Stopping or continuing clopidogrel 12 months after drug-eluting stent placement: the
OPTIDUAL randomized trial
Gérard Helft, Philippe Gabriel Steg, Claude Le Feuvre, Jean-Louis Georges, Didier Carrie, Xavier
Dreyfus, Alain Furber, Florence Leclercq, Hélène Eltchaninoff, Jean-François Falquier, Patrick Henry,
Simon Cattan, Laurent Sebagh, Pierre-Louis Michel, Albert Tuambilangan, Nadjib Hammoudi, Franck
Boccara, Guillaume Cayla, Hervé Douard, Abdourahmane Diallo, Emmanuel Berman, Michel
Komajda, Jean-Philippe Metzger, Eric Vicaut , on behalf of the OPTImal DUAL antiplatelet therapy
Trial Investigators
Contents
Appendix S1. List of study committees and investigators ................................................................................................ 2
Appendix S2. Inclusion and exclusion criteria......................................................................................................................... 4
Appendix S3. Outcome event definitions ................................................................................................................................... 5
Figure 1. Kaplan–Meier curve for the non-prespecified composite of death, myocardial infarction, or
stroke. ........................................................................................................................................................................................................... 8
Figure 2. Main results of additional sensitivity analyses: intention-to-treat (ITT) analysis; ‘as treated’
analysis; and per-protocol (PP) analysis. .................................................................................................................................. 9
References ............................................................................................................................................................................................... 10
1
Appendix S1. List of study committees and investigators
Steering Committee
Gérard Helft, Philippe Gabriel Steg, Jean-Philippe Metzger, Claude Le Feuvre, Eric Vicaut.
Investigators
Participating centres: principal investigators, sub-investigators (number of patients enrolled)
Paris, CHU Pitié-Salpétrière, APHP: G. Helft, C. Le Feuvre, J.Ph. Metzger, O. Barthélémy, J.P.
Batisse, R. Choussat, F. Beygui
Le Chesnay, CH Versailles: J.L. Georges, G. Gibault-Genty, C. Charbonnel, B. Livarek
Toulouse: D. Carrie, M. Galinier, M. Elbaz, N. Boudou, N. Dumonteil
Grenoble: X. Dreyfus
Angers, CHU: A. Furber, S. Delépine, P. Lhoste, F. Prunier
Montpellier, CHU: F. Leclercq
Rouen, CHU: H. Elchaninoff, A. Cribier, C. Tron
Bergerac, polyclinique: J.F. Falquier
Paris, CHU Lariboisière, APHP: P. Henry, J.G. Dillinger, G. Sideris
Montfermeil, CHI: S. Cattan, O. Nallet
Trappe, Hôpital Privé de l’Ouest Parisien: L. Sebagh, J. Anconina
Paris, CHU Tenon, APHP: P.L. Michel, N. Hammoudi, V. Stratiev
Cherbourg, Centre Hospitalier Nord du Cotentin: A. Tuambilangana
Compiègne, CH: A. Luycx-Bore
Bordeaux, CHU Hôpital Cardiologique Haut Lévêque: H. Douard
Tarbes, private office: N. Ley
Bagnols sur Ceze, CH: A. El Jabali
Port Marly, Centre Médico-chirurgical de l’Europe: M. Brami
Kremlin Bicêtre, CHU: A. Bouchachi, P. Assayag
Villefranche de Rouergue, private office: P. Beranger
Nanterre, Hôpital Max Fourestier: F. Digne
Cherbourg, private office: P. Pon-Bache Gabrielsen
Nîmes, CHU: G. Cayla
Nice, Hôpital Pasteur CHU, Pr Ferrari
Creil, private office: Dr Détienne
Caen, CHU: M. Hamon
Nantes, private office: M. Benghanem
Thionville, private office: P. Houplon
Paris, CHU Bichat: G. Steg, L. Feldman, P. Aubry, J.M. Juliard, D. Himbert
Biarritz, private office: M. Ducoudre
Saint-Germain en Laye, private office: M. Sander
Paris, CHU Hôtel-Dieu: J. Blacher
Oulioulles, Polyclinique des Fleurs: P. Barragan
Anthony, Hôpital Privé d’Antholy: P. Dupouy, J.M. Pernes
Rennes, CHU: H. Le Breton, M. Bedossa, D. Boulmier, G. Lecoq
Strasbourg CHU: P. Ohlmann
Sète, private office: J.M. Fournier
Montpellier, private office: C. Léandri
Saint-Denis, Centre cardiologique du Nord: P. Guyon
Metz, CHU: K. Khalife
Strasbourg, private office: J.J. Muller
Clamart, Hôpital Béclère, CHU: M. Slama
Toulon, cardio de ville: J. Zitoun
Rouen, Clinique St Hilaire: J. Berland
Le Chesnay, CMC: G. Dambrin, X. Favereau
Sete, private office: A. Pinzani
Saint-Germain en Laye, private office: C. Halphen
Lagny sur Marne, CHG: S. Elhaddad
2
Clinical Events Committee
L. Payot, O. Varenne, T. Petroni, O. Jobard, F. Laveau.
Data Monitoring Committee
C. Elie, N. Mansencal, E. Durand.
3
Appendix S2. Inclusion and exclusion criteria
Inclusion criteria
1. Patients with DES implanted, then treated with clopidogrel plus aspirin for 12 months
2. Informed, written consent from the patient
Exclusion criteria
1. Age <18 years
2. Oral anticoagulation therapy
3. Drug-eluting stent in an unprotected left main coronary artery
4. Contemporaneous enrolment in a different clinical trial
5. Malignancies or other comorbid conditions with a life expectancy <2 years
6. Known allergy or intolerance to the study medications: aspirin and/or clopidogrel
7. Other revascularization with a DES within 9 months prior to this study
8. Other revascularization with a BMS within 4 weeks prior to this study
4
Appendix S3. Outcome event definitions
Primary outcome
The primary outcome was the composite of all-cause mortality, non-fatal myocardial infarction, stroke,
and major bleeding.
Death
All deaths reported post-enrolment were recorded and adjudicated. Deaths were subclassified by
cardiovascular and non-cardiovascular primary cause. Cardiovascular death included sudden cardiac
death, death due to acute myocardial infarction, death due to heart failure, death due to a
cerebrovascular event, death due to other cardiovascular causes (e.g. pulmonary embolism, aortic
disease, cardiovascular intervention), and deaths for which there was no clearly documented noncardiovascular cause (presumed cardiovascular death).
Myocardial infarction
Myocardial infarction is diagnosed based on the Universal myocardial infarction definition published by
Thygesen et al.1:






For a spontaneous myocardial infarction, detection of rise and/or fall of cardiac biomarkers,
preferably troponin, with at least one value above the 99th percentile of the upper reference limit
(URL) together with evidence of myocardial ischemia with at least one of the following:
o Symptoms of myocardial ischemia
o ECG changes (ST segment, T waves, or new left bundle branch block) indicative of new
ischemia
o Development of pathologic Q waves on the ECG
o Imaging evidence of new loss of viable myocardium or new regional wall motion
abnormality
Sudden unexpected cardiac death, involving cardiac arrest, often with symptoms suggestive of
myocardial ischemia, and accompanied by presumably new ST elevation or new LBBB, and/or
evidence of fresh thrombus by coronary angiography and/or autopsy, but death occurring before
blood samples could be obtained, or at a time before the appearance of cardiac biomarkers in the
blood.
PCI-related myocardial infarction: Elevation of cardiac biomarkers >3x 99th percentile of the URL
within 48 hours after PCI.
CABG-related myocardial infarction: Elevation of cardiac biomarkers >5x 99th percentile of the
URL within 72 hours after CABG, plus either new pathological Q waves or new LBBB, or
angiographically documented new graft or native coronary occlusion, or imaging evidence of loss
of viable myocardium.
Silent myocardial infarction based on ECG or imaging findings.
Pathological findings of an acute myocardial infarction not otherwise meeting above definitions.
Stroke
 Stroke is defined as an acute episode of neurologic dysfunction attributed to a central nervous
system vascular cause. Stroke should be documented by imaging (e.g. CT scan o magnetic
resonance imaging [MRI] scan). Evidence obtained from autopsy can als confirm the diagnosis.
Stroke will be sub classified, when possible, as either:
o Primary ischemic stroke - defined as an acute episode of focal brain, spinal, or retinal
dysfunction caused by an infarction of central nervous system tissue and documented by
imaging. A primary ischemic stroke may also undergo haemorrhagic transformation (i.e.,
no evidence of haemorrhage on an initial imaging study, but appearance on a subsequent
scan).
o Primary haemorrhagic stroke – defined as an acute episode of focal or global brain,
spinal, or retinal dysfunction caused by non-traumatic intraparenchymal, intraventricular,
or subarachnoid haemorrhage as documented by neuroimaging or autopsy.
Microhemorrhages (<10 mm) evident only on MRI are not considered to be a
haemorrhagic stroke. Subdural and epidural bleeding will be considered intracranial
haemorrhage, but not strokes.
 A stroke with unknown aetiology will be classified as an unclassified stroke if the type of stroke
could not be determined by imaging or other means.
5
Major bleeding
Major bleeding was defined according to the ISTH classification:
 Fatal bleeding, and/or
 Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular,
retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome, and/or
 Bleeding causing a fall in haemoglobin level of 20 g/L (1.24 mmol/L) or more, or leading to
transfusion of two or more units of whole blood or red cells.
Secondary outcomes
Stent thrombosis
Definite or probable stent thrombosis was defined according to the Academic Research Consortium
(ARC):
 Definite ST: angiographic confirmation of ST and at least 1 of the following signs present within
48 h: new onset of ischemic symptoms at rest, new electrocardiographic changes suggestive of
acute ischemia, or typical rise and fall in cardiac biomarkers.
 Probable ST: any unexplained death within the first 30 days after intracoronary stenting.
Repeat revascularization of the treated vessel:
Any repeat PCI or bypass surgery to target vessel.
Bleedings were classified according to different classifications: ISTH,2 TIMI,3 GUSTO,4 and BARC5:
Classification Severity
Criteria
TIMI
Major
Minor
Insignificant
GUSTO
Severe
Moderate
Mild
ISTH
BARC
Intracranial bleeding. Overt bleeding with a decrease in
haemoglobin ≥5 g/dL or decrease in haematocrit ≥15%
Spontaneous gross haematuria. Spontaneous hematemesis.
Observed bleeding with decrease in haemoglobin ≥3 g/dL but ≤15%
Blood loss insufficient to meet criteria listed above
Deadly bleeding. Intracerebral bleeding or substantial
Hemodynamic compromise requiring treatment
Bleeding requiring transfusion
Other bleeding not requiring transfusion or causing hemodynamic
Compromise
Fatal bleeding, and/or
Minor
Symptomatic bleeding in a critical area or organ, such as intracranial,
intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or
intramuscular with compartment syndrome, and/or
Bleeding causing a fall in haemoglobin level of ≥1.24 mmol/L (≥20 g/L),
or leading to transfusion of ≥2 units of whole blood or red cells.
All reported bleedings not classified as major
Type 0
No bleeding
Type 1
Bleeding that is not actionable and does not cause the patient to seek
unscheduled performance of studies, hospitalization, or treatment by a
healthcare professional; may include episodes leading to selfdiscontinuation of medical therapy by the patient without consulting a
healthcare professional
Any overt, actionable sign of haemorrhage (eg, more bleeding than
would be expected for a clinical circumstance, including bleeding found
by imaging alone) that does not fit the criteria for type 3, 4, or 5 but
does meet at least one of the following criteria: (1) requiring
nonsurgical, medical intervention by a healthcare professional, (2)
leading to hospitalization or increased level of care, or (3) prompting
evaluation
Overt bleeding plus haemoglobin drop of 3–5 g/dL (provided
haemoglobin drop is related to bleed) Any transfusion with overt
bleeding
Type 2
Type 3a
6
Type 3b
Type 4
Overt bleeding plus haemoglobin drop 5 g/dL (provided haemoglobin
drop is related to bleed) Cardiac tamponade Bleeding requiring surgical
intervention for control (excluding dental/nasal/skin/haemorrhoid)
Bleeding requiring intravenous vasoactive agents
Intracranial haemorrhage (does not include microbleeds or
haemorrhagic transformation, does include intraspinal) Subcategories
confirmed by autopsy or imaging or lumbar puncture Intraocular bleed
compromising vision
CABG-related bleeding
Type 5
Fatal bleeding
Type 3c
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
BARC = Bleeding Academic Research Consortium; GUSTO = Global Utilization of Streptokinase and
Tissue Plasminogen Activator for Occluded Coronary Arteries; ISTH = International Society on
Thrombosis and Haemostasis; TIMI = Thrombolysis In Myocardial Infarction.
7
Figure 1. Kaplan–Meier curve for the non-prespecified composite of death, myocardial
infarction, or stroke.
CI = confidence interval; DAPT = dual antiplatelet therapy; HR = hazard ratio; MI = myocardial
infarction.
8
Figure 2. Main results of additional sensitivity analyses: intention-to-treat (ITT) analysis; ‘as
treated’ analysis; and per-protocol (PP) analysis.
All results are summarized by hazard ratio and 95% confidence intervals.
9
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