Twelve vs 48 months of dual antiplatelet therapy after drug-eluting stent placement

The OPTIDUAL randomized trial

Gérard HELFTon behalf of the OPTIDUAL Investigators

Institut de Cardiologie, Hôpital Pitié-Salpétrière, Assistance Publique Hôpitaux de Paris, Université Pierre et Marie Curie Paris, France

IHU, Institute of Cardiometabolism And Nutrition, Hôpital Pitié-Salpétrière Paris, France

Background (1)The long-term risk of very late thrombosis after PCI does not decrease over time

Nearly half of the recurrent MACE after PCI for ACS are associated with non-culprit lesions at the time of PCI

Wenaweser P et al. JACC 2008;52 Stone G et al. N Engl J Med 2011;364

Background (2)DAPT trial: showed a reduction in rates of MACCE and stent thrombosis but an increase in bleeding

Mauri L et al. N Engl J Med 2014;371:2155

Hypothesis

• On a background of aspirin, continuing clopidogrel for up to 48 months would be superior to stopping clopidogrel at 12 months following drug-eluting stent (DES) implantation in reducing net adverse clinical events (composite of death, MI, stroke or major ISTH bleeding)– Randomized, multicentre, open-label study conducted in 58 sites

in France (January 2009–January 2013)– Funded by the French Ministry of Health. Additional unrestricted

research grants from Fédération Française de Cardiologie, Cordis, Boston, Medtronic, Terumo and Biotronik

Helft G et al, Trials 2013;14:56

Inclusion criteria• Patients with stable

CAD or ACS• With ≥1 lesion with a

significant stenosis in an artery ≥2.25 mm

• Implanted with ≥1 DES of any type

Exclusion criteria• DES implantation in an

unprotected left main coronary artery

• Requirement for oral anticoagulation

• Malignancies or other coexisting conditions associated with a life expectancy of <2 years

Patient selection

DES insertion

12 ± 3 monthsASPIRIN + CLOPIDOGREL

Randomization of patients free of MACCE or bleed

Follow-up (every 6 months between 12 and 48 months)

ASPIRIN + CLOPIDOGRELASPIRIN + CLOPIDOGREL

ASPIRIN ALONEASPIRIN ALONE

End of the study

0 12 months 48 months

Study design

Methods

• Primary endpoint– Net adverse clinical events: composite of all-cause

death, non-fatal MI, stroke, or major bleeding (ISTH classification)

• Secondary endpoints– Individual components of the primary outcome – Stent thrombosis (defined according to the Academic

Research Consortium [ARC])– Repeat revascularization of the treated vessel – Bleeding (ISTH, GUSTO, TIMI, BARC classifications)

Superiority trial: – 983 patients per arm – 80% power, alpha type-I error of 5%– Significant reduction in the primary composite

outcome at 3 years post-randomization from 7% with aspirin alone to 4% with extended DAPT

Owing to lack of resources and slower enrolment than anticipated, the executive committee and sponsor recommended termination of follow-up at the end of September 2014

Statistical analysis

Patient flow chart (CONSORT)

EXTENDED DAPT GROUPn=695

ASPIRIN GROUPn=690

P value

Age (years), mean (SD) 64.1 (10.8) 64.2 (11.5) 0.88

Women 18.3% 20.7% 0.23

Diabetes mellitus 30.6% 32.2% 0.54

Hypertension 57% 60.4% 0.19

Current/recent smoker 61.2% 57.8% 0.21

Previous PCI 25.9% 27.0% 0.66

Previous MI 17.1% 17.7% 0.78

Previous CABG 5.3% 5.1% 0.83

Stroke or TIA 4.2% 3.6% 0.60

Peripheral artery disease

4.9% 6.5% 0.19

Patient baseline characteristics

EXTENDED DAPT GROUP n=695 ASPIRIN GROUP n=690 P value

Indication for PCI

STEMI 10.7% 11.9% 0.47

Non-STEMI 14.2% 17.0% 0.39

Unstable angina 9.5% 9.1% 0.81

Stable angina 34.5% 30.0% 0.07

Silent ischaemia 19.9% 21.9% 0.35

Other 11.2% 10.1% 0.63

Type of DES

Sirolimus 19.9% 17.5% 0.17

Paclitaxel 15.2% 16.0% 0.65

Zotarolimus 8.3% 10.8% 0.05

Everolimus 50.2% 49.2% 0.66

Other 6.4% 6. 5% 0.93

Target vessel

Left main <1% >1% 0.69

LAD 58% 64% 0.007

LCX 33% 31% 0.59

RCA 41% 39% 0.58

Procedural characteristics

65.6%

34.4% 38.0%

62.0%

35.1% 33.5%

Treatment at randomization

R 0.75, 95% CI 0.50-1.28P=0.17

5.8%

7.5%

Primary outcome:Composite of death, MI, stroke, major bleed

Components of the primary endpoint

HR 0.65, CI 0.34-1.22 P=0.18

HR 0.69, CI 0.22-2.18 P=0.53

HR 0.67, CI 0.31-1.44 P=0.31

HR 0.98, CI 0.47-2.05 P=0.95

Death Stroke

MI Major bleed

4.2%

6.4%

HR 0.64, 95% CI 0.40-1.02P=0.06

Post-hoc analysis of ischaemic outcomes: death, stroke, or MI

Bleeding eventsExtended-DAPT

groupAspirin group Difference

Percentage points (95% CI)

P value

GUSTO moderate or severe

1.9% 1.7% 0.1 (-1.3 to 1.5) 0.85

Moderate 1.6% 1.2% 0.4 (-0.8 to 1.7) 0.49

Severe 0.4% 0.6% -0.2 (-0.9 to 0.6) 0.72

BARC type 2.6% 2.9% - 0.3 (-2.0 to 1.4) 0.72

2 0.7% 1.0% -0.3 (-1.3 to 0.7) 0.85

3 1.9% 2.0% -0.1 (-1.6 to 1.3) 0.83

5 0.1% 0 0.1 (-0.1 to 0.4) 1.00

TIMI major or minor 2.6% 2.9% -0.3 (-1.4 to 2.0) 0.72

Major 0.6% 0.6% 0.0 (-0.8 to 0.8) 1.00

Minor 2.2% 2.3% -0.1 (-1.7 to 1.4) 0.84

ISTH major 2.0% 2.0% 0.0 (-1.5 to 1.5) 0.98

ISTH moderate 0.9% 1.0% -0.1 (-1.1 to 0.9) 0.77

Meta-analysis of RCTs testing 12 months vs longer DAPT after DES:

Death, stroke, MI

Meta-analysis of RCTs testing 12 months vs longer DAPT after DES:

Death, stroke, MI

Study limitations

• Only powered to detect major differences in ischaemic and bleeding events

• Termination of the trial before enrolment and follow-up were completed reduced the trial power

• Open-label trial, although all clinical outcomes were adjudicated by an independent clinical event committee blinded to treatment assignment

Conclusions (1)

Extending DAPT duration for up to 48 months did not

achieve statistical superiority compared with stopping

clopidogrel at 12 months with regards to net adverse

clinical outcomes, in patients free of MACCE and

major bleed 12 months after stent implantation

Conclusions (2)

• Borderline but non-statistically significant

reduction in post-hoc analysis of ischaemic

outcomes with extended DAPT

• No apparent increase in bleeding and all-

cause mortality with extended DAPT

Main recruiting sitesCHU Pitié-Salpétrière, Paris, G Helft

CH Versailles, JL Georges

CHU Toulouse, D Carrié

Grenoble, Private office, X Dreyfus

CHU Angers, A Furber

CHU Montpellier, F Leclercq

CHU Rouen, H Eltchaninoff

Polyclinique de Bergerac, Falquier

CHU Lariboisière, Paris, P Henry

CH Le Raincy-Montfermeil, S Cattan

Clinique Turin, Paris, L Sebagh

CHU Tenon, Paris, PL Michel

CH Cherbourg, A Tuambilangana

CHU Nîmes, G Cayla

CHU Bordeaux, H Douard

CH Compiègne, A Luycx-Bore

Tarbes, Private office, N. LeyCH Bagnols sur Ceze, A. El Jabali CMC, Port Marly,, M. Brami CHU Kremlin Bicêtre,, A. Bouchachi, Villefranche de Rouergue, Private office, P.

BerangerCH Nanterre, F Digne Cherbourg, Private office, P. Pon-Bache

Gabrielsen CHU Nice, E Ferrari Creil, Private office, JPh Détienne CHU Caen, M HamonNantes, Private office, M. Benghanem Thionville, : P. Houplon CHU Bichat, Paris, G StegBiarritz, M. DucoudreSaint-Germain en Laye, Private office, M SanderAnd 27 other centres

• Steering Committee – G. Helft, P.G. Steg, J.Ph. Metzger, C. Le Feuvre, E. Vicaut

• Clinical Events Committee– L. Payot, O. Varenne, T. Petroni, O. Jobard, F. Laveau

• Data Monitoring Committee– C. Elie, N. Mansencal, E. Durand

• Study Staff– E. Berman , V. Raghavan, S. Djaileb

Trial organization