization	15 (3.1%)	40 (3.9%)	0.44
Any coronary revascularization	30 (6.2%)	79 (7.7%)	0.28
Coronary-artery bypass grafting	1 (0.2%)	2 (0.2%)	0.96

Values are expressed as number (%).

Cumulative incidence was estimated by Kaplan-Meier method.

ACS = acute coronary syndrome; CAD = coronary artery disease; TIMI = Thrombolysis in Myocardial Infarction; GUSTO = Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries; MI = myocardial infarction; ST = stent thrombosis.

Table 3

Unadjusted and adjusted risks of the ACS versus non-ACS and the effects of the risk-adjusting variables for the primary endpoint.

	Unadjusted	P value	Adjusted	P value
	HR (95%CI)		HR (95%CI)
ACS	0.75 (0.36–1.46)	0.41	0.94 (0.46–1.92)	0.87
Age > = 75 years	2.53 (1.38–4.76)	0.003	2.1 (1.11–3.94)	0.02
Diabetes	0.76 (0.39–1.42)	0.4	0.71 (0.37–1.36)	0.3
Hemodialysis	2.04 (0.49–5.62)	0.28	1.62 (0.49–5.36)	0.43
Atrial fibrillation	2.53 (1.18–4.97)	0.02	2.03 (0.98–4.19)	0.06
Prior myocardial infarction	1.48 (0.69–2.91)	0.29	1.54 (0.74–3.19)	0.24
Peripheral vascular disease	3.14 (1.46–6.15)	0.005	2.54 (1.23–5.28)	0.01
Statins use	0.78 (0.4–1.67)	0.5	0.9 (0.43–1.88)	0.78

ACS = acute coronary syndrome, HR = hazard ratio, CI = confidence interval.

Fig 4

Clinical outcomes at 1-year.

Event rates indicated the cumulative 1-year incidence estimated by Kaplan-Meier method. Primary endpoint was defined as a composite of CV death, MI, stroke, definite ST and TIMI major/minor bleeding. ACS, acute coronary syndrome; CAD, coronary artery disease; CV death, cardiovascular death; MI, myocardial infarction; ST, stent thrombosis; TIMI, Thrombolysis in Myocardial Infarction.

Clinical outcomes between 3- and 12-month

Between 3- and 12-month, the cumulative incidence of the primary endpoint was not significantly different between the ACS and stable CAD groups (1.3% versus 2.4%, P = 0.16) (Fig 5 and Table 4). Regarding the major secondary endpoints, the cumulative incidences of TIMI major/minor bleeding and a composite of cardiovascular death, MI, stroke and definite ST were also not significantly different between the ACS and stable CAD groups. No patients had definite or probable ST between 3- and 12-month in both groups. Cumulative incidences of all-cause death, non-cardiac death and a composite of death or MI were significantly lower in the ACS group than in the stable CAD group (Table 4).

Fig 5

Cumulative incidence of the primary endpoint between 3-month and 12-month.

Primary endpoint was defined as a composite of cardiovascular death, MI, stroke, definite ST and TIMI major/minor bleeding.

Table 4

Clinical outcomes between 3-month and 12-month.

	No. of patients with at least one event		P Value
	(Cumulative incidence)
	ACS	Stable CAD
Primary Endpoint	6 (1.3%)	24 (2.4%)	0.16
Death
All-cause	2 (0.4%)	23 (2.2%)	0.01
Cardiac death	1 (0.2%)	7 (0.7%)	0.24
Cardiovascular death	1 (0.2%)	7 (0.7%)	0.24
Non-cardiac death	1 (0.2%)	16 (1.6%)	0.02
Myocardial infarction	1 (0.2%)	1 (0.1%)	0.59
Stroke
Any	1 (0.2%)	10 (1.0%)	0.1
Ischemic	1 (0.2%)	8 (0.8%)	0.18
Hemorrhagic	1 (0.2%)	2 (0.2%)	0.96
Bleeding
TIMI major	3 (0.6%)	7 (0.7%)	0.89
TIMI minor/major	4 (0.8%)	8 (0.8%)	0.92
TIMI minimal/minor/major	10 (2.1%)	16 (1.6%)	0.48
GUSTO severe	3 (0.6%)	4 (0.4%)	0.54
GUSTO moderate/severe	3 (0.6%)	8 (0.8%)	0.73
Definite stent thrombosis	0 (0%)	0 (0%)
Stent thrombosis
Possible	0 (0%)	6 (0.6%)	0.09
Probable	0 (0%)	0 (0%)
Definite or probable	0 (0%)	0 (0%)
Definite, probable or possible	0 (0%)	6 (0.6%)	0.09
Death or myocardial infarction	3 (0.6%)	24 (2.3%)	0.02
Cardiovascular death or myocardial infarction	2 (0.4%)	8 (0.8%)	0.41
Cardiovascular death, MI or stroke	3 (0.6%)	18 (1.8%)	0.08
Cardiovascular death, MI, stroke or definite ST	3 (0.6%)	18 (1.8%)	0.08
Target-lesion revascularization	8 (1.7%)	21 (2.1%)	0.6
Target-vessel revascularization	15 (3.1%)	37 (3.6%)	0.61
Any coronary revascularization	29 (6.0%)	69 (6.8%)	0.56
Coronary-artery bypass grafting	1 (0.2%)	2 (0.2%)	0.96

Values are expressed as number (%).

Cumulative incidence was estimated by Kaplan-Meier method.

Abbreviations are as in Table 2.

Propensity matched analysis

As a sensitivity analysis, we compared the clinical outcomes between the ACS and stable CAD patients in the propensity matched cohort. Baseline characteristics were similar in terms of higher age, diabetes, hemodialysis, AF, prior MI, PVD and statin use between the 2 groups. Dyslipidemia, prior PCI and multivessel disease were more included in the stable CAD group, while current smoker were more often found in the ACS group (S2 Table). Cumulative 1-year incidence of the primary endpoint were similar between the ACS and stable CAD groups (2.3% versus 2.1%, P = 0.82) (Fig 6 and S3 Table).

Fig 6

Clinical outcomes at 1-year in the propensity matched cohort.

Event rates indicated the cumulative 1-year incidence estimated by Kaplan-Meier method. Primary endpoint was defined as a composite of CV death, MI, stroke, definite ST and TIMI major/minor bleeding. ACS, acute coronary syndrome; CAD, coronary artery disease; CV death, cardiovascular death; MI, myocardial infarction; ST, stent thrombosis; TIMI, Thrombolysis in Myocardial Infarction.

Discussion

The main finding of the current study is that stopping DAPT at 3-month after CoCr-EES implantation in patients with ACS was as safe as that in patients with stable CAD.

The current guidelines recommend 6-month DAPT after DES implantation in patients with stable CAD.[1,2] However, there is a widely recognized notion that patients who presented with ACS have increased risk for subsequent atherothrombotic events as compared with those with stable CAD. Therefore, prolonged DAPT duration is recommended for more intensive prophylaxis for progressive atherothrombosis.[11,12] Current recommendation of at least 1 year DAPT duration in ACS patients is based on the assumption that increased plaque vulnerability in ACS patients would be stabilized up to 1 year after the index ACS event. However, we previously reported that patients with acute myocardial infarction (AMI) as compared with those without AMI have similar cardiovascular event risk beyond 3 months after PCI, suggesting that stabilization of plaque vulnerability in ACS patients might have been achieved earlier than the currently assumed time period of 1 year.[13] In the meta-analyses of trials comparing DAPT duration after PCI, prolonged DAPT as compared with short DAPT was associated with increased risk of major bleeding and with a signal of increased mortality. [14,15] Therefore, we have a reasonable rationale to explore shortening of the mandatory DAPT duration after DES implantation in ACS patients.

There is a scarcity of randomized trials exploring short DAPT in ACS patients. In the PCI-CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) study, long-term administration of clopidogrel after PCI in patients with non-ST elevation ACS was associated with a lower rate of cardiovascular death, MI, or any revascularization.[16] However, the study was conducted almost 20 years ago, when the implementation of the secondary preventive measures was much different from that in contemporary clinical practice. Furthermore, the study design of the PCI-CURE study might be flawed, because pretreatment of clopidogrel before PCI was implemented only in those patients assigned to long-term clopidogrel, but not in those patients assigned to placebo. In the SMART-DATE (Six-month versus 12-month or longer dual antiplatelet therapy after percutaneous coronary intervention in patients with acute coronary syndromes) trial, 6-month DAPT was non-inferior to 12-month DAPT in patients with ACS with new-generation DES in terms of a composite of all-cause death, MI, or stroke at 18 months (4.7% versus 4.2%, P for non-inferiority = 0.03).[17] In the DAPT-STEMI (Six Versus Twelve Months of Dual Antiplatelet Therapy After Drug-Eluting Stent Implantation in ST-Elevation Myocardial Infarction) trial, 6-month DAPT was also non-inferior to 12-month DAPT in patients with STEMI undergoing PCI with zotarolimus-eluting stent in terms of the primary endpoint of a composite of all-cause mortality, MI, revascularization, stroke, and TIMI major bleeding at 18 months (4.8% versus 6.6%, P for non-inferiority = 0.004, and P for superiority = 0.26).[18] In contrast, in a network meta-analysis, 3-month DAPT, but not 6-month DAPT, was associated with higher rates of MI or ST as compared to 12-month DAPT in ACS patients, but not in stable CAD patients.[19] In this meta-analysis, data of the 3-month DAPT were derived from the RESET (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation), and the OPTIMIZE (Optimized Duration of Clopidogrel Therapy Following Treatment With the Zotarolimus-Eluting Stent in Real-World Clinical Practice) randomized trials. [20,21] In the RESET and OPTIMIZE trials, 3-month DAPT was evaluated with use of Endeavor™ zotarolimus-eluting stents, which has late lumen loss similar to BMS. CoCr-EES was reported to have significantly lower rates for ST as compared with BMS in patients with STEMI in the 1-year results of the EXAMINATION (Everolimus-Eluting Stents Versus Bare-Metal Stents in ST-Segment Elevation Myocardial Infarction) trial.[22] Therefore, the efficacy of short DAPT in ACS patients should be evaluated in those patients treated with new-generation DES, CoCr-EES in particular. The GLOBAL LEADERS trial explored the efficacy of the experimental regimen of 1-month DAPT followed by ticagrelor monotherapy as compared with the standard regimen of 12-month DAPT followed by aspirin monotheray in patients with stable CAD or ACS who underwent PCI with a biolimus A9-eluting stent.[23] Overall, the study failed to demonstrate the superiority of the experimental regimen for the primary endpoint of all-cause death or new Q-wave MI (rate ratio 0.87 [95% CI 0.75–1.01]; p = 0.073).[23] However in the ACS population, dropping aspirin beyond 1-month and continuing ticagrelor monotherapy was associated with a significantly lower risk for major bleeding with a trend for decreasing mortality at 1-year, suggesting that the current DAPT regimen with aspirin and ticagrelor for 1 year in ACS patients might be too intensive. [24]

In the present post-hoc analysis of the STOPDAPT trial demonstrated that 3-month DAPT after CoCr-EES implantation was associated with similarly low event rate for the primary endpoint without any definite ST events in both ACS and stable CAD patients, although 47% of ACS patients had troponin-negative UA at low-risk of event recurrence. Furthermore, the STOPDAPT trial had mostly enrolled stable patients after PCI, which might be one of the reasons for the low event rate even in ACS patients. Therefore, 3-month DAPT could be an option in selected patients with ACS in the new-generation DES era. In the STOPDAPT-2 trial including approximately 40% of ACS patients, 1-month DAPT followed by clopidogrel mono-therapy provided a net clinical benefit for ischemic and bleeding events over 12-month DAPT with aspirin and clopidogrel after CoCr-EES implantation.[25] The STOPDAPT-2 ACS trial are ongoing to evaluate 1-month DAPT followed by clopidogrel monotherapy as compared with 12-month DAPT with aspirin and clopidogrel in all-comer patients undergoing PCI using CoCr-EES (ClinicalTrials.gov: NCT03462498).

Study limitation

There are several important limitations in the current study. First, selection bias toward inclusion of patients with lower ischemic risk should be considered when interpreting the result of this study. Despite the all-comer study design, those ACS patients with large thrombotic burden and/or extensive atherosclerotic burden might well have not been included in this short DAPT trial. Indeed, patients with STEMI and NSTEMI were more often included in the non-enrolled group. Second, baseline characteristics were more complex in the stable CAD group than in the ACS group. Multivariable analysis might not be able to fully adjust the measured and unmeasured confounders. Third, patients received clopidogrel as a P2Y12 receptor blocker even in patients with ACS. Prasugrel or ticagrelor were not available in the enrollment period between 2012 and 2013 in Japan. Prasugrel or ticagrelor are generally preferred in ACS patients in the current clinical practice, especially in non-Asian patients. Fourth, as this study was conducted only in Japanese centers, the external validity to non-Asian patients would be limited. Finally, the sample size calculation was conducted for the main analysis, but not for this post-hoc analysis. Therefore, the number of patients enrolled in this study was underpowered, and not large enough to evaluate the low frequency event such as ST, especially in those with ACS.

Conclusion

Stopping DAPT at 3 months after CoCr-EES implantation in patients with ACS including 47% of unstable angina was as safe as that in patients with stable CAD.

Patient characteristics: Enrolled versus non-enrolled patients.

(DOCX)

Click here for additional data file.

Patient characteristics in propensity matched cohort.

(DOCX)

Click here for additional data file.

Clinical outcomes at 12 months in propensity matched cohort.

(DOCX)

Click here for additional data file.

STOPDAPT ShorT and OPtimal duration of Dual AntiPlatelet Therapy study.

(PDF)

Click here for additional data file.

(DOCX)

Click here for additional data file.

24 Sep 2019

PONE-D-19-23933

One-year Clinical Outcomes of Patients With versus Without Acute Coronary Syndrome with 3-Month Duration of Dual Antiplatelet Therapy after Everolimus-eluting Stent Implantation

PLOS ONE

Dear Dr. Kimura,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

All reviewers have raised serious concerns about the comparison between two very different populations (ACS vs non-ACS) in terms of baseline characteristics and the about low incidence of events in the ACS group, that mostly consists of patients with unstable angina.

Reviewer 2 has raised concerns about population selection bias, that may hamper the generalizability of these results, and especially about the need to provide non-inferiority analysis rather than a superiority analysis.

Reviewer 4 has raised concerns about the actual differences between ACS and stable patients and suggested to adjust for residual confounders by providing a propensity matching.

All reviewers raised concerns about the actual risk of patients with ACS as compared to stable. CAD. Indeed, reviewers underline that the risk of events was higher in stable CAD patients and that ACS appears protective at univariate analysis, that is contraintutive.

Statistical reviewer (Reviewer 3) has requested to upload data and codes to comply with Journal’s guidelines and policy.

I have concerns about the real need to compare two different populations from two different trials. Probably this part of the study should be omitted, else a complex propensity matching between patients from the different trials should be performed.

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Reviewers' comments:

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Comments to the Author

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Reviewer #5: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

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Reviewer #2: No

Reviewer #3: Yes

Reviewer #4: No

Reviewer #5: I Don't Know

**********

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

Reviewer #4: Yes

Reviewer #5: No

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The submitted manuscript is a post-hoc analysis of the STOPDAPT trial, investigating the safety of a 3-month DAPT regimen after successful CoCr-EES implantation in patients with or without ACS. The authors aimed at evaluating if a short DAPT regimen is similarly safe in SCAD and ACS patients since those with an acute presentation have been traditionally considered at higher risk for recurrent thrombotic events and so in need for a more prolonged (at least 1-year) DAPT. The trial has a valid scientific ground, and methods and analyses are rigorously conducted. The authors concluded that “Stopping DAPT at 3-month after CoCr-EES implantation in patients with ACS was as safe as that in patients with stable CAD.”

Detailed comments to be considered:

- In the main paper published in 2016, a sub-group analysis investigating the ACS vs. non-ACS group already showed the absence of a significant interaction between clinical presentation and outcomes. Thus, these results are only confirmatory of previously published data. However, taking into account the recognized limits of sub-group analyses, the presented data are of potential interest addressing this issue with a more rigorous and detailed approach.

- The rate of the primary endpoint events was similar in the two cohorts of patients. However, while the rate of events in the stable CAD group (3%) is in line with recent epidemiological studies, the rate of 1-year events for the ACS (2.3%) appears unusually low as compared with other reports, and less than half of the RESET cohort (4.8%) that was used as historical reference by the authors. Surprisingly, the rate of events results even higher (although only numerically) in the SCAD group compared with the ACS, which is difficult to justify biologically. This difference is even more evident at the land-mark analysis, where the risk of future events in SCAD is almost twice of that in ACS (2.4% s. 1.3%). These results might be at least in part related to the high prevalence of patients with unstable angina in the ACS group. Indeed, 1,266 patients out of 1,525 (83% of the total population) had a non-MI presentation, with only 44 patients having an NSTEMI. For this reason, no conclusions should be drawn for the ACS “troponin-positive” patients, which actually represent those at higher risk of recurrent thrombotic events and for which more concerns exist in the case of premature DAPT discontinuation. Accordingly, the present results cannot be applied to the whole ACS spectrum but limited to those at low-risk of event recurrence (comparable to those with SCAD). The authors should carefully discuss this point in the manuscript and be more cautious with their conclusions.

- It is not clear which proportion of patients received intracoronary imaging to guide PCI. In the STOPDAPT-2, the (same) investigators reported a high rate of intracoronary imaging guidance according to the clinical practice in Japan. They stated "...the vast majority of patents in this study underwent PCI guided by intracoronary imaging devices, which are rarely used in the United States and Europe. Therefore, caution is warranted in extrapolating the current study results outside of Japan". Please, clarify the percentage of patients receiving intracoronary imaging in the present analysis, also reporting data for stable CAD and ACS patients separately (if available).

- Introduction: “However, it is unclear whether the distinction between ACS and stable CAD regarding the recommendation on the DAPT duration was based on a solid scientific rationale.” This sentence should be probably reworded, as the scientific rationale for recommending a longer DAPT in patients with ACS, compared with those with stable CAD, is robust and based on the higher risk of future thrombotic events.

- “Ethics” section: The full list of the individual centers participating in the trial can be reported in the supplementary appendix.

- “Procedures” section: “Antiplatelet regimen included aspirin (≥81mg daily) …”. Which was the maximum dose of daily aspirin allowed in the trial? Did any patients receive ASA >100 mg? Please, report these data (if available).

- All patients enrolled in the trial were treated with clopidogrel. Please, briefly discuss the absence of patients receiving ticagrelor/prasugrel.

- Endpoint and definition: In the era of high-sensitivity troponin, the diagnosis of UA is becoming rarer than in the past. Please clarify in the text which cardiac biomarkers were used for distinguishing UA vs NSTEMI, and how troponin was evaluated in the study (high-sensitivity?). Were the same methods for dosing cardiac biomarkers used across the 58 centers involved in the study (or not)? This might be a potential source of confounding in a multicentre study. Moreover, the proportion of UA patients appears very high in what the authors define as an all-comers population, also if compared with the STOPDAPT-2 population. The authors report in the flow-chart of the study that 2,054 patients were excluded (actually, more than those enrolled). Can the authors clarify which was the proportion of patients with an ACS (UA, STEMI, and NSTEMI) or SCAD in the "non-enrolled" population? We can assume most of these patients were excluded because presenting with STEMI or NSTEMI and then considered by the physicians at high-risk of complications if treated with a short DAPT. This (prudent) attitude by the investigators might have biased patients enrollment, resulting in a "low-risk" study population (substantially including UA and SCAD, and excluding STEMI and NSTEMI), for which the conclusions should be applied. In this context, it would be of interest if the authors could provide the GRACE score of the NSTE-ACS patients.

- Statistical analysis: “Sample size calculation of this study was previously described.” The sample size was previously described for the main analysis, and not for this post-hoc analysis. Conversely, the present analysis seems to be underpowered and non-conclusive for its purpose. Please clarify.

- How were the patients on oral anticoagulants managed? Did the duration of DAPT in this subgroup differ from the rest of the population?

- Conclusions: should be extended, and reworded to clarify that most of ACS patients were UA.

- Please, better define which medications were considered among "strong statins".

- Please, diffusely correct typos in the text: i.e., "Statins use" instead of "Stains use" in Table 3.

Reviewer #2: In this study the authors aim at comparing the outcome in patients with ACS versus stable CAD undergoing PCI and subsequent double antiplatelet therapy (DAPT) with clopidogrel plus aspirin) for 3 months, followed by single antiplatelet therapy (SAPT) with aspirin for 12 months. Furthermore, the authors compared the clinical outcomes of the STOPDAPT trial with the RESET trial in both ACS and stable CAD patients. The authors concluded that a 3-month DAPT in ACS patients is as safe as in stable CAD patients.

The aim of this study is interesting; however, I have several comments to the authors.

Major comments:

• The authors stated that, among candidate patients, only those judged eligible by the physician were enrolled. In fact, among 3580 candidate patients, 2054 (far more than the half) were not enrolled. As the authors stated in the limitation section, this leads to a selection bias, that should be more clearly explained by the authors in discussing the results. Furthermore, as in a previous paper of the same trial (DOI 10.1007/s12928-015-0366-9), the main characteristics of not enrolled patients should be presented (also in appendix) or, at east, cited.

• Although the eligibility criteria of the RESET were comparable to those of the STOPDAPT, in the former study all patients with previous DES were excluded. Considering that, in RESET study, more patients that in STOPDAPT had previous PCI, a consistent number of patients in this study had a previous BMS implanted. Furthermore, in STOPDAPT only those judged eligible by the physician were enrolled. Importantly the baseline characteristics of the population of the two trials are strongly different (as shown in table s1), suggesting a higher risk profile in RESET population (more diabetics, more end stage CKD, more MVD…). This suggest that many confounders could bias the results and an adjustment through a propensity score should be performed before comparing the outcome of this two populations.

• There are significant differences between the ACS and stable CAD group in terms of many important variables (more AF, PAD, previous MI, Previous PCI/CABG, MVD in stable CAD group). Since these large differences between the two arms could be not adequately adjusted by a multivariable analysis, an adjustment throughout a propensity score would be a better option.

• The fact that in stable CAD 6 possible stent thrombosis occurred against 0 in ACS group clearly reflect a difference among the two populations. The same is for the difference, in terms death ((particularly non-cardiac death), between ACS and CAD at the landmark analysis. It is difficult to believe that that chronic CAD patients had a worse outcome.

• If the aim of the study is to demonstrate that, after an ACS, a 3-month DAPT after CoCr-EES implantation in patients with ACS is as safe as (or not less safe than) in stable CAD patients, a non-inferiority analysis should be planned. In fact, the non-significance at a superiority analysis cannot be used to demonstrate that there is not any significant difference between the two arms nor that an arm is not inferior to a second arm. This is particularly true for the endpoint for which the study is underpowered (e.g. stent thrombosis).

• It should be discussed that, for this study, the external validity to non-Asian patients is limited firstly because the study was conducted only in Japanese centres, secondly because the main P2Y12 inhibitor used was Clopidogrel (whereas ticagrelor or prasugrel should be generally preferred, especially in non-Asian patients)

Minor comments:

• In line 268, why do the authors use the plural form for STOPDAPT-2 ACS trial?

• I think that hyphens are sometimes incorrectly used. For example, in conclusion section, “Stopping DAPT at 3-month” should be replaced with “Stopping DAPT at 3 months”.

Reviewer #3: The manuscript addresses an interesting topic. The data are of certain interest and the employed methods are sound. The results might be very useful for future researchers.

Some comments follow.

1. Data are not fully available. This is not in line with the journal's guidelines. Please, update the data and the code used to obtain parameters estimates. This would ensure the reproducibility of the results and allow the reviewers to check for the appropriateness of the methods.

2. My main doubts concern some aspects of the modelling.

2a. Firstly, the authors must check for heterogeneity between centers. A major, and quite strong, assumption in the modelling is that patients belonging to different centers are homogeneous, i.e. no differences arise between multiple centers. Please, provide an extension of the modelling that takes into account for the presence of heterogeneity between centers. A random effects model may be an option.

2b. The use of Cox survival modelling is sound. Nevertheless, several assumptions must be fulfilled to ensure a proper statistical inference. It is desirable to determine whether a fitted Cox regression model adequately describes the data. I will briefly consider three kinds of diagnostics: for violation of the assumption of proportional hazards; for influential data; and for nonlinearity in the relationship between the log hazard and the covariates. Please, provide evidence that model assumptions are fulfilled or, if thery not, modify the model specification accordingly.

2c. As minor points: please explain the difference between adjusted and non-adjusted coefficients; furthermore, please consider a model selection procedure (e.g. LASSO) to identify the relevant variables.

Reviewer #4: - In consideration of the relevant clinical and angiographic differences between the two compared groups, you have to perform a propensity pair-matched analysis, to increase accuracy of your results. Your current adjusted analysis is very limited and you have the number to perform a better analysis.

- Events tended to be higher in the stable CAD groups, please provides analysis to better understand this greater risk.

- You have to better explain what are the scientific and practical implications of your data and findings. Try to reinforce the overall meaning of your data.

Reviewer #5: It is unclear how events occurred more often in the Stable CAD rather than in the ACS arm. ACS patients including NSTEMI and STEMI patients have a significantly higher risk of ischemic and bleeding complication compared to stable patients. This point should be thoroughly evaluated as it hampers to draft conclusion from this data. In fact ACS at univariate analysis seems tendentially protective from adverse events, which tend to lessen after adjustment. Ultimately it is not clear to this reviewer the comparison between ACS and SCAD for clinical events considering that due to more conservative patient selection in the ACS arm (see Table 1). STOPDAPT as a single arm study cannot either give information regarding the impact of different terms of DAPT duration.

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Reviewer #1: Yes: Felice Gragnano

Reviewer #2: No

Reviewer #3: No

Reviewer #4: No

Reviewer #5: No

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17 Nov 2019

Responses to the editor’s comments

We appreciate the kind editing and comments from the editor.

We amended the manuscript as suggested by the editor.

Editor:

I have concerns about the real need to compare two different populations from two different trials. Probably this part of the study should be omitted, else a complex propensity matching between patients from the different trials should be performed.

We appreciate the comments.

As the editor suggested, we omitted the comparison of two different populations from the STOPDAPT and RESET trials.

Submitted filename: Responses to reviewers STOPDAPT ACS final.docx

Click here for additional data file.

3 Dec 2019

PONE-D-19-23933R1

One-year Clinical Outcomes of Patients With versus Without Acute Coronary Syndrome with 3-Month Duration of Dual Antiplatelet Therapy after Everolimus-eluting Stent Implantation

PLOS ONE

Dear Dr. Kimura,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

All reviewers appreciated your revised versions of the manuscript. While clinical reviewers do not have further  concerns, statistical reviewer asks to address a residual comment about the Cox model. Importantly, this comment will not influence the final decision to accept this manuscript.

We would appreciate receiving your revised manuscript by Jan 17 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

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Giuseppe Andò, M.D., Ph.D.

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PLOS ONE

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Reviewers' comments:

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Comments to the Author

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Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

Reviewer #3: (No Response)

Reviewer #4: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: The authors addressed appropriately all the comments in the manuscript. No further comments are needed.

Reviewer #2: All my comments have been addressed.

Reviewer #3: Thank you very for having addressed most of the comments I raised.

One point needs still to be addressed. Influential observations and nonlinearities in the Cox model should be analysed. Yhe martingale residuals may be plotted against covariates to detect nonlinearity, and may

also be used to form component-plus-residual (or partial-residual) plots, again in the manner of linear and

generalized linear models. A matrix of estimated changes in the regression coefficients upon deleting each observation in turn may be used to detect influential observations.

Reviewer #4: Reviewer comments were addressed and the manuscript has been improved. I have no further comments.

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Reviewer #1: No

Reviewer #2: Yes: Marco Di Maio

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18 Dec 2019

Responses to the reviewer’s comments

We appreciate the kind editing and comments from the editor and the reviewers.

Reviewer #3:

One point needs still to be addressed. Influential observations and nonlinearities in the Cox model should be analyzed. Yhe martingale residuals may be plotted against covariates to detect nonlinearity, and may also be used to form component-plus-residual (or partial-residual) plots, again in the manner of linear and generalized linear models. A matrix of estimated changes in the regression coefficients upon deleting each observation in turn may be used to detect influential observations.

Thank you very much for your comment.

As reviewer commented, influential observations and nonlinearities in the Cox model could be analyzed. Proportional hazard assumptions for the risk-adjusting variables were assessed on the plots of log (time) versus log [-log (survival)] stratified by the variable. The assumptions were verified to be acceptable for all the variables. We thus here show the plots for age, atrial fibrillation (AF), and peripheral vascular disease (PVD) because these variables had smaller p-values.

The main comparison of this study is ACS versus non-ACS patients, and thus other covariates are used for adjustment in the multivariate models and not relevant to the main results of this study. Therefore, the detailed inspections for residuals or linearity are not considered relevant to the manuscript and they do not affect on our results. However, we are happy to conduct these analyses if the editors and reviewers considered it necessary to accept our manuscript.

Submitted filename: Responses to reviewers STOPDAPT ACS revise2 final version.docx

Click here for additional data file.

26 Dec 2019

One-year Clinical Outcomes of Patients With versus Without Acute Coronary Syndrome with 3-Month Duration of Dual Antiplatelet Therapy after Everolimus-eluting Stent Implantation

PONE-D-19-23933R2

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12 Feb 2020

PONE-D-19-23933R2

One-year Clinical Outcomes of Patients With versus Without Acute Coronary Syndrome with 3-Month Duration of Dual Antiplatelet Therapy after Everolimus-eluting Stent Implantation

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