supplementary online content · chiarito m, cao d, cannata f, et al. direct anticoagulants in...

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Supplementary Online Content

Chiarito M, Cao D, Cannata F, et al. Direct anticoagulants in addition to antiplatelet therapy for secondary prevention after acute coronary syndromes: a systematic review and meta-analysis. JAMA Cardiol. Published online February 7, 2018. doi: 10.1001/jamacardio.2017.5306

eTable. Risk of Bias Assessment

eAppendix.

eFigure 1. Funnel Plot for the Primary Efficacy End Point (Egger test, P = 0.708)

eFigure 2. Funnel Plot for the Primary Safety End Point (Egger test, P = 0.787)

eFigure 3. Risk of Cardiovascular Death With DOAC Versus Alacebo in Addition to APT Stratified by ACS Type

eFigure 4. Risk of Myocardial Infarction With DOAC Versus Placebo in Addition to APT Stratified by ACS Type.

eFigure 5. Risk of Stroke With DOAC Versus Placebo in Addition to APT Stratified by

ACS type.

eFigure 6. Meta-regression Analysis: Impact on Death from All Causes of Major Bleedings.

eFigure 7. Meta-regression Analysis: Impact on Death from All Causes of Clinically Relevant Bleedings

eReferences

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eTable. Risk of Bias Assessment.

Study Publication date

Bias arising from the randomization process

Bias due to deviations from intended interventions

Bias due to missing outcome data

Bias in measurement of the outcome

Bias in selection of the reported result

Overall bias

APPRAISE 2009 LOW LOW LOW LOW LOW LOW

APPRAISE 2 2011 LOW LOW LOW LOW LOW LOW

APPRAISE J 2013 LOW LOW LOW LOW LOW LOW

ATLAS ACS

TIMI 46

2009 LOW LOW LOW LOW LOW LOW

ATLAS ACS 2

TIMI 51

2012 LOW LOW LOW LOW LOW LOW

REDEEM 2011 LOW LOW LOW LOW LOW LOW



eAppendix.

Search strategy: PubMed

("dabigatran"[tiab] OR "rivaroxaban"[tiab] OR "apixaban"[tiab] OR "edoxaban"[tiab] OR

"anticoagulation"[tiab] OR "coumadin"[tiab] OR "anticoagulant"[tiab] OR "warfarin"[tiab]) AND

("acute coronary syndrome"[tiab] OR "myocardial infarction"[tiab] OR "STEMI"[tiab] OR "STE-

ACS"[tiab]) AND "clinical trial"[Publication Type]

End point definitions1–6

ATLAS ACS TIMI 46

Bleeding definition: Thrombolysis in Myocardial Infarction (TIMI) definition

Primary efficacy endpoint: composite of death, myocardial infarction/urgent revascularization

requiring revascularisation up to 6 months from enrolment, stroke

Secondary efficacy endpoint: composite of death, myocardial infarction, or stroke

ATLAS ACS 2 TIMI 51


Primary efficacy endpoint: death from cardiovascular causes, myocardial infarction, or stroke

(ischemic, hemorrhagic, or stroke of uncertain cause).

APPRAISE

Bleeding definition: International Society of Thrombosis and Hemostasis (ISTH) definition

Primary efficacy endpoint: composite of cardiovascular death, MI, severe recurrent ischemia, or

ischemic stroke

APPRAISE 2




Primary efficacy endpoint: composite of cardiovascular death, myocardial infarction, or ischemic

stroke

APPRAISE J

Bleeding definition: International Society on Thrombosis and Haemostasis (ISTH) definition

Primary efficacy endpoint: not defined. All the events occured during follow-up are clearly

described in the Results section.

RE-DEEM

Bleeding definition: International Society of Thrombosis and Haemostasis (ISTH) definition

Primary efficacy endpoint: not defined. Data about the composite of cardiovascular death, non-

fatal myocardial infarction, or non-haemorrhagic stroke clearly reported in Table 5.



eFigure 1. Funnel Plot for the Primary Efficacy End Point (Egger test, P = 0.708)



eFigure 2. Funnel Plot for the Primary Safety End Point (Egger test, P = 0.787)



eFigure 3. Risk of cardiovascular death with DOAC versus placebo in addition to APT stratified by ACS type. Only studies that reported outcomes stratified for the index event are included.



eFigure 4. Risk of myocardial infarction with DOAC versus placebo in addition to APT stratified by ACS type. Only studies that reported outcomes stratified for the index event are included.



eFigure 5. Risk of stroke with DOAC versus placebo in addition to APT stratified by ACS type.

Only studies that reported outcomes stratified for the index event are included.



eFigure 6. Meta-regression analysis: impact on death from all causes of major bleedings.



eFigure 7. Meta-regression analysis: impact on death from all causes of clinically relevant bleedings



eReferences

1. Mega JL, Braunwald E, Mohanavelu S, Burton P, Poulter R, Misselwitz F, Hricak V,

Barnathan ES, Bordes P, Witkowski A, Markov V, Oppenheimer L, Gibson CM, ATLAS

ACS-TIMI 46 study group. Rivaroxaban versus placebo in patients with acute coronary

syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet

(London, England) 2009;374:29–38.

2. Mega JL, Braunwald E, Wiviott SD, Bassand J-P, Bhatt DL, Bode C, Burton P, Cohen M,

Cook-Bruns N, Fox KAA, Goto S, Murphy SA, Plotnikov AN, Schneider D, Sun X,

Verheugt FWA, Gibson CM, ATLAS ACS 2–TIMI 51 Investigators. Rivaroxaban in patients

with a recent acute coronary syndrome. N Engl J Med 2012;366:9–19.

3. APPRAISE Steering Committee and Investigators, Alexander JH, Becker RC, Bhatt DL,

Cools F, Crea F, Dellborg M, Fox KAA, Goodman SG, Harrington RA, Huber K, Husted S,

Lewis BS, Lopez-Sendon J, Mohan P, Montalescot G, Ruda M, Ruzyllo W, Verheugt F,

Wallentin L. Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with

antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of

Acute Ischemic and Safety Events (APPRAISE) trial. Circulation 2009;119:2877–2885.

4. Alexander JH, Lopes RD, James S, Kilaru R, He Y, Mohan P, Bhatt DL, Goodman S,

Verheugt FW, Flather M, Huber K, Liaw D, Husted SE, Lopez-Sendon J, Caterina R De,

Jansky P, Darius H, Vinereanu D, Cornel JH, Cools F, Atar D, Leiva-Pons JL, Keltai M,

Ogawa H, Pais P, Parkhomenko A, Ruzyllo W, Diaz R, White H, Ruda M, et al. Apixaban

with Antiplatelet Therapy after Acute Coronary Syndrome. N Engl J Med 2011;365:699–

708.

5. Oldgren J, Budaj A, Granger CB, Khder Y, Roberts J, Siegbahn A, Tijssen JGP, Werf F Van

de, Wallentin L, RE-DEEM Investigators. Dabigatran vs. placebo in patients with acute



coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial.

Eur Heart J 2011;32:2781–2789.

6. Ogawa H, Goto S, Matsuzaki M, Hiro S, Shima D, APPRAISE-J investigators. Randomized,

double-blind trial to evaluate the safety of apixaban with antiplatelet therapy after acute

coronary syndrome in Japanese patients (APPRAISE-J). Circ J 2013;77:2341–2348.


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