Sensitivity Analysis
The overall treatment effect of S-DAPT versus L-DAPT remained consistent for most of the endpoints using either a random
or a fixed effects model and by stratifying for prevalence of acute coronary syndrome presentation and patient age ≥ 65 year-old
(Online Supplementary Figure 3). However, the thrombotic benefit in stent thrombosis and myocardial infarction associated with LDAPT was attenuated in studies with a mean patient age ≥ 65 year-old. Conversely, the lower risk of bleeding associated with SDAPT was of similar magnitude and direction across the subgroups.
Following exclusion of the DAPT study from the analyses, ST association with S-DAPT was still statistically significant using
a fixed effect model (OR: 1.51; 95% CI: 1.05 – 2.16; p = 0.024), while it was of borderline significance using a random effect model
(OR: 1.43; 95% CI: 0.98 – 2.07; p = 0.059). Conversely, even after DAPT study exclusion, S-DAPT was still associated with lower
risk of clinically significant bleeding (CSB) with both fixed and random effect model. Following exclusion of the DAPT trial all-cause
mortality OR between S-DAPT and L-DAPT was 0.92 (95% CI: 0.76 – 1.10; p = 0.387). All the other endpoints after DAPT trial
exclusion remained consistent with the primary analysis.
1
Online Supplementary Table 1. Bleeding definitions used in randomized controlled trials.
Definition
Severity
BARC
3 (Major)
Description
Type 3a: Overt bleeding plus hemoglobin drop of 3 to < 5 g/dL* (provided hemoglobin drop is related to bleed); Any transfusion
with overt bleeding.
Type 3b: Overt bleeding plus hemoglobin drop ≥ 5 g/dL* (provided hemoglobin drop is related to bleed); Cardiac tamponade;
Bleeding requiring surgical intervention for control (excluding dental/nasal/skin/hemorrhoid); Bleeding requiring intravenous
vasoactive agents.
Type 3c: Intracranial hemorrhage (does not include microbleeds or hemorrhagic transformation, does include intraspinal);
Subcategories confirmed by autopsy or imaging or lumbar puncture;
Intraocular bleed compromising vision.
5 (Fatal)
Type 5a: Probable fatal bleeding; no autopsy or imaging confirmation but clinically suspicious.
Type 5b: Definite fatal bleeding; overt bleeding or autopsy or imaging confirmation.
TIMI
Major
Any intracranial bleeding (excluding microhemorrhages < 10 mm evident only on gradient-echo MRI); Clinically overt signs of
hemorrhage associated with a drop in hemoglobin of ≥ 5 g/dL; Fatal bleeding (bleeding that directly results in death within 7 d).
GUSTO
Minor
Clinically overt (including imaging), resulting in hemoglobin drop of 3 to < 5 g/dL.
Severe
Intracerebral hemorrhage; Resulting in substantial hemodynamic compromise requiring treatment.
Moderate
STEEPLE
Major
Requiring blood transfusion but not resulting in hemodynamic compromise.
Fatal bleeding; Retroperitoneal, intracranial, or intraocular bleeding; Bleeding that causes hemodynamic compromise requiring
specific treatment; Bleeding that requires intervention (surgical or endoscopic) or decompression of a closed space to stop or
control the event.
Clinically overt bleeding, requiring any transfusion of ≥ 1 U PRBC or whole blood; Clinically overt bleeding, causing a decrease
in hemoglobin of ≥ 3 g/dL (or, if hemoglobin level is not available, a decrease in hematocrit of ≥ 10%).
OPTIMIZE
Major
Incorporate severe GUSTO definition and major REPLACE-2 (Randomized Evaluation of PCI Linking Angiomax to Reduced
2
Clinical Events) definition (Intracranial, intraocular, or retroperitoneal bleeding;
Overt blood loss with hemoglobin decrease > 3 g/dl; Any hemoglobin decrease > 4 g/dL; Transfusion of ≥ 2 U blood products).
3
Online Supplementary Table 2. Randomized Clinical Trials design and definitions. APT: Antiplatelet; ARC: Academic Research
Consortium; BARC: Bleeding Academic Research Consortium; BMS: Bare Metal Stent; CVA: Cerebro-Vascular Accident; CTO:
Chronic Total Occlusion; DAPT: Dual Antiplatelet Therapy; DES: Drug-Eluting Stent; ISR: In-Stent Restenosis; LM: Left Main; MI:
Myocardial Infarction; NSTEMI: Non-ST-Elevation Myocardial Infarction; PCI: Percutaneous Coronary Intervention; STEMI: STElevation Myocardial Infarction; ST: Stent Thrombosis; TE: Thrombo-Embolism; SVG: Saphenous Vein Graft; TIMI: Thrombolysis
In Myocardial Infarction; VKA: Vitamin K Antagonists; WHO: World Heart Organization.
Trial
Year
Randomization
Blinding
Key Exclusion Criteria
Time
ST
MI
Bleeding
Stroke
Definitions
Definitions
Definitions
Definitions
ARC
Universal
TIMI and
Protocol
12-Month Discontinued DAPT Trials
DAPT(8)
2014
12 Months
Double-
Planned surgery needing DAPT interruption within the 30
blind
months after enrollment; life expectancy < 3 years; subjects on
BARC
oral anticoagulation therapy; subjects treated with both BMS
and DES during the index procedure, PCI or surgery between 6
weeks from the index procedure and randomization
DES-LATE(30)
2014
12 Months
Open-label
Contraindication to APT; life expectancy < 1 year;
ARC
Universal
TIMI
Protocol
ARC
Protocol
STEEPLE
Protocol
ARC
NA
TIMI
NA
concomitant vascular disease that required the long-term use of
clopidogrel or other established indications for Clopidogrel
therapy.
ARCTIC-
2014
12 Months
Open-label
Interruption(31)
Indication for chronic anticoagulation with VKA; ongoing
bleeding or recent (< 3 weeks) major surgery; primary PCI for
STEMI; prior history of major bleeding or any contraindication
to APT; high-risk feature of poor compliance to DAPT; any
scheduled surgery during the year after enrollment.
3- or 6-Month Discontinued DAPT Trials
ISAR-SAFE(24)
2014
6 Months
Double-
Previous ST; DES in LM; STEMI or NSTEMI in the previous
4
blind
6 months; Planned surgery within next 6 months with the need
to discontinue DAPT; Active bleeding or bleeding diathesis
ITALIC(23)
2014
Procedure
Open-label
Prior DES implantation within 1 year; Bleeding diathesis;
ARC
Protocol
TIMI
Protocol
ARC
Protocol
BARC
Protocol
ARC
WHO
Protocol
Protocol
ARC
Universal
TIMI
Protocol
ARC
ARC
TIMI
NA
ARC
ARC
TIMI
Protocol
Contraindication to aspirin or Clopidogrel (Prasugrel or
Ticagrelor); Major surgery within the preceding 6 weeks; Any
scheduled surgery during the year after enrollment.
SECURITY(28)
2014
Procedure
-
SVGs lesions; ISRs; LM lesions; STEMI in the 48 hours
before the procedure; NSTEMI in the previous 6 months;
active bleeding or high bleeding risk.
OPTIMIZE(21)
2014
Procedure
Open-label
STEMI for Primary or Rescue PCI; BMS implanted less than 6
months prior to index procedure; previous treatment with DES;
scheduled surgery within 12 months; SVGs lesions; ISRs;
PRODIGY(25)
2012
1 Month
Open-label
History of bleeding diathesis; Major surgery within 15 days;
Active bleeding or previous stroke in the past 6 months; Need
for anticoagulation therapy; planned surgery within 24 months
requiring DAPT interruption
RESET(29)
2012
Procedure
Open-label
MI within 48 hours; Contraindication to anti-platelet agents or
bleeding history within prior 3 months; Prior history of ST,
CVAs, TEs, ST; left main stenosis > 50%; ISRs; CTOs;
bifurcation lesions requiring 2-stent strategy; History of DES
implantation; Overlapped DESs
EXCELLENT
2011
Procedure
Open-label
MI within 72 hours; any stent implanted in the target vessel;
major bleeding within 3 months; elective surgical procedure
within 12 months; left main stenosis > 50%; CTOs; bifurcation
lesions requiring 2-stent strategy
5
Online Supplementary Table 3. Event adjudication by a clinical event committee in randomized controlled trials.
Trial
ST
MI
Stroke
Bleeding
Death
DAPT
+
+
+
+
+
ISAR-SAFE
+
+
+
+
+
ITALIC
+
+
+
+
+
+
+
+
+
+
ARCTIC-Interruption
+
+
+
+
+
OPTIMIZE
+
+
+
+
+
DES-LATE
+
+
+
+
+
PRODIGY
+
+
+
+
+
RESET
+
+
+
+
+
EXCELLENT
+
+
+
+
+
SECURITY
6
Supplementary Figure Legends
Online Supplementary Figure 1. Extended DAPT trials design.
Descriptive diagram illustrating the study design of randomized clinical trials in which dual antiplatelet therapy was discontinued at 12
months. Red Bar: DAPT (Thienopyridine + ASA); Orange Bar: Aspirin alone; Blue Bar: Event-free observational period before
randomization. ASA: Aspirin; DES: Drug-Eluting Stent; PCI: Percutaneous Coronary Intervention.
7
Online Supplementary Figure 2. Abbreviated DAPT trials design.
Descriptive diagram illustrating the study design of randomized clinical trials in which dual antiplatelet therapy was discontinued 3 or
6 months. Red Bar: DAPT (Thienopyridine + ASA); Orange Bar: Aspirin alone; Blue Bar: Event-free observational period before
randomization. ASA: Aspirin; DES: Drug-Eluting Stent; PCI: Percutaneous Coronary Intervention.
8
Online Supplementary Figure 3. Stratified Outcomes in Randomized Clinical Trials.
The combined estimates are reported as odds ratio. Rhombus indicates point estimates and lines indicate the 95% confidence interval.
ACS: Acute Coronary Syndrome; DAPT: Dual Antiplatelet Therapy; S-DAPT: Shorter DAPT; L-DAPT: Longer-DAPT.
9