SUPPLEMENTAL MATERIAL

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SUPPLEMENTAL MATERIAL

Supplementary Fig. S1 Study Flowchart

Records identified through database searching and duplicates removed (n =1,961)

Records excluded due to non- randomized controlled trials and

trials-design (n =35) Additional articles

retrieved from citations and references (n =1)

Records excluded based on titles and abstracts (n =1,922)

Full-text articles assessed for eligibility

(n =39)

Studies included in quantitative synthesis (meta-analysis)

(n =5)

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Supplementary Table S1. Search strategy for relevant literature

1. MEDLINE, PreMEDLINE, and other related databases via PubMed search interface

#1 Search ("Percutaneous Coronary Intervention"[Mesh] or "percutaneous coronary intervention" or PCI or "Angioplasty, Balloon, Coronary"[Mesh] or "coronary stenting")

#2 Search ("Atrial Fibrillation"[Mesh] or "Atrial Fibrillation" or AF or "Acute Coronary Syndrome"[Mesh] or "Acute Coronary Syndrome")

#3 Search (#1 and #2)

#4

Search ("Warfarin"[Mesh] or Warfarin or "vitamin K antagonist" or "Anticoagulants"[Mesh] or Anticoagulant* or (Anticoagulant Drug*) or (Anticoagulation Agent*) or "oral anticoagulant*" or "new oral anticoagulant*" or "direct oral anticoagulant*" or "direct thrombin

inhibitor*" or "factor Xa inhibitor*" or "novel oral anticoagulant*" or "non-vitamin K antagonist oral anticoagulant*" or NOAC or dabigatran or rivaroxaban or apixaban or edoxaban)

#5

Search ("Platelet Aggregation Inhibitors"[Mesh] or "Platelet Aggregation Inhibitor*" or (antiplatelet agent*) or (antiplatelet drug*) or aspirin or clopidogrel or thienopyridine or "P2Y12 inhibitor*" or "Purinergic P2Y Receptor Antagonist*" or "dual antiplatelet therapy" or DAPT or "triple therapy" or TAT)

#8 Search (#3 and #6) Filters: Randomized Controlled Trial; Controlled Clinical Trial; Clinical Trial 2. Embase via Elsevier search interface

#1 'percutaneous coronary intervention'/exp OR 'percutaneous coronary intervention' OR 'transluminal coronary angioplasty'/exp OR 'transluminal coronary angioplasty' OR 'coronary stenting'/exp OR 'coronary stenting'

#2 'atrial fibrillation'/exp OR 'atrial fibrillation' OR af OR 'acute coronary syndrome'/exp OR 'acute coronary syndrome'

#3 #1 AND #2

#4

'warfarin'/exp OR warfarin OR 'anticoagulant agent'/exp OR 'anticoagulant agent*' OR 'anticoagulant drug*' OR 'oral anticoagulant*' OR 'new oral anticoagulant*' OR 'direct oral anticoagulant*' OR 'direct thrombin inhibitor*' OR 'factor xa inhibitor*' OR 'novel oral

anticoagulant*' OR 'non-vitamin k antagonist oral anticoagulant*' OR noac OR dabigatran OR rivaroxaban OR apixaban OR edoxaban

#5

'platelet aggregation inhibitor*' OR 'anticoagulant agent'/exp OR 'antiplatelet agent*' OR 'antiplatelet drug*' OR aspirin OR clopidogrel OR thienopyridine OR 'p2y12 inhibitor*' OR 'purinergic p2y receptor antagonist*' OR 'dual antiplatelet therapy' OR dapt OR 'triple therapy' OR tat

#6 #4 AND #5

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#7 #3 AND #6

#8 #3 AND #6 AND ([controlled clinical trial]/lim OR [randomized controlled trial]/lim) 3. Cochrane Library via Wiley search interface

#1 MeSH descriptor: [Percutaneous Coronary Intervention] explode all trees

#2 "percutaneous coronary intervention" or PCI (Word variations have been searched)

#3 MeSH descriptor: [Angioplasty, Balloon, Coronary] explode all trees

#4 "coronary stenting" (Word variations have been searched)

#5 #1 or #2 or #3 or #4

#6 MeSH descriptor: [Atrial Fibrillation] explode all trees

#7 "Atrial Fibrillation" or AF (Word variations have been searched)

#8 MeSH descriptor: [Acute Coronary Syndrome] explode all trees

#9 "Acute Coronary Syndrome" (Word variations have been searched)

#10 #6 or #7 or #8 or #9

#11 #5 and #10

#12 MeSH descriptor: [Warfarin] explode all trees

#13 Warfarin or "vitamin K antagonist" (Word variations have been searched)

#14 MeSH descriptor: [Anticoagulants] explode all trees

#15

Anticoagulant or "Anticoagulant Drug" or "Anticoagulation Agent" or "oral anticoagulant" or "new oral anticoagulant" or "direct oral anticoagulant" or "direct thrombin inhibitor" or "factor Xa inhibitor" or "novel oral anticoagulant" or "non-vitamin K antagonist oral anticoagulant" or NOAC or dabigatran or rivaroxaban or apixaban or edoxaban (Word variations have been searched)

#16 #12 or #13 or #14 or #15

#17 MeSH descriptor: [Platelet Aggregation Inhibitors] explode all trees

#18

"Platelet Aggregation Inhibitor" or "antiplatelet agent" or "antiplatelet drug" or aspirin or clopidogrel or thienopyridine or "P2Y12 inhibitor" or "Purinergic P2Y Receptor Antagonist" or "dual antiplatelet therapy" or DAPT or "triple therapy" or TAT (Word variations have been searched)

#19 #17 or #18

#20 #16 or #19

#21 #11 and #20 in Trials

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Supplementary Fig. S2 Risk of bias summary: review authors' judgments about each risk of bias item for each included study

Supplementary Fig. S3 Risk of bias graph: review authors' judgments about each risk of bias item for each included study

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Supplementary Table S2. Network meta-analysis results (A) safety outcomes (B) efficacy outcomes (A) Satety Outcome

TIMI major bleeding

VKA + DAPT 0.59 (0.32 - 1.05) 0.71 (0.41 - 1.21) 0.52 (0.34 - 0.78) VKA + P2Y12 inhibitor 1.22 (0.60 - 2.44) 0.89 (0.47 - 1.74) NOAC + DAPT 0.73 (0.42 - 1.33)

NOAC+ P2Y12 inhibitor TIMI major or minor bleeding

NOAC+ P2Y12 inhibitor Trial-defined primary safety outcome

NOAC+ P2Y12 inhibitor Intracranial hemorrhage

NOAC+ P2Y12 inhibitor (B) Efficacy outcome

Trial-defined primary MACE outcome

NOAC+ P2Y12 inhibitor All-cause death

NOAC+ P2Y12 inhibitor Cardiovascular death

NOAC+ P2Y12 inhibitor Myocardial infarction

NOAC+ P2Y12 inhibitor Stroke

NOAC+ P2Y12 inhibitor Stent thrombosis

NOAC+ P2Y12 inhibitor DAPT, dual antiplatelet therapy; NOAC, non-vitamin K oral anticoagulant; VKA, Vitamin K Antagonist.

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Supplementary Fig. S4 Node splitting results for (A) safety outcome and (B) efficacy outcomes. A: VKA + DAPT, B: VKA + P2Y¹²inhibitor, C: NOAC + DAPT, D: NOAC + P2Y¹²inhibitor. DAPT, dual antiplatelet therapy; NOAC, non-vitamin K oral anticoagulant; VKA, Vitamin K Antagonist.

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Supplementary Fig. S5 Ranking of treatment strategies based on the probability and surface under the cumulative ranking curve (SUCRA) values of their protective effects to prevent the safety and efficacy outcomes: (A) Safety outcome (B) Efficacy outcome. Rank 1 is best and Rank 4 is worst. DAPT, dual antiplatelet therapy; NOAC, non-vitamin K oral anticoagulant; VKA, Vitamin K Antagonist.

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Supplementary Fig. S6 Funnel plots for assessing publication bias.

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Supplementary Fig. S7 Sensitivity analysis for the safety and efficacy outcomes including NOAC-based trials. DAPT, dual antiplatelet therapy; NOAC, non-vitamin K oral anticoagulant; VKA, Vitamin K Antagonist.

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Supplementary Fig. S8 Pairwise meta-analysis and trial sequential analysis of four trials evaluating the efficacy and safety of dual antithrombotic therapy against triple antithrombotic therapy. For TSA, the required information size (RIS) was calculated using different assumptions of the relative risk reduction (RRR) or relative risk increase (RRI), control event rate (CER) and model-estimated diversity for each outcome. We used an anticipated RRR of 35% for the safety outcomes and an RRI of 10% for

cardiovascular death, 20% for myocardial infarction, and 35% for stent thrombosis. The cumulative Z -curve (bold solid line) was constructed using a random-effects model. The horizontal dashed line at cumulative Z

= ±1.96 indicates a conventional level of statistical significance. The converging dotted line and the

divergent dotted line represent the trial sequential significance boundary and futility boundary, respectively.

These monitoring boundaries were constructed based on the O’Brien-Fleming method. D, diversity; DAT, dual antithrombotic therapy; M-H, Mantel-Haenszel; TAT, triple antithrombotic therapy, TSA, trial

sequential analysis.

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Supplementary Table S3. GRADE summary of findings table

Certainty assessment № of patients Effect

Certainty Importance

№ of studies

Study

design Risk of bias Inconsistency Indirectness Imprecision Other

considerations DAT TAT Relative (95% CI)

Absolute (95% CI) TIMI major bleeding

5 randomized

trials not serious not serious not serious not serious none 99/5739

(1.7%) 163/5691

(2.9%) RR 0.59

(0.46 to 0.75) 12 fewer per 1,000 (from 15 fewer to 7

fewer)

⨁⨁⨁⨁

HIGH CRITICAL

TIMI major or minor bleeding 5 randomized

trials not serious not serious not serious not serious none 323/5739

(5.6%) 498/5691

(8.8%) RR 0.61

fewer)

⨁⨁⨁⨁

HIGH

CRITICAL

Intracranial hemorrhage 5 randomized

trials not serious not serious not serious serious^* none 23/5739

(0.4%) 40/5691

(0.7%) RR 0.59

fewer)

⨁⨁⨁◯

MODERAT E

IMPORTANT

Cardiovascular death 5 randomized

trials

not serious not serious not serious serious^* none 151/5775 (2.6%)

132/5726 (2.3%)

RR 1.06 (0.84 to 1.34)

1 more per 1,000 (from 4 fewer to 8

more)

⨁⨁⨁◯

MODERAT E

IMPORTANT

Myocardial infraction 5 randomized

trials

171/5726

(3.0%) RR 1.19

(0.97 to 1.46) 6 more per 1,000 (from 1 fewer to 14

more)

⨁⨁⨁◯

MODERAT E

IMPORTANT

Stent thrombosis 5 randomized

trials

56/5726

(1.0%) RR 1.32

(0.88 to 1.98) 3 more per 1,000 (from 1 fewer to 10

more)

⨁⨁⨁◯

MODERAT E

IMPORTANT

CI: Confidence interval; RR: Risk ratio.

*The trial sequential analysis (TSA) showed that cumulative Z curves did not cross the trial sequential monitoring boundary, and the current number of patients was few to achieve the required information size. We therefore downgraded by one level for imprecision.

GRADE Working Group grades of evidence.

High quality: Further research is very unlikely to change our confidence in the estimate of effect.

Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Very low quality: We are very uncertain about the estimate.

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Supplementary Fig. S9 Effects of NOAC-based antithrombotic therapy on (A) safety outcome and (B) efficacy outcomes. DAT, dual antithrombotic therapy; NOAC, non-vitamin K oral anticoagulant; TAT, triple antithrombotic therapy.