Versus Plus Clopidogrel as Antithrombotic Treatment Following Transcatheter Aortic Valve Replacement With a Balloon-Expandable Valve The ARTE Randomized Clinical Trial Josep Rodés-Cabau, MD, on behalf of the ARTE investigators
Conflict of interest: Institutional research grants from Edwards Lifesciences
ARTE Trial Investigator initiated trial, supported by a grant from Edwards Lifesciences and the Research Center of the Quebec Heart and Lung Institute PARTICIPATING CENTERS Quebec Heart & Lung Institute, Laval University, Quebec City, Quebec, Canada Josep Rodés-Cabau, MD; Éric Dumont, MD; Mélanie Côté, MSc Centre Hospitalier Universitaire de Montreal, Montreal, Quebec, Canada Jean-Bernard Masson, MD University of Alberta Hospital, Edmonton, Alberta, Canada Robert Welsh, MD Hospital Universitari Vall d Hebron, Barcelona, Spain Bruno Garcia del Blanco, MD; Vicenç Serra, MD Saint John s Regional Hospital, Saint John, New Brunswick, Canada Marc Pelletier, MD St. Paul s Hospital, Vancouver, British Columbia, Canada John G. Webb, MD Foothills Hospital, Calgary, Alberta Faisal Al-Qoofi, MD Hôpital du Sacré Coeur de Montreal, Montreal, Quebec, Canada Philippe Généreux, MD Hospital San Borja Arriaran, Santiago de Chile, Chile Gabriel Maluenda, MD
ARTE Trial - Introduction (long term) + clopidogrel (1 to 6 months) has been the recommended antithrombotic treatment following TAVR This antithrombotic regimen has been recommended on an empirical basis, and no studies have as yet shown the efficacy of dual versus single antiplatelet therapy in preventing ischemic events following TAVR Patients undergoing TAVR nowadays are generally elderly and very frequently exhibit comorbidities that significantly increase the risk for major bleeding. Indeed, TAVR procedures can be associated with major vascular complications, which in turn can complicate with major or life-threatening bleeding
ARTE Trial - Objective/Endpoints Objective To compare aspirin plus clopidogrel vs. aspirin alone as antithrombotic treatment following TAVR for the prevention of ischemic events (MI, stroke or transient ischemic attack [TIA]) and death without increasing the risk of major or life-threatening bleeding events Primary endpoint Rate of death, MI, ischemic stroke or TIA, or major or life-threatening bleeding at 3- month follow-up* Secondary endpoints Incidence of 1) MI, 2) ischemic stroke or TIA, 3) major or life-threatening bleeding, 4) death at 3 months post-tavr * *Events adjudicated by an independent adjudication committee according to VARC-2 definitions
ARTE Trial - Inclusion/Exclusion Inclusion criteria Clinical indication for TAVR with a balloon-expandable Edwards SAPIEN XT or SAPIEN 3 valve Exclusion criteria 1) Need for chronic anticoagulation treatment 2) Major bleeding within the 3 months prior to the TAVR procedure 3) Prior intracranial bleeding 4) Drug eluting stent implantation within the year prior to the TAVR procedure 5) Allergy to clopidogrel and/or aspirin
ARTE Trial - Study Design Prospective, randomized, open label, multicenter study Patients randomized (the day prior to the TAVR procedure) 80-100mg/d -Start at least 24hrs before TAVR -Continued for at least 6 months 80-100mg/d + Clopidogrel 75mg/d Clopidogrel treatment -Initial dose of 300 mg followed by 75 mg/d Transfemoral approach -Start within 24hrs before TAVR -Continued for 3 months Transapical/Transaortic/Transcarotid approach -Start within 24hrs after TAVR -Continued for 3 months Clinical visit/phone contact at 1-3- and 12-month follow-up
ARTE Trial - Sample Size No studies comparing different antiplatelet therapy strategies, specifically singleantiplatelet therapy post-tavr, were available at the time the ARTE trial was designed Sample size: empirically estimated at 300 patients The study was prematurely stopped after the inclusion of 222 patients (74% of the planned study population) because of slow enrollment and lack of continued financial support Patients were enrolled from March 2012 to February 2017. (The ARTE Trial [ARTE], NCT01559298) The main changes after the trial commenced were the addition of the SAPIEN 3 valve and the change in the time point for the primary endpoint from 12 to 3 months (protocol amendment: NCT02640794)
ARTE Trial - Results Flowchart of the Study Population 222 Patients undergoing TAVR randomized 111 Randomized to receive aspirin + clopidogrel 110 Received intervention as randomized 1 Did not receive the allocated treatment (clopidogrel never started) 111 Randomized to receive aspirin 109 Received intervention as randomized 2 Did not receive the allocated treatment (clopidogrel prescribed by the physician responsible for the patient) 3-month follow-up 0 Lost to follow-up 3-month follow-up 0 Lost to follow-up 111 included in primary analysis 111 included in primary analysis
Baseline Characteristics of the Study Population + Clopidogrel n=111 n=111 P value Baseline characteristics Age (years) Male Diabetes Hypertension Previous myocardial infarction Previous coronary artery bypass graft Peripheral vascular disease COPD Chronic renal failure (GFR <60 ml/min) STS-PROM score (%) Echocardiographic variables Mean gradient (mm Hg) Indexed AVA (cm2/m2) Ejection fraction (%) Aortic regurgitation None/trace Mild Moderate/severe 79±9 70 (63.1) 41 (36.9) 86 (77.5) 26 (23.4) 39 (35.1) 28 (25.2) 28 (25.2) 70 (63.1) 6.2±4.4 43±16 0.42±0.13 55±12 51 (48.1) 30 (28.3) 25 (23.6) 79±9 59 (53.2) 36 (32.7) 87 (79.8) 20 (18.4) 42 (38.5) 22 (20.0) 33 (30.0) 70 (63.1) 6.4±4.6 43±15 0.40±0.11 54±13 47 (45.6) 40 (38.8) 16 (15.6) 0.716 0.174 0.573 0.743 0.409 0.886 0.422 0.455 0.999 0.769 0.713 0.095 0.675 0.409 Values are mean SD or n (%).
Procedural Characteristics + Clopidogrel n=111 n=111 P value Procedural characteristics Approach Femoral Transapical Transaortic Transcarotid Valve type SAPIEN XT SAPIEN 3 Need for second valve Conversion to open heart surgery Major vascular complications New-onset atrial fibrillation Procedural success Echocardiography at discharge Mean gradient (mm Hg) Indexed AVA (cm2/m2) Ejection fraction (%) Aortic regurgitation None/trace Mild Moderate/severe 80 (72.1) 18 (16.2) 10 (9.0) 3 (2.7) 104 (93.7) 7 (6.3) 3 (2.7) 2 (1.8) 10 (9.0) 12 (10.8) 101 (90.9) 10.8±5.3 0.95±0.34 54±11 59 (61.4) 28 (29.2) 9 (9.4) 73 (65.8)) 20 (18.0) 14 (12.6) 4 (3.6) 101 (90.9) 10 (9.0) 3 (2.7) 7 (6.4) 12 (10.8) 94 (86.2) 10.3±5.7 0.99±0.34 54±12 66 (68.7) 24 (25.0) 6 (6.3) 0.788 0.615 0.623 0.683 0.615 0.999 0.294 0.539 0.991 0.999 0.571
Study Outcomes (90 days) + Clopidogrel n=111 n=111 OR (95% CI) P value Combined endpoint* (primary endpoint) 17 (15.3) 8 (7.2) 2.31 (0.95 5.62) 0.065 Major/life-threatening bleeding 12 (10.8) 4 (3.6) 3.22 (1.01 10.34) 0.038 Major bleeding 5 (4.5) 3 (2.7) 1.68 (0.39 7.21) 0.484 Life-threatening bleeding 7 (6.3) 7.34 (0.89 60.71) 0.065 Myocardial infarction 4 (3.6) 4.13 (0.45 37.60) 0.175 Stroke/TIA 3 (2.7) 3.11 (0.32 30.43) 0.313 Disabling stroke 0.97 (0.06 15.81) 0.983 Nondisabling stroke 2 (1.8) 0 TIA 0 0 Death 7 (6.3) 4 (3.6) 1.78 (0.51 6.27) 0.370 *Death, myocardial infarction, stroke or TIA, or major or life-threatening bleeding. Values are n (%)
Kaplan-Meier Curves (Combined Endpoint) + Clopidogrel
Kaplan-Meier Curves (Ischemic, Bleeding Events) Major or life-threatening bleeding Stroke or TIA + Clopidogrel + Clopidogrel Myocardial infarction (MI) Death + Clopidogrel + Clopidogrel
Type, Timing and Severity of Bleeding Events Cause of bleeding Vascular complication GI Bleeding Timing of bleeding events 72 hrs >72 hrs Severity of bleeding events Life-threatening Major + Clopidogrel n=12 7 5* 7 5 7 5 n=4 4 0 4 0 1 3 GI = gastrointestinal *All patients were on PPI therapy at the time of the event
Study Outcomes at 90 days (As-Treated Population) + Clopidogrel n=110 n=109 OR (95% CI) P value Combined endpoint* 17 (15.5) 8 (7.3) 2.27 (0.93 5.52) 0.060 Major/life-threatening bleeding 12 (10.9) 4 (3.7) 3.16 (1.00 10.14) 0.040 Major bleeding 5 (4.6) 3 (2.8) 1.64 (0.38 7.06) 0.484 Life-threatening bleeding 7 (6.4) 7.21 (0.87 59.69) 0.067 Myocardial infarction 4 (3.6) 4.12 (0.45 37.58) 0.178 Stroke/TIA 3 (2.7) 3.12 (0.32 30.74) 0.317 Disabling stroke 0.95 (0.06 15.43) 0.970 Nondisabling stroke 2 (1.8) 0 TIA 0 0 Death 7 (6.4) 4 (3.7) 1.75 (0.50 6.16) 0.381 *Death, myocardial infarction, stroke or TIA, or major or life-threatening bleeding.
ARTE Trial Study limitations Small trial with an open-label design These results do not apply to the significant proportion of TAVR candidates who present with atrial fibrillation requiring anticoagulation or with coronary artery disease requiring DAPT Results were obtained in patients receiving balloonexpandable transcatheter valves and may not apply to those undergoing TAVR with other valve platforms
ARTE Trial Conclusions (vs. + Clopidogrel) tended to reduce the occurrence of major adverse events following TAVR Single antiplatelet therapy () reduced the risk of major or life-threatening bleeding events while not increasing the risk of MI or stroke These results should serve to design a definitive trial for determining the optimal antithrombotic treatment in TAVR candidates Meanwhile, the results of the ARTE trial may help us to guide clinical practice beyond empirical recommendations