Clinical trial NCT02696226
Conditions: Aortic Valve Disorder
Sponsor: The Cleveland Clinic
Start date: 2016-02-01; Completion date: 2017-07-28
Enrollment: 3 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a prospective, randomized pilot study in patients undergoing Sugical Aortic Valve Replacement (SAVR) and Transcatheter Aortic Valve Replacement (TAVR) to estimate the incidence of reduced leaflet motion and assess the impact of perioperative anticoagulation on the incidence of reduced leaflet motion.

Detailed description:
This will be a pilot prospective randomized controlled trial.The study will enroll 50 adult patients scheduled to undergo SAVR and 50 adult patients scheduled to undergo TAVR. Subjects who satisfy Inclusion/Exclusion Criteria will be approached for informed consent. Those who give informed consent will be enrolled. After induction of anesthesia, a computer program will be used to randomize patients to one of the 2 treatment groups.

1. SAVR patients will get either Warfarin or aspirin
2. TAVR patients will get either Warfarin or aspirin.

Patients will be seen at 4-6 weeks postoperatively for Transthoracic ECHO (TTE), 4 dimensional (4D), Multidetector computed tomography (MDCT) scan and review of medical history. Phone follow up at 6,9 and 12 months post-operatively.

Data from this pilot study will enable us to determine the feasibility of a larger randomized controlled clinical trial to investigate the phenomenon of reduced leaflet motion/subclinical valve thrombosis and, possibly, its clinical importance

Arms: arm 1: Warfarin arm-(target INR of 2-3) arm 2: Warfarin (target INR of 2-3) and Clopidogrel (75mg/day) arm arm 3: Aspirin arm (81mg/day) arm 4: Aspirin (81mg/day) and Clopidogrel (75mg/day) arm
Interventions: intervention 1: SAVR Warfarin intervention 2: SAVR Aspirin intervention 3: TAVR Warfarin and clopidogrel intervention 4: TAVR Aspirin and clopidogrel
Intervention descriptions: intervention 1: Warfarin treatment for 12 weeks with a target INR of 2-3 Warfarin treatment to begin on postoperative day 1-3 according to the patient's clinical status When warfarin treatment is discontinued, patients will be treated according to standard of care (aspirin 81 mg/day) indefinitely intervention 2: Aspirin (81 mg/day) to begin within 1-3 postoperative days according to the patient's clinical status and continue indefinitely per standard of care. intervention 3: Begin Warfarin and clopidogrel (75 mg/day) treatment within 1-3 days postop for 12 weeks with a target INR of 2-3 When warfarin is discontinued, begin aspirin (81 mg/day) and continue aspirin/clopidogrel for 12 weeks At 24 weeks, study treatment will end and patients will be treated according to standard of care (aspirin 81 mg/day) indefinitely intervention 4: Aspirin (81 mg/day) and clopidogrel (75 mg/day) in periprocedural period and continue for 24 weeks At 24 weeks, study treatment will end and patients will be treated according to standard of care (aspirin 81 mg/day) indefinitely

Protocol documents:
Prot_SAP_000.pdf: 
Version 5May2016 
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A Pilot Study of Subclinical Leaflet Thrombosis in Bioprosthetic Aortic Valves: 
A Randomized Controlled Trial 
 
Principal Investigator: Douglas Johnston, MD 
 
Introduction 
A recent study published in the New England Journal of Medicine identified 
reduced aortic-valve leaflet motion in patients with bioprosthetic aortic valves. 
Based upon the observation that this finding resolved with therapeutic 
anticoagulation, the authors suggested that reduced leaflet motion may be 
attributable to subclinical leaflet thrombosis. The incidence of reduced leaflet 
motion varied from 7.4% after surgical aortic valve replacement (SAVR) to 43% 
after transcatheter aortic valve replacement (TAVR). Altered leaflet motion was 
detected with both 4-dimensional contrast-enhanced cardiac multidetector 
computed tomography(MDCT) and transesophageal echocardiography (TEE), but 
could not be identified on transthoracic echocardiography (TTE). The clinical 
significance of this finding is uncertain. 
The true incidence of this finding and the impact of periprocedural 
anticoagulation on leaflet motion are unknown. In addition, our review of available 
MDCT scans from the NEJM article raises questions concerning the validity of 
reduced leaflet motion after SAVR. Therefore, we propose a prospective, 
randomized pilot study in patients undergoing SAVR and TAVR to 1) Estimate the 
incidence of reduced leaflet motion and 2) Assess the impact of perioperative 
anticoagulation on the incidence of reduced leaflet motion. Data from this pilot 
study will enable us to determine the feasibility of a larger randomized controlled 
clinical trial to investigate the phenomenon of reduced leaflet motion/subclinical 
valve thrombosis and, possibly, its clinical importance.   
 
Background and Significance 
Aortic valve replacement prolongs survival in patients with severe aortic 
valve disease. Over the last decade, there has been a gradual shift to bioprosthetic 
valves in the surgical arena. TAVR involves implantation of bioprostheses, making 
bioprosthetic aortic valve replacement the most common overall treatment for 
severe aortic valve disease. 
The need for periprocedural warfarin after bioprosthetic aortic valve 
replacement is uncertain. While some centers treat patients with warfarin for 6 to 
12 weeks after bioprosthetic SAVR, others (including the Cleveland Clinic), employ a 
strategy of aspirin alone. A recent Scandinavian registry-based study suggests that 
short-term warfarin may improve outcomes after SAVR, but there are no large, 
prospective studies that validate this strategy. 
Anticoagulants are also used to treat TAVR postoperatively.  Typically 
patients will be on aspirin and clopidogrel for 12 weeks before switching them to 
aspirin alone. Patients who are on warfarin for atrial fibrillation may be treated with 
warfarin and clopidogrel for 3 months, while others are treated with aspirin and 
warfarin. No substantial research has shown one treatment to be more effective 
than the other.  


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The observation of reduced leaflet motion after SAVR and TAVR with the 
possibility of subclinical valve leaflet thrombosis has reignited the debate over 
periprocedural anticoagulation. The authors of the recent NEJM study point out that 
we need “better characterization of this observation …to determine its frequency 
and evaluate its clinical effect.” The purpose of this pilot trial is to determine the 
frequency of reduced leaflet motion after SAVR and TAVR and to determine whether 
perioperative anticoagulation with warfarin impacts this frequency. 
 
Study Design 
Methods: This will be a pilot prospective randomized controlled trial. 
 
Sample: The study will enroll 50 adult patients scheduled to undergo SAVR and 50 
adult patients scheduled to undergo TAVR.  
 
Inclusion Criteria 
Scheduled for SAVR or TAVR with or without the following concomitant procedures: 
 Tricuspid valve surgery  
 PFO closure  
 ASD closure  
 MV repair  
 Myectomy 
Age > 18 years 
Able and willing to give informed consent 
Able and willing to return for follow up 
 
Exclusion Criteria 
Contraindications to warfarin, Plavix or aspirin 
Pre-existing medical indication for warfarin, Plavix or aspirin 
History of previous coronary artery stenting 
Requirement for concomitant coronary artery bypass grafting or mitral valve 
replacement  
Contraindications to contrast-enhanced MDCT including anaphylactic iodine allergy, 
History of atrial fibrillation  
Renal dysfunction (GFR < 60 ml/min).  
 
 
Research Procedures 
Screening 
Patients scheduled for SAVR or TAVR will be identified by nurse practice managers 
and their records examined to determine eligibility. Potential subjects will be 
contacted by a research nurse, who will determine the presence of 
Inclusion/Exclusion Criteria. Subjects who satisfy Inclusion/Exclusion Criteria will 
be approached for informed consent. Those who give informed consent will be 
enrolled. 
Review of  medical records will be done to obtain medical history.  


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Intra-op Aortic Valve Procedure  
Randomization and Anticoagulation/Antiplatelet Regimen 
After induction of anesthesia, a computer program will be used to randomize 
patients to one of the treatment groups below, according to their scheduled 
procedure: 
 
SAVR 
Warfarin group (n=25) 
Warfarin treatment for 12 weeks with a target INR of 2-3 
Warfarin treatment to begin on postoperative day 1-3 according to 
the patient’s clinical status 
When warfarin treatment is discontinued, patients will be  treated 
according to standard of care (aspirin 81 mg/day) indefinitely 
Aspirin group (n=25) 
Aspirin (81 mg/day) to begin within 1-3 postoperative days according 
to the patient’s clinical status and continue indefinitely per standard 
of care. 
TAVR 
Warfarin group (n=25) 
Begin Warfarin and Aspirin (81 mg/day) treatment within 1-3 days 
postop for 12 weeks with a target INR of 2-3 
At 12 weeks, study treatment will end and patients will be treated 
according to standard of care (aspirin 81 mg/day) indefinitely 
Aspirin group (n=25) 
Begin aspirin (81 mg/day) and clopidogrel (75 mg/day) in 
periprocedural period and continue for 12 weeks 
At 12 weeks, study treatment will end and patients will be treated 
according to standard of care (aspirin 81 mg/day) indefinitely 
A transesophageal echo (TEE) will be performed prior to implant Patients will 
undergo SAVR or TAVR according to standard clinical protocol. 
 
Follow up 
Patients will be seen at 4-6 weeks postoperatively for the following procedures: 
 TTE 
 4D MDCT scan 
 Review of medical history 
 
At 6 months (+/- 7days), 9 months (+/- 7days) and 12 months (+/- 7days) post 
operatively, patients will be contacted by phone  to assess for change in 
medications, assessment of bleeding, stroke, TIA or MI signs and symptoms, and to 
obtain any INR results and imaging tests if done. 
 
 
 


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Imaging 
 
Baseline intraoperative TEE 
 Periprocedural TEE will be performed to confirm normal bioprosthetic 
aortic valve function and establish a “valve footprint”. This will include standard2D, 
spectral Doppler, color Doppler, full volume 3D and live 3D acquisitions. In addition, 
baseline aortic valve gradients will be recorded. 
 
 
Transthoracic echocardiography (4-6 weeks post-procedure) 
All patients will undergo a clinically indicated comprehensive TTE. Along 
with standard chamber dimension assessment, we will record LV outflow tract 
diameter in a standard fashion on parasternal long-axis view. Pulsed-wave and 
continuous-wave Doppler will be used to record velocities across the LV outflow 
tract (LVOT) and AV, respectively. AV will be examined from multiple windows 
including apical, suprasternal and right parasternal to obtain the peak AV velocity 
and the mean AV gradient. Additionally, dimensionless index will be calculated 
using the ratio of velocity time integral of LVOT obtained on pulse wave velocity 
divided by velocity time integral across aortic valve on continuous wave Doppler. 
AVA will be calculated using the continuity equation.  In addition, attempts will be 
made to visualize AV leaflets and assess mobility as described below in “leaflet 
motion analysis”.  
 
 
Contrast enhanced 4D MDCT   
All subjects will be scanned on standard MDCT scanners (Definition Dual 
Source/Definition Flash, Siemens Medical Solutions, Erlangen, Germany; or Brilliance 
256-slice, Philips Medical Systems, Best, The Netherlands) after administration of 
iodinated contrast (80-100 mL of Ultravist 370) at 4-5 mL/s followed by 30-50 mL of 
normal saline.  Bolus tracking technique using a region of interest in ascending aorta will 
be used, and scanning (from the carina to the mid left ventricle) will be performed 
initiated in the craniocaudal direction during a single inspiratory breath-hold. Spiral data 
will be acquired with retrospective electrocardiogram gating using the following 
parameters: gantry rotation time=270-330 ms; beam collimation ranging from 128 x 0.6 
mm to 32 x 0.6mm; tube voltage=100-120 kVp; tube current adjusted per patient weight; 
and beam pitch of 0.2-0.5.  Electrocardiogram-based tube current modulation will be 
used for all patients, with maximum current turned on between 30-70 % phases of the 
cardiac cycle (hence maintaining image quality during the systolic phases).  4-
dimensional images will be reconstructed during 10 phases of the cardiac cycle with a 
section thickness of 0.75 mm. Radiation in the study sample will typically be < 12 
mSEV. 
 
 


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Leaflet motion analysis 
Based upon the 4D MDCT data, we will attempt to measure leaflet tip 
thickness. In addition, leaflet motion will be judged as normal, mildly reduced 
(<50% reduction in motion), moderately reduced (50 to 70% reduction), severely 
reduced (>70% reduction), or immobile (lack of motion of at least one valve leaflet). 
For the purposes of analysis, leaflet motion will be considered reduced if it is 
moderately reduced, severely reduced, or immobile. The 4D CT scans will be 
interpreted by a reviewer who is blinded to the anticoagulation/antiplatelet 
regimen for the patient. 
 
 
 
Crossovers 
 
Patients who are randomized to an aspirin group and who develop a new 
indication for periprocedural anticoagulation (e.g. perioperative atrial fibrillation) 
will be crossed over into the warfarin group. Patients who are randomized to a 
warfarin group who develop contraindications to warfarin will be crossed over to 
the aspirin group. Patients who are randomized to an aspirin group who develop 
overt leaflet thrombosis, as detected by clinical standard of care imaging may be 
treated with warfarin at the discretion of the treating physician. However, the 
physicians will be blinded to the results of the 4D MDCT scan till the completion of 
the study.  
 
 
Funding 
Funding will be provided by the Mary Elizabeth Holdworth treasury fund 
(000000991924, T56338). 
 
Adverse Events and Independent Medical Safety Officer 
Adverse events will be reported directly to the IRB.   
 
An Unanticipated Problem Involving Risks to Participants or Others is any event 
that (1) is unforeseen, (2) caused harm or placed a person at increased risk of harm, 
and (3) is related to the research procedures. 
 
An Adverse Event (AE) defined for this pilot study is any untoward or unfavorable 
medical occurrence related to structural valve deterioration, bleeding, stroke, TIA or 
MI. 
 
A Serious Adverse Event (SAE) is any adverse experience that results in any of the 
following outcomes:  
death  
a life-threatening experience  
inpatient hospitalization or prolongation of existing hospitalization  
a persistent or significant disability/incapacity  
a congenital anomaly/birth defect  
Important medical events that may not result in death, be life-threatening, or 


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require hospitalization may be considered a serious adverse drug experience 
when, based upon appropriate medical judgment, they may jeopardize the patient 
or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
 
The independent Medical Safety Officer will routinely review all deaths, SAEs, 
adverse events and imaging.  The medical safety officer will be separate and 
independent from clinical staff or anyone responsible for patient care.     
 
Statistical Analysis 
A statician will analyze using the following: Standard descriptive analysis will be 
performed. Continuous variables will be compared using t-testing or analysis of 
variance. Categorical variables will be compared using Chi-square. Outcomes will be 
compared in 2 groups using standard survival analysis. Predictors of 30-day 
outcomes will be determined using logistic regression analysis. All analysis will be 
done by standard software (SPSS and SAS). A p-value <0.05 will be considered 
significant.