Rationale and design of POPular-TAVI: antiPlatelet therapy fOr Patients undergoing Transcatheter Aortic Valve Implantation

Trial Design

Rationale and design of POPular-TAVI: antiPlatelet therapy fOr Patients undergoing Transcatheter Aortic Valve Implantation Vincent Johan Nijenhuis, MD, a Naoual Bennaghmouch, MD, a Mariella Hassell, MD, b Jan Baan, Jr., MD, PhD, b Jan Peter van Kuijk, MD, PhD, a Pierfrancesco Agostoni, MD, PhD, a Arnoud van ‘t Hof, MD, PhD, c Peter C. Kievit, MD, PhD, d Leo Veenstra, MD, e Pim van der Harst, MD, PhD, f Ad F. M. van den Heuvel, MD, PhD, f Peter den Heijer, MD, PhD, g Johannes C. Kelder, MD, PhD, a Vera H. Deneer, PharmD, PhD, h Frank van der Kley, MD, i Francesco Onorati, MD, PhD, j Jean Philippe Collet, MD, PhD, k Francesco Maisano, MD, PhD, l Azeem Latib, MD, PhD, m Kurt Huber, MD, PhD, n Pieter R. Stella, MD, PhD, o and Jurrien M. ten Berg, MD, PhD a Nieuwegein, Amsterdam, Zwolle, Nijmegen, Maastricht, Groningen, Breda, Leiden, the Netherlands; Verona, Italy; Paris, France; Zürich, Switzerland; Milan, Italy; Vienna, Austria; and Utrecht, the Netherlands

Background Despite improving experience and techniques, ischemic and bleeding complications after transcatheter aortic valve implantation (TAVI) remain prevalent and impair survival. Current guidelines recommend the temporary addition of clopidogrel in the initial period after TAVI to prevent thromboembolic events. However, explorative studies suggest that this is associated with a higher rate of major bleeding without a decrease in thromboembolic complications. Methods

The POPular TAVI trial is a prospective randomized, controlled, open-label multicenter clinical trial to test the hypothesis that monotherapy with aspirin or oral anticoagulation (OAC) after TAVI is safer than the addition of clopidogrel for 3 months, without compromising clinical benefit. This trial encompasses 2 cohorts: cohort A, patients are randomized 1:1 to aspirin vs aspirin + clopidogrel, and cohort B, patients on OAC therapy are randomized 1:1 to OAC vs OAC + clopidogrel. Primary outcome is freedom from non–procedure-related bleeding at 1 year. Secondary net-clinical benefit outcome is freedom from the composite of cardiovascular death, non–procedural-related bleeding, myocardial infarction, or stroke at 1 year. The primary outcome is analyzed for superiority, whereas the secondary outcome is analyzed for noninferiority. Recruitment began in February 2014, and the trial will continue until a total of 1,000 patients (684 expected in cohort A and 316 in cohort B) are included and followed up for 1 year.

Summary The POPular TAVI trial (NCT02247128) is the first large randomized controlled trial to test if monotherapy with aspirin or OAC vs additional clopidogrel after TAVI reduces bleeding with a favorable net-clinical benefit. (Am Heart J 2016;173:77-85.)

From the aDepartment of Cardiology, St Antonius Hospital, Nieuwegein, the Netherlands, b

Department of Cardiology, Academic Medical Centre, Amsterdam, the Netherlands, Department of Cardiology, Isala Klinieken, Zwolle, the Netherlands, dDepartment of Cardiology, University Medical Centre St Radboud, Nijmegen, the Netherlands, e Department of Cardiology, Medical University Centre, Maastricht, the Netherlands, f Department of Cardiology, University Medical Centre, Groningen, the Netherlands, g Department of Cardiology, Amphia Hospital, Breda, the Netherlands, hDepartment of Clinical Pharmacy, St Antonius Hospital, Nieuwegein, the Netherlands, iDepartment of c

Cardiology, University Medical Centre, Leiden, the Netherlands, jDepartment of Cardiac Surgery, University of Verona, Verona, Italy, kDepartment of Cardiology, Hôpital Universitaire Pitié Salpêtrière, Paris, France, lDepartment of Cardiovascular Surgery, UniversitätsSpital Zürich, Zürich, Switzerland, mDepartment of Cardiology, Università Vita-Salute San Raffaele Milano, Milan, Italy, nDepartment of Cardiology, Wilhelminenspital, Vienna, Austria, and oDepartment of Cardiology, University Medical Centre Utrecht, Utrecht, the Netherlands. RCT#NCT02247128 Submitted September 24, 2014; accepted November 15, 2015. Reprint requests: Jurriën ten Berg, MD, PhD, FESC, FACC, Department of Cardiology, St Antonius Hospital, Koekoekslaan 1, 3435 CM, Nieuwegein, the Netherlands. E-mail: [email protected] 0002-8703 © 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ahj.2015.11.008

Transcatheter aortic valve implantation (TAVI) has become an established treatment for patients with severe symptomatic aortic stenosis. Since the Placement of Aortic Transcatheter Valves (PARTNER) trials and the US CoreValve High Risk Study, TAVI is approved for patients deemed nonoperable or high risk for conventional surgical aortic valve replacement. 1-3 The first randomized PARTNER trial showed that TAVI offered better survival rates than medical therapy, but was associated with a high incidence of stroke (6% at 30 days) and bleeding (17% at 30 days). 2 Despite a vast growth in experience and advancement to next-generation prostheses and smaller-caliber delivery systems, the risks of bleeding and thromboembolic complications after TAVI remain high. Registries show that according to the definitions proposed by the Valve Academic Research Consortium (VARC), stroke at 30 days occurs in approximately 3% (VARC reported 0%-9%) 4 and major bleeding in approximately 15% (VARC reported 2%-31%). 4

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Despite the vulnerable population and consequent high impact of ischemic and bleeding complications, the effects of antiplatelet and antithrombotic treatment have not yet been investigated in large randomized controlled trials. After TAVI, dual antiplatelet therapy (DAPT) consisting of aspirin (lifelong) and clopidogrel (initial period) is currently recommended (level of evidence C). 5-7 However, this is a purely assumptive extension of the percutaneous coronary intervention experience. In patients with atrial fibrillation (AF) or another indication for oral anticoagulation (OAC), the best antithrombotic and antiplatelet treatment regimen after TAVI is unknown but a combination of OAC and aspirin or clopidogrel is usually used. 6,7 A small pilot study suggested no difference between DAPT vs aspirin monotherapy regarding bleeding and thromboembolic complications at 3 months. 8 Moreover, small retrospective studies show a higher bleeding risk in patients receiving DAPT vs antiplatelet monotherapy. 9-11 This is important because bleeding has been found to significantly impair survival after TAVI. 12-16 Furthermore, the omission of clopidogrel after TAVI does not seem to increase the rate of thromboembolic complications. 11,10 Thus, evidence on optimal antiplatelet and antithrombotic regimen is urgently needed in patients undergoing TAVI, both with or without an indication for OAC. 17 Accordingly, we designed the POPular TAVI trial (NCT02247128) to test the hypothesis that monotherapy with aspirin or OAC after TAVI is safer than the addition of clopidogrel for 3 months, without compromising clinical benefit in terms of thromboembolic and/or ischemic complications.

Methods Trial design The POPular TAVI trial is a prospective, randomized, parallel group, open-label multicenter trial designed to investigate the effect of monotherapy with aspirin or OAC after TAVI compared with the addition of clopidogrel for 3 months on safety, efficacy, and clinical-benefit during follow-up. The POPular TAVI trial encompasses 2 cohorts. Cohort A comprises patients without an indication for long-term OAC at the time of randomization. Cohort B comprises patients with an indication for long-term OAC at the time of randomization (eg, AF and mechanical mitral valve prosthesis). A total of 1,000 patients are allocated to the appropriate cohort and consequently randomized (1:1) to aspirin (cohort A, expected n = 684) or OAC monotherapy (cohort B, expected n = 316) vs the addition of clopidogrel. A flowchart of the study design is provided in Figure. Patient selection The studied population will be a “real-life” TAVI population consisting of both high-risk surgical and inoperable patients. The key exclusion criterion for cohort A is the need

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for long-term OAC. The main exclusion criteria for cohort A and B are as follows: (1) drug-eluting stent implantation within 3 months prior to TAVI procedure, (2) bare-metal stent implantation within 1 month prior to TAVI procedure, and (3) allergy or intolerance to clopidogrel. In cohort B, the use of a non–vitamin K OAC (NOAC) is an exclusion criterion. A complete listening of the entry criteria is provided in Table I.

Study treatments and duration Patients in cohort A are randomized to aspirin (≤100 mg once daily [qD], minimum 1 year) vs aspirin (≤100 mg qD, minimum 1 year) + clopidogrel (75 mg qD, 3 months). Patients in cohort B are randomized to OAC (dose according to international normalized ratio [INR]) vs OAC + clopidogrel (75 mg qD, 3 months). In aspirin-naive patients in cohort A, a loading dose of 300 mg aspirin is advised to be given within 24 hours prior to TAVI but may be given for up to 24 hours after TAVI. The loading dose for clopidogrel is 300 mg and is advised to be given within 24 hours prior to TAVI but may be given for up to 24 hours after TAVI. In patients already treated with clopidogrel, we recommend patients to be switched to aspirin or OAC monotherapy at least 5 days prior to TAVI because of the pharmacokinetics of clopidogrel. In patients randomized to clopidogrel, clopidogrel is omitted at 3 months after TAVI and no other antiplatelet drug will be (re)commenced during follow-up. We advise aspirin to be continued indefinitely, but at least during follow-up (1 year). In patients using OAC at baseline, it is our aim to continue the OAC therapy periprocedure (INR aimed at 2.0). We advise no bridging therapy, but leave the choice to continue OAC therapy or bridging (eg, high thrombotic risk) to the attending physician's discretion. During the procedure, we recommend the use of unfractionated heparin with an activated clotting time (ACT) of more than 250 seconds for both cohorts. However, for patients in whom OAC is continued (cohort B), the ACT may be lower (eg, 200 seconds). In general, we leave the final decision regarding the regimen (unfractionated heparin, bivalirudin) and minimal ACT to the attending physician's discretion. Follow-up visits are planned at 30 days, 3 months, 6 months, and 12 months after TAVI and may be performed at the treating and/or referring hospital, by telephone, or in writing. Transthoracic echocardiogram is performed at 6 ± 3 months. Follow-up questionnaires are sent to the patients at 3, 6, and 12 months after TAVI. Primary outcome The primary outcome is a safety end point, defined as freedom from non–procedure-related bleeding complications at 1 year after TAVI. The co-primary outcome is the safety end point defined as all bleeding complications at 1 year after TAVI. Bleeding complications are primarily classified according to the Bleeding Academic Research

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Figure

POPular TAVI study design. After inclusion, patients are stratified according to the presence or absence of OAC therapy. The day before TAVI, patients are randomized in a 1:1 manner to clopidogrel or no clopidogrel in addition to aspirin (cohort A) or OAC (cohort B).

Consortium Definition for Bleeding 18 classification as recommended by the VARC-2. 19 Bleeding complications are also classified according to the Thrombolysis in Myocardial Infarction 20,21 and Global Use of Strategies to Open Occluded Arteries 22 bleeding classification. Transfusions, hemoglobin, INR (in cohort B), and the clinical site of bleeding will be recorded and reported.

Secondary outcome The secondary outcome is a net-clinical benefit end point, defined as freedom from the nonhierarchical composite of cardiovascular mortality, non–procedure-related bleeding, stroke, or myocardial infarction (MI) at 1 year after TAVI. The co-secondary outcome is an efficacy end point, defined as freedom from the nonhierarchical composite of cardiovascular mortality, ischemic stroke, or MI at 1 year after TAVI. Detailed criteria for each type of outcome event are described in Table II. Further outcomes consist of the components of primary and secondary end points, pharmacogenetics that interplay a role in the metabolism of aspirin and clopidogrel (CYP2C19 and PTGS2 allele), quality of life (12-Item Short Form Health Survey and EuroQol 5D), and cost-effectiveness (quality-adjusted life years). Other clinical outcomes are registered and reported according to the VARC-2. 19 Sample size and statistical analysis In each cohort, the safety outcome (primary and co-primary) will be analyzed for superiority, whereas the net-clinical benefit efficacy end point will be analyzed for noninferiority. Cohort A Regarding the (co-)primary safety outcome in cohort A, we anticipate an incidence of 36% of all cause bleeding and 26% of non–procedure-related bleeding at 1 year.

These results are based on several reports in the literature. 1,2,23-25 We predict a 1.9-fold reduction within the first 3 months of follow-up and 0% thereafter for aspirin alone vs DAPT.26,27 To prove superiority for the reduction of both non– procedure-related bleeding and all bleeding and at 1 year, 648 patients are needed with a β of 0.20 and a 2-sided α of .05. Regarding the secondary net-clinical benefit outcome in cohort A, we expect a total incidence of approximately 34% in the test arm (monotherapy) and 39% in the control arm (clopidogrel). To prove noninferiority with a noninferiority margin of Δ = 0.075, 466 patients are required with a β of 0.20 and a 1-sided α of .025 with a one-sided 95% CI. With an expected dropout of approximately 6% at 1-year follow-up, 684 patients are needed in cohort A with 342 patients in each arm.

Cohort B Regarding the (co-)primary safety outcome in cohort B, we predict a 3-fold reduction in the first 3 months of follow-up and 0% thereafter, for OAC alone vs OAC + clopidogrel. 28 To prove superiority, 284 patients are needed with a β of 0.20 and a 2-sided α of .05. Regarding the secondary net-clinical benefit outcome in cohort A, we expect a total incidence of approximately 31% in the test arm (monotherapy) and 39% in the control arm (clopidogrel). To prove noninferiority with a noninferiority margin of Δ = 0.075, 296 patients are required with a β of 0.20 and a 1-sided α of .025. With an expected dropout and crossover rate of approximately 6% at 1-year follow-up, 316 patients are needed in cohort A with 158 patients in each arm. Noninferiority margin The noninferiority margin represents what is thought to be the whole effect of the control relative to placebo in

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Table I. Principal inclusion and exclusion criteria Inclusion criteria Cohort A

1. Patient has provided written informed consent. Cohort B

1. Need for long-term OAC 2. Patient has provided written informed consent. Exclusion criteria Cohort A

1. Need for long-term OAC 2. Drug-eluting stent implantation within 3 mo prior to TAVI procedure 3. Bare-metal stent implantation within 1 mo prior to TAVI procedure 4. Allergy or intolerance to aspirin or clopidogrel Cohort B

1. Drug-eluting stent implantation within 3 mo prior to TAVI procedure 2. Bare-metal stent implantation within 1 mo prior to TAVI procedure 3. Use of NOAC 4. Allergy or intolerance to OAC or clopidogrel the noninferiority study. However, the control (ie, aspirin + clopidogrel in cohort A, OAC + clopidogrel in cohort B) has never been tested against placebo. In addition, complications after TAVI in registries and randomized trials have not been consequently described according to antithrombotic regimen. The PARTNER trial used the Food and Drug Administration–requested strict margin of Δ = 0.075. 1 Although we compare a composite end point with consequent wider CIs, we decided to adopt this margin of Δ = 0.075.

Statistical testing Patients will be followed up and analyzed in the group to which they are allocated. Time to the first occurrence of the (co-)primary and (co-)secondary outcome will be presented using the Kaplan-Meier curves. The rate of occurrence will be compared using the log-rank statistics. Composite end point will be tested using a prespecified fixed sequence analysis at the same nominal α level after rejection of the global null hypothesis. Using the Cox proportional hazards model, the hazard ratio and its associated 95% CI will derive treatment effect. Various demographic factors and comorbid conditions will be evaluated in univariate analysis. Univariate associations with a P b .10 will be included in a multivariable model. For additional analyses, a prespecified patient level pooled analysis will be performed with the US-extended Clopidogrel to LOwer advErse ischemic events after transcatheter aortic valve replacement (CLOE) trial (estimated pooled n = 5,000).

Ethical considerations The study will be conducted according to the principles of the Declaration of Helsinki amended by the 59th WMA General Assembly, Seoul, October 2008 and in accordance with the Medical Research Involving Human Subjects Act (WMO) and other guidelines, regulations, and acts. In accordance with the WMO, major adverse events defined as all-cause death, MI, major or life-threatening/disabling bleeding, and stroke will be reported to the Data Safety Monitoring Board (DSMB) and the accredited medical research ethics committee. The DSMB reviews adverse event data, other safety data, quality and completeness of study data, and enrollment data to ensure proper trial conduct. A blinded clinical end point committee will adjudicate all primary and secondary end points prior to presentation of data to the DSMB. An interim analysis is planned after the follow-up data at 30 days of the first 250 patients that have been included in cohort A and B are obtained. In addition, the sponsor will submit, once a year throughout the clinical trial, a safety report to the accredited medical research ethics committee, competent authority, Medicine Evaluation Board, and competent authorities of the concerned Member States. Before participation, the investigator informs the patient orally and in writing about the scope and purpose, rights, duties, and possible risks/benefits of the study in lay language. Written informed consent from the patient is a prerequisite to participate in the study. To maintain confidentiality, patients are identified only by their identification code. Study organization The POPular TAVI trial is funded by the Dutch Organization for Health Research and Development (ZonMW) and the St Antonius Hospital, Nieuwegein, the Netherlands. The POPular TAVI trial is a collaboration between St Antonius Hospital and University Medical Centre Utrecht. The POPular TAVI trial is a European trial, in which more than 15 centers are anticipated to collaborate. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the manuscript, and its final contents. Initial recruitment of patients at the St Antonius Hospital began in December 2013. The trial will continue until 1,000 patients are included in total and followed for 12 months. Further information on the POPular TAVI trial can be obtained by contacting the corresponding author.

Discussion The POPular TAVI trial is the first randomized trial to test both aspirin and OAC monotherapy vs the currently recommended addition of clopidogrel for 3 months after TAVI. This is highly relevant because the current

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Table II. Definitions of safety, net-clinical benefit, and efficacy outcomes Safety outcome Non–procedure-related bleeding

Life-threatening or disabling bleeding

Major bleeding

Minor bleeding

All bleedings excluding any satisfying the following criteria (BARC type 4): Perioperative intracranial bleeding within 48 h, OR Reoperation after closure of sternotomy for the purpose of controlling bleeding, OR Transfusion of ≥5 U whole blood or packed RBC within a 48-h period, OR Chest tube output ≥2 L within a 24-h period Fatal bleeding (BARC type 5), OR Bleeding in a critical organ, such as intracranial, intraspinal, intraocular, or pericardial necessitating pericardiocentesis, or intramuscular with compartment syndrome (BARC types 3b and 3c), OR Bleeding causing hypovolemic shock or severe hypotension requiring vasopressors or surgery (BARC type 3b), OR Overt source of bleeding with drop in hemoglobin N5 g/dL or whole blood or packed RBC transfusion N4 U* (BARC type 3b) Overt bleeding either associated with a drop in the hemoglobin level of at least 3.0 g/dL or requiring transfusion of 2 or 3 U of whole blood/RBC, or causing hospitalization or permanent injury, or requiring surgery, AND Does not meet the criteria of life-threatening or disabling bleeding Any bleeding worthy of clinical mention (eg, access site hematoma) that does not qualify as life-threatening, disabling, or major bleeding

Net-clinical benefit outcome Cardiovascular death

MI

Stroke

Any of the following criteria: Death due to proximate cardiac cause (eg, MI, cardiac tamponade, worsening heart failure), OR Death caused by noncoronary vascular conditions such as neurologic events, pulmonary embolism, ruptured aortic aneurysm, dissecting aneurysm, or other vascular disease, OR All procedure-related deaths, including those related to a complication of the procedure or treatment of a complication of the procedure, OR All valve-related deaths including structural or nonstructural valve dysfunction or other valve-related adverse events, OR Sudden or unwitnessed death, OR Death of unknown cause Periprocedural MI (b72 h after the index procedure) New ischemic symptoms (eg, chest pain or shortness of breath), or new ischemic signs (eg, ventricular arrhythmias, new or worsening heart failure, new ST-segment changes, hemodynamic instability, new pathological Q waves in at least 2 contiguous leads, imaging evidence of new loss of viable myocardium or new wall motion abnormality), AND Elevated cardiac biomarkers (preferable CK-MB) within 72 h after the index procedure, consisting of at least one sample postprocedure with a peak value exceeding 15× as the upper reference limit for troponin or 5× for CK-MB. If cardiac biomarkers are increased at baseline (N99th percentile), a further increase in at least 50% postprocedure is required AND the peak value must exceed the previously stated limit Spontaneous MI (N72 h after the index procedure) Any one of the following criteria: Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with at least 1 value above the 99th percentile URL, together with the evidence of myocardial ischemia with at least one of the following: symptoms of ischemia, OR electrocardiogram changes indicative of new ischemia (new ST-T changes or new LBBB), OR new pathological Q waves in at least 2 contiguous leads, OR imaging evidence of a new loss of viable myocardium or new wall motion abnormality, OR 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 at autopsy, but death occurring before blood samples could be obtained, or at a time before the appearance of cardiac biomarkers in the blood, OR Pathological findings of an acute MI Acute episode of a focal or global neurologic deficit with at least one of the following: change in the level of consciousness, hemiplegia, hemiparesis, numbness, or sensory loss affecting one side of the body, dysphasia or aphasia, hemianopia, amaurosis fugax, or other neurologic signs or symptoms consistent with stroke Stroke: duration of a focal or global neurologic deficit N 24 h; OR b24 h if available neuroimaging documents a new hemorrhage or infarct; OR the neurologic deficit results in death No other readily identifiable nonstroke cause for the clinical presentation (eg, brain tumor, trauma, infection, hypoglycemia, peripheral lesion, and pharmacological influences), to be determined by or in conjunction with the designated neurologist. (Patients with nonfocal global encephalopathy will not be reported as a stroke without unequivocal evidence of cerebral infarction-based on neuroimaging studies.) (continued on next page)

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Table II (continued) Table II (continued) Safety outcome

Non–procedure-related bleeding

Confirmation of the diagnosis by at least one of the following: Neurologist or neurosurgical specialist, OR Neuroimaging procedure (CT scan or brain MRI), but stroke may be diagnosed on clinical grounds alone See above

Efficacy outcome Cardiovascular death MI Ischemic stroke

See above See above Stroke defined as above, confirmed to be of ischemic origin by a neuroimaging procedure (CT scan or brain MRI)

Definitions according to VARC-2.19 Abbreviations: BARC = Bleeding Academic Research Consortium; MI = myocardial infarction; CK-MB = creatine kinase myocardial b fraction; URL = upper reference limit; LBBB = left bundle branch block; CT, computed tomography; MRI = magnetic resonance imaging. * Given that one unit (U) of packed red blood cell (RBC) typically will raise the hemoglobin concentration by 1 g/dl, an estimated decrease in hemoglobin will be calculated.

antiplatelet/antithrombotic regimen after TAVI is based on expert opinion. As a result of the low level of evidence, a previous study demonstrated that antiplatelet and antithrombotic treatment after TAVI is very heterogeneous. 29 Given the risks and high impact of bleeding and stroke, research on the antiplatelet and antithrombotic regimen after TAVI is of recent high interest. The strategy of additional antiplatelet or anticoagulation therapy to prevent device-mediated risk of thrombosis/embolization is based on the assumption that these events are primarily due to platelet-based or thrombin based clot formation. Like in surgical aortic bioprosthetic valves, endothelialization of a TAVI prosthesis takes approximately 3 months. 30,31 Valve thrombosis after TAVI is described only sporadically, and more than 75% of cases presented after the critical period of 3 months. 4 Transient increased pressure gradients without signs of prosthetic thrombosis have been described after 3 months, possibly dependent on antiplatelet therapy. 32 However, in a study by Latib et al, 33 many thromboses were not related to DAPT discontinuation, whereas others occurred while patients were on DAPT. Acute stroke is more frequent after TAVI than surgical aortic valve replacement or balloon aortic valvuloplasty. 1,2 The stroke rate at 30 days is approximately 3% (VARC reported 0%-9%). 4 Stroke occurs more than 50% within 24 hours after TAVI and is strongly associated with procedural factors such as valve manipulation and implantation. 34 After 72 hours, no new cerebral lesions have been identified on magnetic resonance imaging (MRI). 35 This suggests that hypothetical ongoing thrombogenicity in the first 3 months after TAVI does not play a major role in the etiology of stroke. Indeed, a small randomized study did not show any difference in outcomes between aspirin monotherapy vs DAPT (ie, aspirin and clopidogrel). 8 In the PARTNER IB trial, the proportion of hemorrhagic stroke after 30 days was higher after TAVI than medical treatment, 36 emphasizing the double-edged sword of antithrombotic treatment in the elderly.

Bleeding is a frequent complication after TAVI; major bleeding at 30 days occurs in approximately 15% (VARC reported 2%-31%). 4 Although not extensively studied after TAVI, major and disabling or life-threatening bleedings are an important predictor of mortality. 12-16 The causes of bleeding could be mechanical (eg, vascular complication) or nonmechanical (eg, antithrombotic medication). The occurrence of major vascular complications after TAVI is associated with bleeding, transfusions, and increased mortality. 24 Although vascular complications are more common in transarterial than transapical procedures (14% vs 3%), 25 the transapical approach is the most important predictor of life-threatening bleeding after TAVI. 12,37 This is possibly related to a higher-risk population and supports that life-threatening bleedings of nonmechanical origin remain prevalent and of clinical significance. In-hospital bleeding is associated with the use of clopidogrel after TAVI. 9 Furthermore, both early and late bleeding are more prevalent in patients on DAPT than aspirin monotherapy before TAVI. 9 Durand et al 11 found that antiplatelet monotherapy vs DAPT is associated with a lower number of vascular and bleeding complications and transfusions, without a higher rate in ischemic complications. A recent individual participant data meta-analysis of 672 patients found that aspirin monotherapy was associated with less major and life-threatening bleeding, whereas the number of net adverse clinical and cerebral events was not significantly different. 38 Regarding patients with AF or another indication for OAC, the best antithrombotic treatment regimen after TAVI is currently unknown. In these patients, a combination of OAC and aspirin or clopidogrel is generally used. 5-7 Concerning mechanical valve prostheses, the OAC + aspirin vs OAC + placebo indeed reduced the composite of major systemic embolism, nonfatal intracranial hemorrhage, fatal hemorrhage, and death from vascular causes (3.9% vs 9.9%). 39 However, the risk of bleeding was 55% higher for patients on aspirin. Moreover, approximately half of the valves were in mitral

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position and results have not been reported according to valve location. Consequently, these results are not directly applicable for biological valve prostheses and TAVI. Concomitant antiplatelet drugs have shown to increase the risk for major bleeding in patients with AF. 28,40,41 Most studies have been performed in patients with an acute MI. Triple antithrombotic therapy vs OAC + clopidogrel has no lower recurrent coronary events but is associated with a higher bleeding risk. 42 In the What is the Optimal antiplatElet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing (WOEST) trial, OAC + clopidogrel was superior to triple therapy in patients with AF undergoing drug-eluting stent placement regarding minor + major bleeding and all-cause mortality at 1 year. 43 A Danish registry study showed that in patients with an acute MI, the risk of fatal and nonfatal bleeding was almost 3-fold higher for OAC + clopidogrel vs OAC alone, whereas mortality rates did not significantly differ. 44 After TAVI, the use of triple therapy is also associated with an increased risk of the composite of death, stroke, embolism, or major bleeding. 45 However, the need for additional antiplatelet therapy vs OAC monotherapy has not yet been investigated in patients undergoing TAVI. Randomized trials on antiplatelet treatment after TAVI are much needed in order to support clinical practice in this fragile patient population. In addition to the current study design, several other randomized trials have been initiated. The Aspirin Versus Aspirin + ClopidogRel Following Transcatheter Aortic Valve Implantation (ARTE) trial (NCT01559298) is a double-blinded randomized controlled trial testing the efficacy of aspirin monotherapy (80 mg qD of at least 6 months) vs aspirin (80 mg qD for at least 6 months) + clopidogrel (75 mg qD for 3 months) in preventing death, MI, ischemic stroke/ transient ischemic attack, or life-threatening/major bleeding at 1 year in 200 patients without the need for OAC. Second, the Dual Antiplatelet Therapy Versus Oral Anticoagulation for a Short Time to Prevent Cerebral Embolism After TAVI (AUREA) (NCT01642134) is single-blinded randomized controlled trial testing the efficacy of aspirin (80 mg/d for at least 6 months) + clopidogrel (75 mg/d for 3 months) vs OAC in preventing cerebral thromboembolism assessed with MRI at 3 months in 124 patients without the need for OAC. The CLOE trial will be initiated in the United States to evaluate the efficacy and safety of clopidogrel in patients with or without indication to OAC undergoing TAVI. Similarly to the POPular TAVI trial, 2 cohorts (OAC or no OAC) will be randomized in an open-label manner to the monotherapy or the addition of clopidogrel (6 months). A prespecified patient-level pooled analysis of the CLOE and the POPular-TAVI trials will provide additional statistical power to test primary outcomes as well as the evaluation of the components of the primary and secondary end points.

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Two sponsored trials studying the role of NOAC in TAVI patients have recently been initiated. First, the phase III GALILEO trial will randomize to rivaroxaban 10 mg once daily plus aspirin 75-100 mg once daily for 3 months, followed by rivaroxaban 10 mg once daily alone, or clopidogrel 75 mg once daily plus aspirin 75-100 mg for 3 months, followed by aspirin 75-100 mg once daily alone in approximately 1,500 patients after successful TAVI who do not have AF. Second, the phase III ATLANTIS trial will randomize to apixaban 5 mg twice daily vs vitamin K antagonist in patients with an indication for OAC and to apixaban 5 mg twice daily vs DAPT in patients without an indication for OAC, in a total of 1,500 patients with a follow-up of 6 months. In view of these trials, the POPular TAVI trial is distinguished by the investigator initiated character, studying 2 very different patient populations (with and without the indication for OAC), the all-comers model, the clinical relevant duration of clopidogrel for 3 months, the large sample size of 1,000 patients, the prespecified patient-level pooled analysis with the CLOE trial, and by studying pharmacogenetics.

Summary Currently, DAPT is empirically used in the initial period after TAVI (mostly 1-6 months). However, small explorative studies show a higher bleeding risk in patients receiving DAPT vs antiplatelet monotherapy without a higher rate of ischemic complications. In patients with OAC, the additive role of clopidogrel has not been tested. We designed the POPular TAVI trial to test the hypothesis that monotherapy with aspirin (in patients without an indication for OAC) or OAC (in patients with an indication for OAC) after TAVI is safer than the addition of clopidogrel for 3 months, without compromising clinical benefit.

Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.ahj.2015.11.008.

References 1. Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med 2011;364(23):2187-98. 2. Leon MB, Smith CR, Mack M, et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010;363(17):1597-607. 3. Adams DH, Popma JJ, Reardon MJ, et al. Transcatheter aortic-valve replacement with a self-expanding prosthesis. N Engl J Med 2014;370(19):1790-8.

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4. Nijenhuis VJ, Bennaghmouch N, van Kuijk J-P, et al. Antithrombotic treatment in patients undergoing transcatheter aortic valve implantation (TAVI). Thromb Haemost 2015;5:113(4). 5. Vahanian A, Alfieri O, Andreotti F, et al. Guidelines on the management of valvular heart disease (version 2012). Eur Heart J 2012;33(19):2451-96. 6. Holmes DR, Mack MJ, Kaul S, et al. 2012 ACCF/AATS/SCAI/STS expert consensus document on transcatheter aortic valve replacement. J Am Coll Cardiol. Elsevier Inc 2012;59(13):1200-54. 7. Webb J, Rodés-Cabau J, Fremes S, et al. Transcatheter aortic valve implantation: a Canadian Cardiovascular Society position statement. Can J Cardiol 2012;28(5):520-8. 8. Ussia GP, Scarabelli M, Mulè M, et al. Dual antiplatelet therapy versus aspirin alone in patients undergoing transcatheter aortic valve implantation. Am J Cardiol. Elsevier Inc 2011;108(12):1772-6. 9. Stępińska J, Czerwińska K, Witkowski A, et al. Risk factors for bleeding complications in patients undergoing transcatheter aortic valve implantation (TAVI). Cardiol J 2013;20(2):125-33. 10. Poliacikova P, Cockburn J, de Belder A, et al. Antiplatelet and antithrombotic treatment after transcatheter aortic valve implantation - comparison of regimes. J Invasive Cardiol 2013;25(10):544-8. 11. Durand E, Blanchard D, Chassaing S, et al. Comparison of two antiplatelet therapy strategies in patients undergoing transcatheter aortic valve implantation. Am J Cardiol 2014;113(2):355-60. [Durand, E., University Paris-Descartes, AP-HP, European Georges Pompidou Hospital, Departments of Cardiology and Cardiac Surgery, Paris, France]. 12. Borz B, Durand E, Godin M, et al. Incidence, predictors and impact of bleeding after transcatheter aortic valve implantation using the balloon-expandable Edwards prosthesis. Heart 2013;99(12):860-5. 13. Halliday BP, Dworakowski R, Brickham B, et al. Usefulness of periprocedural bleeding to predict outcome after transcatheter aortic valve implantation. Am J Cardiol. Elsevier Inc 2012;109(5):724-8. 14. Van Mieghem NM, Nuis R-J, Tzikas A, et al. Prevalence and prognostic implications of baseline anaemia in patients undergoing transcatheter aortic valve implantation. EuroIntervention 2011;7(2): 184-91. 15. Ussia GP, Barbanti M, Petronio AS, et al. Transcatheter aortic valve implantation: 3-year outcomes of self-expanding CoreValve prosthesis. Eur Heart J 2012;33(8):969-76. 16. Kodali SK, Williams MR, Smith CR, et al. Two-year outcomes after transcatheter or surgical aortic-valve replacement. N Engl J Med 2012;366(18):1686-95. 17. Rodés-Cabau J, Dauerman HL, Cohen MG, et al. Antithrombotic treatment in transcatheter aortic valve implantation: insights for cerebrovascular and bleeding events. Elsevier Ltd: J Am Coll Cardiol. 2013. 18. Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation 2011;123(23): 2736-47. 19. Kappetein AP, Head SJ, Généreux P, et al. Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document. J Am Coll Cardiol. Elsevier Inc 2012;60(15):1438-54. 20. Mega JL, Braunwald E, Mohanavelu S, et al. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet. Elsevier Ltd 2009;374(9683):29-38. 21. Sabatine MS, Antman EM, Widimsky P, et al. Otamixaban for the treatment of patients with non–ST-elevation acute coronary syndromes (SEPIA-ACS1 TIMI 42): a randomised, double-blind,

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

active-controlled, phase 2 trial. Lancet. Elsevier Ltd 2009;374(9692): 787-95. The GUSTO. Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329(10):673-82. Généreux P, Head SJ, Van Mieghem NM, et al. Clinical outcomes after transcatheter aortic valve replacement using Valve Academic Research Consortium definitions: a weighted meta-analysis of 3,519 patients from 16 studies. J Am Coll Cardiol 2012;59(25):2317-26. Généreux P, Webb JG, Svensson LG, et al. Vascular complications after transcatheter aortic valve replacement: insights from the PARTNER (Placement of AoRTic TraNscathetER Valve) trial. J Am Coll Cardiol 2012;60(12):1043-52. Khatri PJ, Webb JG, Rodes-Cabau J, et al. Adverse effects associated with transcatheter aortic valve implantation: a meta-analysis of contemporary studies. Ann Intern Med 2013;158(1):35-46. Yusuf S, Fox KAA, Tognoni G, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345(7):494-502. Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 2005;352(12):1179-89. Hansen ML, Sørensen R, Clausen MT, et al. Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation. Arch Intern Med 2010;170(16):1433-41. Nijenhuis VJ, Stella PR, Baan J, et al. Antithrombotic therapy in patients undergoing TAVI: an overview of Dutch hospitals. Neth Heart J 2013;28. Mérie C, Køber L, Skov Olsen P, et al. Association of warfarin therapy duration after bioprosthetic aortic valve replacement with risk of mortality, thromboembolic complications, and bleeding. JAMA 2012;308(20):2118-25. Noble S, Asgar A, Cartier R, et al. Anatomo-pathological analysis after CoreValve Revalving system implantation. EuroIntervention 2009;5(1):78-85. Al-Rashid F, Konorza TFM, Plicht B, et al. Transient increase in pressure gradients after termination of dual antiplatelet therapy in a patient after transfemoral aortic valve implantation. Circ Cardiovasc Interv 2012;5(2):318-20. Latib A, Naganuma T, Abdel-Wahab M, et al. Treatment and clinical outcomes of transcatheter heart valve thrombosis. Circ Cardiovasc Interv 2015;8(4), e001779. Nombela-Franco L, Webb JG, de Jaegere PP, et al. Timing, predictive factors, and prognostic value of cerebrovascular events in a large cohort of patients undergoing transcatheter aortic valve implantation. Circulation 2012;126(25):3041-53. Kahlert P, Knipp SC, Schlamann M, et al. Silent and apparent cerebral ischemia after percutaneous transfemoral aortic valve implantation: a diffusion-weighted magnetic resonance imaging study. Circulation 2010;121(7):870-8. Makkar RR, Fontana GP, Jilaihawi H, et al. Transcatheter aortic-valve replacement for inoperable severe aortic stenosis. N Engl J Med 2012;366(18):1696-704. Pilgrim T, Stortecky S, Luterbacher F, et al. Transcatheter aortic valve implantation and bleeding: incidence, predictors and prognosis. J Thromb Thrombolysis 2013;35(4):456-62. Hassell MECJ, Hildick-Smith D, Durand E, et al. Antiplatelet therapy following transcatheter aortic valve implantation. Heart 2015;101(14):1118-25. Turpie AG, Gent M, Laupacis A, et al. A comparison of aspirin with placebo in patients treated with warfarin after heart-valve replacement. N Engl J Med 1993;329(8):524-9.

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40. Dans AL, Connolly SJ, Wallentin L, et al. Concomitant use of antiplatelet therapy with dabigatran or warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial. Circulation 2013;127(5):634-40. 41. Karjalainen PP, Porela P, Ylitalo A, et al. Safety and efficacy of combined antiplatelet-warfarin therapy after coronary stenting. Eur Heart J 2007;28(6):726-32. 42. Lamberts M, Gislason GH, Olesen JB, et al. Oral anticoagulation and antiplatelets in atrial fibrillation patients after myocardial infarction and coronary intervention. J Am Coll Cardiol 2013;62(11):981-9. 43. Dewilde WJ, Oirbans T, Verheugt FW, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant

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therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 2013;12: 1107-15. 44. Sørensen R, Hansen ML, Abildstrom SZ, et al. Risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data. Lancet 2009;374(9706):1967-74. 45. Zeymer U, Zahn R, Gerckens U, Richardt G, Figulla H-R, Denges J. Antithrombotic therapy after transfemoral aortic valve implantation (TAVI). Potential hazard of triple-therapy (abstr). Eur Heart J 2011;32:900.