Prospective Randomized On-X Anticoagulation Clinical Trial (PROACT)
Phase: NA
Conditions: Heart Valve Disease
Sponsor: On-X Life Technologies, Inc.

Protocol Cover Page for clinicaltrials.gov 
 
 
 
 
Clinical Trial of the On-X® Valve Using Low Dose Anticoagulation  
(also known as PROACT: Prospective Randomized On-X Anticoagulation Clinical Trial) 
 
NCT00291525 
 
Study Protocol - Rev. N, March 3, 2014 
 
 

Investigational Plan
Clinical Trial of the On-X® Valve Using Low Dose Anticoagulation
John Ely
On-X Life Technologies, Inc.
2005-01, Rev. N, March 3, 2014
MVR Arm Late Enrollment Only

i
Clinical Trial of the On-X® Valve Using Low Dose Anticoagulation
Table of Contents
Pages
I.
Hypothesis
II.
Study Design
1
A.
Patient Inclusion
1
B.
Patient Exclusion
1
C.
Test and Control Group Drug Therapies
3
D.
Sample Size
3
E.
Center Participation
6
F.
Study Responsibilities
7
III.
Patient Follow-up
9
A.
Endpoints
9
B.
Follow-up Regime and Intervals
10
C.
Investigational Procedures
10
D.
Echocardiography Procedures
22
E.
Explant Procedures
23
F.
Adverse Events
24
G.
Study Review
24
H.
Data Analysis
25
I.
Reports
25
IV.
Device Description and Risk Analysis
25
V.
Monitoring Procedures
27
VI.
Legal/Ethical Considerations
29
VII.
References
30
Appendix A
Case Report Forms
Appendix B
Investigators Agreement
Appendix C
Example Informed Consent
Appendix D
Labeling
Appendix E
IRB and Investigator Information
Appendix F
Echocardiography Procedures

1
Clinical Trial of the On-X® Valve Using Low Dose Anticoagulation
I.
Hypothesis
Various patient groups with the On-X Valve can be maintained safely on lower doses 
of Coumadin® or on antiplatelet drugs only rather than the standard dose of Coumadin
and aspirin presently recommended by ACC/AHA or ACCP professional societies.
II.
Study Design
This is a longitudinal, randomized (randomization to occur at the 3 month follow-up) 
study comparing the On-X valve on low dose anticoagulation (test group) to  
concomitant control groups of On-X valves receiving standard Coumadin/aspirin
therapy, and also to FDA objective performance criteria (OPC)[1]. It is a multicenter 
study consisting of up to 50 centers in the United States, Canada and Italy enrolling
and randomizing no more than 1200 patients as described in Section II.D.  A list of 
participating centers is included in Appendix E with updates available upon request or 
as required by the FDA approval order.
A. Patient Inclusion 
1. Patients requiring isolated aortic valve replacement (AVR), or isolated 
mitral valve replacement (MVR). 
2. AVR patients receiving low dose or antiplatelet only anticoagulation will 
be divided into groups at low risk and high risk for thromboembolism with 
all patients being in the low risk group except for patients with the 
following conditions which place a patient in the high risk group:
Chronic atrial fibrillation (see definition below)
Left ventricular ejection fraction < 30 %
Enlarged left atrium >50mm diameter
Spontaneous echo contrasts in the left atrium
Vascular pathology (see definition below)
Neurological events (see definition below)
Hypercoagulability (see definition below)
Left or right ventricular aneurysm
Lack of platelet response to aspirin or clopidogrel (see definition
below)
Women receiving estrogen replacement therapy
3. Concomitant cardiac surgery is allowed
4. Adult patients
B. Patient Exclusion
1. Right side valve replacement
2. Double (aortic plus mitral) valve replacement
3. Patients with active endocarditis at the time of implant

2
4. Previous confirmed or suspected thromboembolic event or 
thrombophlebitis occurring or resolving within the last year prior to 
enrollment
5. Other terminal illness
6. Patients who are in an emergency state
7. Inability to return for required follow-ups
8. Patients with an On-X valve implanted within the study and subsequently 
explanted
9. Patients who are known to be pregnant, plan to become pregnant or are 
lactating
10. Patients with acquired immunodeficiency syndrome or know to be HIV 
positive
11. Patients who are prison inmates or known drug or alcohol abusers
12. Patients unable to give adequate informed consent.
All patients meeting the criteria will be invited to participate.  
Definitions –
Anticoagulation or anticoagulant –
For the purposes of this study anticoagulation shall mean any drug therapy that 
interferes with the coagulation of the blood whether by inhibition of vitamin K 
(Coumadin) or inhibition of platelet aggregation (aspirin or clopidogrel).  
Anticoagulant regime shall be specified whenever discussed.
Chronic Atrial Fibrillation –
Atrial fibrillation that is unresponsive to medical or cardioversion therapy and that 
has become the primary heart rhythm of the patient, also called persistent atrial 
fibrillation, having been present in the patient for at least 1 month.
Hypercoagulability –
Hypercoagulability in AVR patients will be defined by the following blood tests and 
results done preoperatively with the patient not on Coumadin:
1. APC resistance (Factor-V-Leiden mutation) – heterozygous or homozygous
2. Prothrombin mutation – heterozygous or homozygous
3. AT-III activity – below normal
4. Protein C activity – below normal
5. Protein S activity - below normal
6. Factor VIII activity – elevated above 250%.
7. Lipoprotein – above normal
Antiplatelet Resistance (Treatment Failure) –
Resistance to aspirin or clopidogrel in AVR patients will be defined by clinical 
laboratory tests and results done preoperatively or postoperatively after patients have 
been taking aspirin and clopidogrel for at least 1 week (see section III C page 12 for 
enrollment processes):
1. Urine 11 dehydro thromboxane B2 – not reduced after aspirin treatment  
2. P2Y 12 not reduced 

3
Vascular Pathology –
For the purposes of determining AVR risk in this study, vascular pathology shall 
include any historical evidence of carotid or peripheral artery occlusion of at least 
50% by ultrasound or angiography, arterial aneurysms, claudication and/or ischemic 
ulcers of the lower extremities.
Neurological events –
For the purposes of determining AVR risk in this study, neurological events shall 
include any historical evidence of transient ischemic attack (TIA), stroke or cerebral 
aneurysm.
C.
Test and Control Group Drug Therapies
Isolated Aortic Valve Replacement –
Test Group I (high risk AVR) – First 3-months postoperation, Coumadin at an INR 
target of 2.0 to 3.0 with 81 mg/day aspirin will be used. After 3-months, Coumadin
dose will be reduced to an INR target of 1.5 to 2.0 with 81 mg/day of aspirin
continued. Enrollment in this arm has ceased.
Test Group II (low risk AVR) – First 3-months postoperation, Coumadin at an INR 
target of 2.0 to 3.0 with 81 mg/day aspirin will be used.  After 3-months, Coumadin
dose will be removed and clopidogrel will be added using a loading dose of 300 mg 
followed by 75 mg/day with aspirin at 325 mg/day. AVR low risk patients who do 
not pass hypercoagulability or drug response tests will no longer be moved to the high 
risk group. This arm has been closed. See Addendum A for close out process for this 
test group and its control.
Control Groups – Postoperatively Coumadin with an INR target of 2.0 to 3.0 with 81 
mg/day aspirin throughout the study.  A separate control group will be used for each 
test group above.
Mitral Valve Replacement –
Test Group III, (regardless of risk) – First 3-months postoperation, Coumadin at an 
INR target of 2.5 to 3.5 with 81 mg/day (75 mg/day in Italy) aspirin will be used.  
After 3-months, Coumadin dose will be reduced to an INR target of 2.0 to 2.5 with 81 
mg/day (75 mg/day in Italy) of aspirin continued.
Control Group – Postoperatively Coumadin with an INR target on 2.5 to 3.5 with 81 
mg/day (75 mg/day in Italy) aspirin throughout the study.
D. Sample Size
A sample size estimate was conducted based on FDA OPC criteria [1].  The study is 
expected to test the safety of low dose (LD) therapy for anticoagulant therapy in On-
X valve patients with LD therapy consisting of the use of Coumadin in combination 
with aspirin or the use of antiplatelet therapy alone. This study is designed as a non-
inferiority study requiring only that LD therapy is not inferior to standard 

4
Coumadin/aspirin treatment.  Testing the superiority of LD therapy with adverse 
event rates as low as expected would require exposure of a prohibitively large patient 
group.  It was necessary for the sample size calculation to assume an acceptable event 
rate for the primary endpoints of thromboembolism, thrombosis and bleeding events 
derived by summing the FDA OPC’s.  The incident rate of the sum of these three 
events needs to be at least as low as the OPC sum, 7.3%.  Table 1 gives the resulting 
sample size requirements based on a variety of outcomes.
The number of patients to be enrolled in the clinical trial is based first on the ability to 
show that linearized adverse event rates for the primary endpoints in the test groups 
are not inferior to the corresponding control groups and second on the ability to show 
that all valve related adverse event rates in the test groups do not equal or exceed 2
times the rates determined to be acceptable for mechanical valves.
For the first criterion above, the test group will need to have less than 6%/ptyr 
cumulative rate of the three events for the study to reach significance with a 
randomized patient population of between 150 and 250 per group followed for 
between 5 and 6.7 years at a statistical power of 80% with type I error of 0.05 and a 
maximum allowable difference between groups of 1.5%.  It is expected that each of 
50 centers will be able to enroll an average of 30 patients into the study balanced to 
provide adequate population in each sub-group, providing sufficient patient-years to 
test the hypothesis, which under the above conditions is around 1000 as shown in 
Table 1. Thus the study has 200 patients per group in AVR high risk with an average 
of 5 years of follow-up, or alternatively 150 patients in AVR low risk averaging 6.7 
years of follow-up and and up to 250 MVR averaging 4 years of follow-up, providing
the approximately 1000 patient-years per group estimated to meet hypothesis.
For the second criterion above, the established rates are the objective performance 
criteria (OPC) given in the FDA guidance document (1). The adverse event rates for 
which OPCs are established include the primary endpoints of thrombosis, 
thromboembolism and bleeding and the secondary endpoints of paravalvular leak and 
endocarditis as listed below:
Adverse Event
% per valve year (RA)
Thrombosis
0.8
Thromboembolism
3.0
All Bleeding
3.5
Major Bleeding
1.5
Paravalvular Leak
1.2
Endocarditis
1.2
In the comparison to OPCs for each adverse event, the null hypothesis being tested is 
that the true adverse event rate for each test group is equal to or greater than twice the 
acceptable rate.  Rejecting the null hypothesis would conclude that the rate for the test 
groups is less than two times the acceptable rate.  The null and alternative hypotheses 
can be written as:
Null hypothesis:
R 5A
Alternative hypothesis:
R < 2RA

5
Table 1
Sample Size Estimation for On-X Trial
LD Therapy vs. Control
The sample size estimation is based on one-sided proportion test, which 
tests that the incidence rate of thrombosis, thromboembolism and 
hemorrhage in the LD therapy groups are at least as low as the control 
groups.
Type I Error
(One-sided 
Test) 
Statistical 
Power
Expected 
Proportion 
In  Control 
Group
Expected 
Proportion 
In  Low Dose 
Group
Maximum Allowable 
Difference
between Two Groups
to Declare Non-inferiority
Needed 
Patient 
Years
0.05
80%
7.3%
4.5%
2.0%
309
5.0%
2.0%
398
6.0%
2.0%
719
7.3%
2.0%
2112
4.5%
1.5%
381
5.0%
1.5%
504
6.0%
1.5%
992
7.3%
1.5%
3739
4.5%
1.0%
483
5.0%
1.0%
663
6.0%
1.0%
1461
7.3%
1.0%
8388
0.025
80%
7.3%
4.5%
2.0%
393
5.0%
2.0%
506
6.0%
2.0%
914
7.3%
2.0%
2682
4.5%
1.5%
484
5.0%
1.5%
641
6.0%
1.5%
1260
7.3%
1.5%
4748
4.5%
1.0%
613
5.0%
1.0%
842
6.0%
1.0%
1856
7.3%
1.0%
10650

6
Where R is the observed event rate and RA is the corresponding OPC.  FDA’s 
guidance document estimates that 800 patient years are required to test this 
hypothesis assuming 95% confidence, 80% power and an annual attrition of 5%.  
This amount of trial experience is consistent with the requirements of the first 
criterion shown in Table 1 indicating that a patient group of 200 followed for 5 years
average or 150 followed for 6.7 years average will be adequate for both purposes.
E.  Center Participation
The principal investigators selected will be responsible for fulfilling the clinical trial 
requirements that are outlined in this investigational plan.  The investigational center 
should have the necessary resources to allow the investigator to adhere to all clinical 
trial requirements. The following criteria will be used to select centers and 
investigators for participation in this clinical trial:
x
Expertise in clinical areas relevant to the On-X heart valve LD therapy 
clinical trial. This includes an extensive background in cardiovascular 
surgery and management of patients with prosthetic heart valves, and prior 
experience in conducting clinical studies on prosthetic heart valves.
x
Appropriate and sufficient personnel should be available to obtain and 
report data as required by the investigational plan. There should be an 
investigational group at each center consisting of at least: the investigator 
(a cardiovascular surgeon); co-investigators, who will also implant the 
study valve; and a center study coordinator to manage, organize and 
coordinate the routine activities of the clinical trial.
x
Appropriate and sufficient patient population should be available to meet 
the implant schedule requirements for aortic and mitral prostheses.
x
Access to a hospital and/or clinic having the equipment necessary to 
perform the clinical trial. 
x
Willingness to comply with all aspects of the clinical trial as described in 
the investigational plan. This includes collection of complete and accurate 
data in a timely manner according to the prescribed patient follow-up
schedule. Additionally, investigators should be accessible to their support 
staff, and sponsor and monitor personnel.
A visit by the sponsor and/or monitor will be scheduled with the investigator and 
members of the investigational group to provide in-depth training and discussion of 
the investigational plan and clinical trial requirements prior to the first implant.
Topics to be covered at the pre-study visit will include: 
x
Review of the study protocol requirements - particularly patient selection 
and informed consent;
x
Review of proper data management;
x
Review of follow-up requirements and monitoring procedures;

7
x
Review of anticoagulant regime;
x
Review of complication definitions and reporting;
x
Review of explant procedures; and
x
Review of reporting requirements.
F.  Study Responsibilities (Records And Reports)
Sponsor –
The sponsor shall be responsible for the following activities:
a) selection and training of investigators;
b) ensuring that all information within the study is properly distributed;
c) providing all study materials, such as preclinical data and documentation, 
valves, case report forms, etc.;
d) obtaining and keeping records of all approvals, and agreements;
e) selection of monitors;
f)
ensuring that provisions for compensation in the event of injury are made;
g) ensuring compliance (through the monitor) with the investigational plan;
h) maintaining all correspondence pertaining to the investigation;
i)
obtaining, keeping and reporting adverse device effects per the protocol 
and all rules and regulations;
j)
reporting any approval withdrawals, and if necessary, terminating the 
study;
k) keeping a current investigator list;
l)
filing appropriate progress and final reports; and
m) reporting any failure to obtain prior informed consent.
Monitor –
The monitor shall be responsible for the following activities:
a) secure compliance with the investigational plan;
b) evaluate and report adverse effects (expected or unanticipated);
c) if necessary, assist in termination of the study;
d) identify protocol deviations or problems;
e) audit data from case reports;
f)
confirm informed consent;

8
g) help train centers in conduct of the study;
h) maintain sponsor to investigator communications;
i)
determine cause of plan deviations and work to remedy those deviations; 
and
j)
document any patient withdrawals.
The monitor must establish a good working relationship with the administrator (study 
coordinator) at each clinical center.
Investigator –
The principal investigator at each center is responsible for the following activities:
a) ensures that the investigation is conducted in accordance with the plan;
b) ensures protection of patient rights and welfare;
c) works to achieve adequate patient enrollment;
d) obtains and maintains local institutional approval;
e) supervises the use of the device by any co-investigator;
f)
maintains accurate and complete records on each patient within the study, 
including and especially informed consent, and forwards these records on 
a timely basis;
g) keeps records of all communications regarding the study;
h) properly reports any deviation from the protocol, especially failure to 
obtain informed consent, any withdrawal of local approval, and any 
unanticipated adverse event; 
i)
reports regularly on the progress of the study;
j)
reviews and approves, by signature, the data forwarded to the sponsor; and
k) reviews and approves any final report of the study.
The investigator should use a member of his/her staff as a study coordinator, whose 
functions are to conduct the day-to-day administrative activities of the study, such as 
completion of case report forms, scheduling of follow-up, maintenance of records and 
filing of reports. The investigator must sign the agreement contained in Appendix B.
Other participating investigators –
INR monitoring and home testing:
Michael Fine, National Sales Manager
Quality Assured Services, Inc. (QAS) (now Alere Home Monitoring)
1506 N. Orange Blossom Trail
Orlando, Florida  32804-6103
Blood testing services:

9
Marilyn Johnston, President
Hemostasis Reference Centre
Henderson Research Centre
711 Concession Street
Hamilton, ON L8V 1C3
Canada
Core echocardiographer and laboratory:
Dr. Karen Hamilton
Department of Cardiology
University of Florida
1600 SW Archer Rd.
Gainesville, FL 32610
Study pathologist:
Dr. Mark Silberman
Clinical Pathology Laboratories
9200 Wall Street
Austin, Texas 78754
Web-Based Data Management:
Chris Porter, Vice President of Operations
Clinipace, Inc.
3200 Chapel Hill-Nelson Boulevard, Suite 100
Research Triangle Park, North Carolina  27709
III.
Patient Follow-up
A. Endpoints
Safety –
The primary study endpoints are the rates of occurrence of valve thrombosis, 
thromboembolism, all major and minor bleeding events whether or not related to 
drug therapy, reoperation, explant and death.  Other valve related adverse events 
including endocarditis, hemolysis, hemolytic anemia, paravalvular leak and 
structural and non-structural dysfunction are secondary endpoints.  All events 
shall be as defined by the AATS/STS guidelines [2] for reporting valve study 
results.

10
Effectiveness –
Effectiveness endpoints are also secondary endpoints and shall be New York 
Heart Association (NYHA) functional classification and the echocardiographic 
hemodynamic parameters of peak and mean gradient and effective orifice area 
(EOA).  Echocardiographic exams shall also evaluate indexed EOA, performance 
index, cardiac output, cardiac index and amount and location of any valvular 
regurgitation.
B. Follow-up Regime and Intervals
The intent of the study design is to treat mechanical valve patients with less 
aggressive anticoagulation.  The control group drug regimes are those from the 
recommendations for mechanical valves of the ACCP[3] and the AHA/ACC[4],
while test group regimes are either a clopidogrel/aspirin mix for low risk aortic 
patients or reduced Coumadin to just below the present recommendations but with 
aspirin added. Patients will be maintained on Coumadin/aspirin beginning 
immediately postoperatively, with heparin used from operation until INR target is 
reached.  Randomization and transfer to test group will occur at the 3-month visit.  
INR control will be accomplished using home monitoring with the system 
provided by QAS or in Italy with systems as provided within the processes used 
in medical care there.  The patient in consultation with his/her physician will also 
make drug dosage adjustments.
Patients will be followed at 3 months, 6 months and 1-year, then annually 
thereafter until the study is completed when the patient groups reach sufficient 
patient-years experience at up to 8-years of follow-up for any individual patient 
and at least 1-year follow-up for all patients. Visits will be scheduled within 1-
month of the appropriate anniversary.  Follow-up will be conducted by physician 
visit.
C. Investigational Procedures  
The sponsor will provide case report forms (CRFs) or equivalent electronic data 
management tools to each principal investigator for the purpose of recording 
patient data. Assessments will be obtained for the preoperative, operative and 
discharge period and postoperatively at three and six months and annually to 5 
years from the date of implant (Table 2 summarizes the required information at 
each visit). A follow-up schedule will be provided for each patient based on the 
implant date.
This protocol is designed to be used within the normal daily practice of each 
center.  No specific instructions other than those in the labeling are given on valve 
orientation or concomitant drug therapies.  This will result in a study that defines 
complication rates under the various drug therapies.
The investigator will make every attempt to follow the patients and will document 
the information gathered during the follow-up visits on the CRFs. Follow-up 

11
Table 2 - Patient Progress and Data Record
Interval
of Follow-up
From
Implant
or 
Enrollme
nt 
Date 
_______
As 
appropr
iate 
Preoperation
Operation Discharge
3 Month
6 Month
1 Year
2 Year
3 Year
4 Year
5 Year
5+ Year
Form/Data
Preoperative Form CRF 1
Implantation Data Card
Operative Form CRF 2
Follow-up CRF 3
Complication CRF 4
Death Summary/ Autopsy
Reop/Explant CRF 5
Echo CRF 6
Required data
Required only if 
needed
Not 
applicable

12
visits should be made in person; telephone or questionnaire follow-up is not allowed.
The patients will be encouraged by the investigator to report any address or telephone 
number changes. They will also be informed of the importance of returning for 
scheduled follow-up visits even if they are not having any problems. All dates within 
the study will be recorded as month/day/year using numeric designators for months. 
If additional space is needed on any form for any data, the data can be placed on a 
separate sheet and attached to the form.
The study coordinator should submit preoperative, operative and discharge case 
report forms within 30 days of the implant. As an exception, these CRFs may be 
forwarded within 30 days of discharge, if discharge is delayed by patient 
complication. 
All appropriate sections of the CRFs must be filled out accurately and completely. All 
case reports form must be reviewed, signed and dated by the investigator. The CRFs 
should be sent expeditiously to the monitor, when completed, and be kept in the 
patient record notebooks or electronic files provided by the sponsor.
To protect patient confidentiality, the sponsor will use the information from the 
CRF’s for statistical and device tracking purposes only and will treat medical records 
as confidential as required by United States law and regulation. For this reason, the 
sponsor is not routinely collecting patient names, but using a study number or initials, 
if necessary, for patient identification; thus better protecting patient confidentiality.  
A representative of the U.S. Food & Drug Administration or other appropriate 
regulatory authority may look at, and perhaps copy, some of the medical records; 
these organizations also have rules for protection of patient privacy that they must 
follow.
Enrollment Process and Options -
The following procedures may be used for enrolling patients into the study:
AVR High Risk and MVR Patients
x
From review of patient charts determine the patient’s eligibility for inclusion in 
either of these two groups.
x
Patients that eventually qualify for high risk AVR based solely on 
hypercoagulability testing, which must be done preoperatively off warfarin, must 
be recruited preoperatively as described below under low risk AVR.
x
All other patients can be approached for consent either preoperatively or 
postoperatively up to 60 days at the discretion of the investigative site. MVR 
patients may be enrolled up to 1 year postoperatively.
x
Once a patient has consented initiate the patient in the Clinipace database by 
starting a preoperative form which will automatically assign the patient number 
for the study.  Do not assign numbers manually.
x
In North America then complete the home monitoring prescription paperwork and 
forward to QAS right away so the insurance qualification process can begin.
x
In North America randomize the patient 2 weeks prior to their 3 month visit 
postoperative or for MVR patients at enrollment visit if greater than 3 months 
postoperative and provide QAS with the study INR target range for the patient 

13
and the home test machine order. Use Italian home monitoring procedures 
elsewhere, and randomize as above.
x
Conduct the 3 month visit which will start the study for the patient. Change drug 
therapy per the protocol and randomization result.
Low Risk AVR Patients (No longer active arm of trial)
Determine the patient’s potential eligibility for the low risk AVR group understanding 
that the group may change to high risk AVR pending the results of the hypercoagulability 
and drug response testing described below.  
Completely Preoperative Testing Option
x
Approach all eligible patients for informed consent, and once consent is given, 
start the laboratory testing program. At this time also enter the patient into the 
Clinipace database for the assignment of the patient number.
x
Order clopidogrel through Canada Drug or the local VA pharmacy as appropriate.  
This order is for 10 – 75mg tablets to be shipped to the patient’s home overnight.  
The prescription should prescribe a 300 mg loading dose on day 1 and 75mg/day 
for 1 week.  Instruct the patient to take the drug in this manner.  Also instruct the 
patient to buy and take 325 mg aspirin once daily.
x
Have the patient return for testing at least 5 days later. Confirm that they are 
taking their antiplatelet medications. Draw the appropriate blood samples per the 
Accumetrics and HRL instructions and also get the required urine sample.  
Process all the samples for HRL per the HRL instructions and the Accumetrics 
P2Y12 test within 4 hours.  Regardless of the Accumetrics test result, freeze and 
ship all other samples per the HRL instructions. Clopidogrel can be stopped as 
soon as the P2Y12 test is successfully done. A P2Y12 result of <35% inhibition 
disqualifies the patient but the full testing should still be done.  A urine 
thromboxane result of >298 pg/mg disqualifies the patient.
x
Enter the shipment information into the Clinipace database and wait 24 hours for 
the lab to respond that the samples have arrived properly.  Hint: arrange the 
testing and shipment schedule to occur early in the work week to avoid any 
overnight sample arriving at the lab on the weekend.
x
If samples arrived in good condition, instruct the patient to stop taking the drugs 
and schedule the operation for at least 5 days later.
x
Complete the home monitoring prescription paperwork and forward to QAS right 
away so the insurance qualification process can begin in case it is needed after 
randomization.
x
Randomize the patient 2 weeks prior to their 3 month visit and either order 
clopidogrel for test group patients or provide QAS with the study INR target 
range for the control group patients and the home test machine order.  The 
clopidogrel prescription is for a 90 day supply with 7 refills the dosing regime is 
300mg loading dose on day 1 and 75mg/day thereafter.
x
Conduct the 3 month visit which will start the study for the patient. Change drug 
therapy per the protocol and randomization result.

14
Preoperative Hypercoagulability and Postoperative Drug Response Option -
x
Approach all eligible patients for informed consent, and once consent is given, 
start the laboratory testing program.  At this time also enter the patient into the 
Clinipace database for the assignment of the patient number.
x
Draw the appropriate hypercoagulability blood samples per the HRL instructions.  
The patient must be off warfarin for this testing.  Process all the samples for HRL 
per their instructions.
x
Enter the shipment information into the Clinipace database.  Hint: arrange the 
shipment schedule to occur early in the work week to avoid any overnight sample 
arriving at the lab on the weekend, so keep any frozen samples until Monday if 
drawn on Friday for example.
x
Complete the home monitoring prescription paperwork and forward to QAS right 
away so the insurance qualification process can begin in case it is needed after 
randomization.
x
The patient’s surgery can proceed under normal scheduling plans.
x
At 50 days postoperatively, call the patient to determine that the patient’s INR is 
stable and in target range then order clopidogrel through Canada Drug, or the 
local VA pharmacy as appropriate.  This order is for 10 – 75mg tablets to be 
shipped to the patient’s home overnight.  The prescription should prescribe 
75mg/day for 1 week to 10 days (no loading dose).  Instruct the patient to take the 
drug in this manner.  Also instruct the patient to buy and take 325mg aspirin 
daily.  If the patient’s INR is high adjust the Coumadin dose to bring the INR in 
range before starting clopidogrel.  Also confirm that the patient is taking his/her 
antiplatelet medications. It is also recommended that a CBC be done locally to 
make certain that the patient is not clinically anemic, which could create an 
inaccurate P2Y12 measurement.
x
At 60 days bring the patient into the office for their drug response testing.  Draw 
the appropriate blood samples per the Accumetrics instructions and get the 
required urine sample for HRL.  Process the blood sample for the Accumetrics 
P2Y12 test within 4 hours.  Also freeze and ship the urine per the HRL
instructions regardless of the P2Y12 result.  A P2Y12 result of <35% inhibition 
disqualifies the patient but the full testing should still be done.  A urine 
thromboxane result of >298 pg/mg disqualifies the patient.
x
Enter the shipment information into the Clinipace database. In 24 hours the lab 
should respond that the sample has arrived properly.  Hint: arrange the testing and 
shipment schedule to occur early in the work week to avoid any overnight sample 
arriving at the lab on the weekend.
x
Randomize the patient 2 weeks prior to their 3 month visit and either order 
clopidogrel for test group patients or provide QAS with the study INR target 
range for the control group patients and the home test machine order.  The 
clopidogrel prescription is for a 90 day supply with 7 refills the dosing regime is 
300mg loading dose on day 1 and 75mg/day thereafter.

15
x
Conduct the 3 month visit which will start the study for the patient.  Change drug 
therapy per the protocol and randomization result.
Preoperative Procedures –
The investigator will determine and document on CRFs whether each patient meets 
the selection criteria previously outlined before enrollment into the study. He will 
also obtain informed consent for study participation from each patient prior to 
implantation of the study device.  A copy of the informed consent form will be kept 
by the investigator in the patient’s study notebook.  Patients not meeting the selection 
criteria or not receiving informed consent should not be enrolled in the study. 
The investigator will determine and record on CRF1 each patient’s demographics and 
relevant medical history, i.e., age at implant, gender, New York Heart Association 
(NYHA) functional class, cardiac rhythm, disease etiology, previous cardiac surgery,
relevant information to determine thromboembolic risk group and valve lesion (i.e., 
stenosis, regurgitation or mixed stenosis/regurgitation).
These instructions are made to assist the study coordinator in filling out the form. 
Complete all items on the form. If information is unavailable to answer any item, 
make a note on the form and attach an explanation, as appropriate. When asked to 
specify a particular answer, use a short description.  Please check any and all items 
that apply to the patient.
For patient study number, use a 6 digit code. The first two digits are your center 
number, as assigned by the sponsor.  The third number represents the position of the
implant; 1 for aortics, and 2 for mitrals.  The last three digits are assigned sequentially 
to each patient. For example, if your center number is 99, your first aortic patient 
study number is 991001, your first mitral patient study number is 992001, and so 
forth. Once the patient study number is assigned on CRF1, use of the patient study 
number is required to identify the patient on subsequent forms.
NYHA functional class uses the nomenclature of that association. For the purposes of 
this study the commonly used classes of IIa and IIb are not used, either subgroup is 
considered class II.
Any failure to obtain prior informed consent must be reported to the sponsor, and the 
institution within 5 working days.
Previous cardiovascular surgery should be noted with a one or two word name of 
surgery and the date performed (page 2 of CRF1). Room is given for three prior 
procedures. Attach a separate explanation if more prior surgery was done. For 
coronary artery bypass surgery, please note the number of grafts by the following 
notation:  CABG x 2 = double graft; CABG x 3 = triple graft; and so on.
If the patient has been maintained on any permanent or long-term preoperative 
Coumadin therapy, the preoperative INR should be measured and recorded within 72
hours prior to surgery.

16
Operative Procedures –
The surgical technique employed is that developed and perfected by the principal 
investigator in his normal practice of cardiac surgery. Operative details such as 
cardioplegia are not specified in the protocol, but must be documented on CRF2.
The investigator will record on CRF2 information regarding the particular valve(s) 
implanted and other details concerning the surgery such as suture technique and any 
concomitant procedures. Carefully record the valve position, size and serial number.
Use the patient study number assigned on the preoperative form (CRF1) to identify 
the patient. Check any and all of the items that apply to this patient. Where 
explanations are needed, print a brief description of the required data.
For concomitant procedures, there are spaces for these additional procedures. Write in 
the name of the procedure done. For coronary artery bypass grafting, also note the 
number of grafts (i.e., CABG x 2 = double graft, CABG x 3 = triple graft, and so on).
Where requested, attach additional CRFs or reports.
The Implant Registration Card is included with the valve packaging and is used for 
tracking valves within the study. It must be completed and returned to the sponsor 
within 24 hours of the surgery. Sending a copy of the card to the sponsor by facsimile 
or e-mail is adequate to fulfill this requirement.
There is also a permanent patient record card included in the package labeling.  This 
card is to be completed and given to the patient as a form of permanent medical 
identification.
Early Postoperative/Discharge Procedures –
The investigator will record the date of the patient’s discharge from the hospital and 
the date of the early follow-up examination on CRF3. The early follow-up exam 
records the patient’s status at the time of discharge or at 30 days, whichever comes 
first.  The patient’s NYHA and cardiac rhythm status and any complications will be 
noted along with the patient’s amticoagulation therapy. It is important to record the 
international normalized ratio (INR) at the time of the exam. Wherever possible this 
value should be within the therapeutic range required by this protocol in section II C.
At each postoperative assessment, the investigator will need to determine the patient’s 
availability for future follow-up. If any patient needs to be seen at other than a 
regularly scheduled follow-up visit, the same follow-up information as required at 
regular times will be documented by the investigator on the follow-up form, and that 
follow-up will be indicated as an off schedule visit.
Late Follow-up Reporting –
Late follow-up is required in at 3 and 6 months postoperative intervals, and annually 
postoperatively through at least 1 but no more than 8 years. For MVR patients 
enrolled greater than 60 days postoperatively, follow-up will be at 3-months post 
enrollment then annually on the anniversary of implant.  This is also done on CRF3.  
Follow-up must be in person; telephone or questionnaire follow-up is not allowed. If 
a patient misses a scheduled follow-up visit, the investigator must make an effort to 
contact the patient to determine the reason for the missed visit. A new visit should be 
scheduled, but if the patient refuses to return for follow-up or otherwise cannot be 

17
contacted, the patient is then recorded as lost or withdrawn from the study. The 
efforts to maintain contact will be documented on the follow-up form, and every 
effort will be made to minimize the number of patients lost (zero being preferable). 
Thus, a follow-up form (CRF3) is due annually on each patient whether or not 
follow-up has occurred.
At the 3 month follow-up each patient shall be randomized into treatment group.  The 
investigator will log into the data management system to be assigned the random (test 
or control) group for the patient per the web-based procedure briefly described below.
If any patient has suffered a thrombotic or bleeding event during the initial 3 month 
period, he/she shall not be randomized into a group and shall be considered a 
screening failure and the event shall not be analyzed with any group under an intent-
to-treat classification.
The randomization module implements a standard randomization algorithm, 
Marsenne Twister that is implemented in Java.  (Matsumoto M. and Nishimura T., 
“Marsenne Twister: A 623-Dimensionally Equidistributed Uniform Pseudo-Random 
Number Generator”, ACM Transactions on Modeling and Computer Simulation, 
1998;8:3-30.)  The patented randomization module can provide block and stratified 
randomization results.
The procedure automatically executes upon eligibility documentation for a study 
subject.  The randomization result is presented on the screen instantaneously upon 
eligibility documentation using sponsor provided language and is also stored in the 
study database.  The Tempo electronic randomization process ensures only eligible 
subjects are randomized and no errors are made in storing the correct result of 
randomization.  The Tempo system audit trail documents the randomization results 
and time of execution.
Late follow-up information includes in all cases the patient initials or ID, cardiac 
rhythm, NYHA classification, and anticoagulant therapy information, including 
where applicable the most recent INR provided by the patient or QAS.  For any new 
complication, the complication report (CRF4) must be completed and attached. All 
complications that have occurred between follow-up examinations must be reported
on the form. Echocardiography per section III D is required at 1, 3 and 5 years.
Complication Reporting –
All complications should be recorded by the investigator on CRF4. Start and stop 
dates and etiology should be noted. The investigator will attempt to evaluate the 
relationship of all deaths, reoperations, explants, or cardiovascular complications to 
the study valve as presented in the AATS/STS guidelines (2) and will provide 
pertinent details of the event on CRF4. Copies of autopsy report and/or death 
summary must be included where applicable. 
The investigator will report any serious or unexpected complication occurring during 
the investigation to the monitor within 24 hours, followed by a written report in ten
working days, after the investigator first learns of the event. A serious or unexpected 
complication would include those complications not expected, or those occurring at a 
greater rate than expected when compared to the review requirements of this study 
(see section III F).

18
Adverse events are defined by the United States FDA as complications, meaning:
“Operative mortality, morbid events, and consequences of morbid events. 
Complications may or may not be device related.”
This study uses the term “complication” to mean any adverse event or adverse device 
effect (a device-related adverse event), which may be mild, moderate, or severe. If as 
a result of a complication during a clinical investigation a subject has to be 
hospitalized, if hospitalization is unduly prolonged because of potential disability, if 
hospitalization is unduly prolonged because of potential danger to life, if a 
reoperative intervention has been necessary, or if the event is terminal, the 
complication is regarded as severe.
The definitions which appear in the following sections will be used to report 
complications associated with the use of the On-X prosthesis. Complications will be 
recorded and dated when they are observed or estimated to have occurred and 
treatment(s) documented. An event will be recorded once unless there are multiple 
occurrences of that event. For example, a cerebrovascular accident (CVA) reported 
once with sequelae still present at subsequent follow-visits will not be reported again. 
If another CVA occurs that is unrelated to the initial episode, then it is reported as a 
separate incident.
When determining whether a complication is valve related this study will use the 
definitions of the AATS/STS guidelines (2).  More specific guidance on these 
determinations is contained in the following discussions of the various types of 
complications. In any case, adequate documentation must be supplied to support the 
contention that a complication generally regarded as valve related is not valve related. 
Information that pertains to reoperation and death must be recorded on the 
appropriate sections of CRF4. For death, the cause of death must be established, and 
an autopsy performed when possible. Attach supporting hospital reports when 
appropriate. Following completion of the information, the investigator must review, 
date, and sign the CRF.
Specific Instructions for Completing CRF4 –
The complication form (CRF4) is designed to allow the identification of event type, 
then to note how each event was treated; what the outcome of the complication was; 
and what the patient’s status at the time of the event was. Death from unrelated causes 
is also reported on CRF4. 
Study valve related reoperation is defined as any operation that repairs, alters or 
replaces an implanted, study prosthesis, also included are operations that treat other 
valve related complications but do not involve surgery on this valve, i.e., surgery to 
resolve a hemorrhagic complication. This category also includes incidental 
replacement of the prosthesis, e.g., the patient undergoes surgery for a different 
cardiovascular procedure and the surgeon decides to remove the study valve. 
Cardiovascular surgical procedures other than repair or replacement of the study 
valve will also be recorded on the CRF4.
Death will be recorded as cardiac or not, and valve related or not.  Valve related 
deaths include deaths from the following causes:
x
thrombosis or thromboembolism;

19
x
endocarditis;
x
prosthetic valve dysfunction;
x
anticoagulant related hemorrhage;
x
hemolysis; and
x
congestive heart failure, where documentation of a cause other than the 
valve cannot be given; and sudden unexplained death without autopsy 
which can definitely assign other causes than the valve. 
Deaths caused by heart failure in patients with advanced myocardial disease and 
satisfactorily functioning prosthetic valves are not considered valve related. Any 
death that occurs within 30 days of reoperation for a valve related complication is 
considered valve related.
Classification of each complication is described in sections that follow.
Thromboembolism       
Thromboembolism is defined as any valve thrombosis or embolus exclusive of 
infection. This includes any new focal or global neurological deficit (transient or 
permanent), myocardial infarction, prosthetic thrombosis, or peripheral arterial 
embolus.
A transient neurological event is defined as an abrupt onset of a focal neurological 
deficit lasting at least one minute but resolving without permanent sequelae.
Acute myocardial infarction (MI) is included as a thromboembolic complication 
when coronary anatomy was normal at the time of implant and there is no 
angiographic or other clinical evidence that the MI was due to coronary artery spasm 
or newly-developed coronary artery disease.
Thrombosis is any thrombus not caused by infection attached to or near an operated
valve that occludes part of the blood flow path, interferes with valve function or is 
sufficiently large to warrant treatment. This is listed as a subcategory of 
thromboembolism and should be confirmed by imaging study, reoperation (explant) 
or autopsy. Any patient with confirmed prosthetic valve thrombosis is to be treated 
with surgery, thrombolysis and/or heparin based on the clinical assessment of the 
particular patient and on what is considered best and most appropriate treatment for 
the patient.  Clinical judgment can be used to diagnose the presence of thrombosis 
(lack of normal prosthetic valve sound, prolonged lowered blood pressure, loss of 
consciousness, cardiovascular shock) if the clinical diagnosis is accompanied by a 
confirming medical test (echocardiography, cineradiography or angiography).
Thrombi that are secondary to another primary complication; i.e., endocarditis, are 
recorded but also noted to be a secondary event by stating so in their etiology.
Excluded from the thromboembolism category are:
x
Events which occur intraoperatively or within 24 hours of surgery due to 
myocardial infarction or stroke.
x
Any peripheral arterial emboli proven to have originated from another cause, e.g., 
atrial myxoma.

20
x
Failure to awaken from the surgical procedure.
x
Pulmonary emboli.
x
Events due to proven ischemic disease of the extremities.
However, if any of these complications occur, document the events anyway on the 
complication form (CRF4).
For any thromboembolic event it is important to determine the INR of the patient at 
the time of the event, if possible.  Every attempt should be made to do so.
Bleeding Events
Hemorrhage is defined as any episode of internal or external bleeding in patients 
whether or not they are receiving anticoagulant therapy. This also includes any 
episode of hemorrhagic tamponade. Any anticoagulants used and INR at the time of 
hemorrhage should be determined, if possible. These events will be classified as 
major or minor, and are defined as follows.
x
Major:  An episode of internal or external bleeding that causes death, stroke, 
operation, hospitalization, or requires transfusion or pericardiocentesis. Examples 
include nosebleeds that require outpatient transfusion, cerebral bleeding that results in 
neurological damage and/or death, and gastrointestinal bleeding that requires 
hospitalization.
x
Minor:  All other episodes of internal or external loss of blood. Examples include 
nosebleeds that do not require transfusion, hematomas due to trauma or surgery that 
do not require transfusion, and ocular hemorrhage. Bleeding from open traumatic 
wounds (cuts, abrasions, etc.) are excluded, unless the bleeding goes uncontrolled 
enough to require intervention that would place the event in the major category.
Prosthetic Valve Endocarditis
Prosthetic valve endocarditis is defined as documented evidence of infection of the 
prosthesis based on histopathological evidence in a surgical or autopsy specimen 
and/or customary clinical criteria, including an appropriate combination of positive 
blood cultures, clinical signs (fever, new/altered cardiac murmurs, splenomegaly, 
systemic emboli, and immunopathological lesions). The organism(s) involved should 
be identified whenever possible.
Prosthetic Valve Dysfunction
Prosthetic valve dysfunction is defined as any change in valve performance which 
results from intrinsic or extrinsic abnormalities that cause stenosis or regurgitation. 
Prosthetic valve dysfunction can be classified as structural deterioration, nonstructural 
dysfunction, or paravalvular leak.
a.
Structural Valve Deterioration
Structural valve deterioration is any change in function of the prosthesis which results 
from an intrinsic abnormality that causes stenosis or regurgitation. The diagnosis 
should be based on an examination of the explanted or damaged valve. Examples 
include excessive wear, leaflet escape, leaflet fracture, housing crack, leaflet pitting, 

21
or sewing ring deterioration. Excluded from this category is structural deterioration 
which results from endocarditis, paravalvular leak, and thrombosis.
b. Nonstructural Valve Dysfunction
Nonstructural dysfunction of the valve is any change in function of the prosthesis that 
results in stenosis or regurgitation which is not intrinsic to the valve. Examples 
include patient-prosthesis mismatch, leaflet entrapment by suture or pannus,
paravalvular leak and hemolytic anemia. The diagnosis should be confirmed by 
examination of the damaged or explanted valve. Events to be excluded are those 
associated with endocarditis, paravalvular leak, and thrombosis.
c.
Paravalvular Leak
Any evidence of leakage of blood around the prosthesis between the sewing ring and
native annulus. Diagnosis of paravalvular leak may be obtained from 
echocardiography; however, definitive diagnosis will be obtained at reoperation, 
explant, or autopsy. Indicate severity of the leak.
Indicate if the event is secondary to another valve-related complication, e.g., 
endocarditis, hemolysis, thromboembolism, thrombosis. Such events will be 
classified as major (required surgical intervention) or minor (does not require surgical 
intervention).
Hemolytic Anemia
Hemolytic anemia will be recorded as a complication in all cases of anemia that are 
attributable to the valve, based on usual clinical criteria.  Indicate if hemolytic anemia 
is primary or secondary to another valve related adverse event (e.g., paravalvular 
leak). Events that are excluded are those due to liver disease, myocardial infarction, 
or systemic infection, where these causes are confirmed by other clinical evidence.
Hemolysis
On going hemolysis shall be defined by plasma free hemoglobin elevated to 125% of 
laboratory upper normal and serum lactate dehydrogenase (SLDH) values at greater 
than twice (200%) the laboratory upper normal unless the cellular source of the 
SLDH can be determined to be other than the red blood cell as evidenced by 
isoenzyme elevation of LD3, LD4 or LD5, and/or clinical evidence of recent 
myocardial infarction.  Plasma free hemoglobin, serum haptoglobin, reticulocyte 
count and SLDH shall be tested whenever hemolysis is suspected in any patient and 
SLDH isoenzymes shall be fractionated whenever the SLDH test value is above 
175% of upper normal.
Unanticipated Valve-Related Event
It is unknown what kind of event would qualify for the use of this form, but it is 
supplied in case any unknown valve-related complication should arise that does not 
meet any other defined criterion.  Should this happen this event must be reported to 
the monitor immediately, since it is likely to create immediate regulatory reporting 
requirements.  An occurrence of an unknown negative effect is very serious and must 
not be left unreported for any length of time.
Congestive Heart Failure
Congestive heart failure will be considered valve related if the event is new and is not 
continued from a preoperative heart failure condition, and is caused by one of the 

22
following prosthesis-related events:  Anticoagulant-related hemorrhage, endocarditis, 
hemolysis, nonstructural dysfunction, paravalvular leak, structural deterioration, 
thromboembolism, thrombosis, or reoperation.
The most common causes of non-valve related congestive heart failure are coronary 
artery disease, hypertension, valvular heart disease (due to a valve other than the 
study valve), cardiomyopathy, cor pulmonale, congenital heart disease, or unknown 
causes.  When an event is considered not valve related the reasons for that decision
must be recorded.
Other Cardiovascular and Pulmonary Complications
Other cardiovascular and pulmonary complications are defined as a complication or 
any new diagnosis that is not related to the prosthesis, but is important to subsequent 
morbidity and mortality of the patient, e.g., cardiomyopathy, aortic aneurysm, chronic 
obstructive pulmonary disease, pulmonary embolism. These events may be 
characterized by the following factors:  necessity for intervention, new or unduly 
prolonged hospitalization, or death.  Minor events of no importance to the patient’s 
valve related morbidity or mortality, such as acute upper respiratory infections, 
should not be reported.
D. Echocardiography Procedures
Echocardiographic evaluation of the study prosthesis is required by transthoracic 
methods, and at the first, third and fifth annual follow-ups. For MVR patients enrolled
late postoperatively the 1-year echo will occur at the visit closest to 1-year after 
surgery and 3-year and 5-year echoes at 3 and 5 years post surgery.
The echo technician shall ensure that all views have been obtained and that all data 
are reviewed for accuracy before the patient has left the facility. 
The echocardiography protocol used will generally follow that developed by FDA in 
its guidelines(1), but specifically shall follow the steps given in Appendix F.  Echo 
reports along with an electronic copy of the echo shall be sent to the monitor for 
eventual review by the core cardiologist. Only directly measured data will be 
provided by the center, and all calculated data will be derived at the core center.  The 
core cardiologist will reassess thrombus and regurgitation as well.
Transthoracic echocardiographic examinations will follow a step-by-step progression 
of the following interrogation regions:  left parasternal, apical and periapical, right 
parasternal, subcostal, and suprasternal. The progression of interrogation regions is 
transgastric, esophagogastric, and mid-esophageal. For each interrogation include 2D 
and M-mode recording for structure, function and timing data, and color Doppler for 
flow pattern to guide the pulsed (PW) and continuous (CW) Doppler measurements.  
All data reported on CRF 6 should be the average from a minimum of three cycles for 
patients in sinus rhythm or a minimum of five cycles for patients in atrial fibrillation 
or other arrhythmic states.
Provide the patient study number and other basic information listed at the beginning 
of the form. 
Valve hemodynamics are to be gathered from the view giving the best signal. If the 
view used is different from those listed in the progressions noted in the previous 
section, then note the view used for either pressure or regurgitation measurement.

23
Provide the hemodynamic data requested on the form from the view that provides the 
best signal. 
Subaortic diameter measurement should be made from the trailing edge of the left 
septal echo to the leading edge of the anterior mitral leaflet echo.  If severe left 
ventricular hypertrophy or bowing of the anterior mitral leaflet exist, this measure 
should not be made and the space should be noted as unavailable on the CRF.
E.  Reoperation and/or Explant Procedures
Whenever a valve reoperation occurs whether or not as a result of one of the 
complications described in Section C above complete and return CRF 5.
Explants are requested at autopsy whenever practical.  Reoperative explants may also 
occur.  Return of explanted valves within the study is required.
Specific explant analysis requirements are included in this plan. Explanted
mechanical valve prosthesis refers to a study valve that has been removed from the 
patient at reoperation or autopsy. The recommended procedures have been developed 
to ensure accuracy, consistency and completeness of the analysis of explanted valves. 
This section outlines in detail the procedures for explanting, recording data and 
returning the explanted valves.
Explanting the Valve
When explanting a valve at reoperation or autopsy:
1) Inspect the mechanical valve prosthesis prior to removal including the 
condition of the annulus for evidence of dysfunction such as thrombi, 
paravalvular leak, vegetations, pannus overgrowth. Culture of pertinent areas 
of the valve when appropriate is mandatory.
2) Examine the lining of the chambers of the heart, both proximal and distal to 
the valve for possible jet lesions or endocardial fibrosis.
3) Special attention should be paid to the possibility of extrinsic interference 
with the valve function, particularly by retained mitral valve leaflet tissue or 
sutures.
4) If possible, photograph the mechanical valve prosthesis in situ. For valves 
obtained at autopsy, photograph both the inflow and outflow aspects.
5) DO NOT rinse the valve.
6) Request an explant kit from the sponsor and place the valve in the jar provided 
in the explant kit.
7) If no explant kit is available, place the valve in either 1% glutaraldehyde 
solution or 10% buffered formalin until a kit is obtained. 
8) Record observations on CRF5 in the appropriate locations.
Data and Shipping Requirements
To send the data and return the valve to study sponsor:

24
1) Attach a copy of the reoperative or autopsy report to the appropriate 
CRF5.
2)
Attach any in situ photographs to CRF5.
3) Ship the valve as instructed in the explant kit, clearly marked as an 
explant, and inform the monitor by telephone or telefax of its 
shipment.
4) Notify your clinical research monitor if the valve cannot be returned.
5) If the valve is examined by a pathologist at the hospital where it was 
explanted, send that report to the monitor as well.
Each returned heart valve received by the sponsor (or monitor) will be tracked 
and analysis information compiled and stored. Each explant will be analyzed by 
the independent study pathologist and his/her report will be provided to the 
investigator and monitor.  
F. Adverse Events
If a test group patient suffers a thrombotic event during the trial, he/she will be 
removed from the cohort and returned to standard Coumadin therapy. If a test group 
patient suffers a bleeding event during the trial, he/she may continue with the LD
therapy regime or may be removed from the study depending upon the principal 
investigator’s clinical judgment. In any case such patients shall be followed and 
remain in the test group for analysis purposes based on an intent-to-treat 
classification.
G. Study review
At least 3 independent advisors, including at least one each from cardiology, cardiac 
surgery and statistics, will act as the Data Safety Monitoring Committee. The 
Committee will examine reports of adverse events and their rates of occurrence on a 
regular basis, no less often than annually. The Committee will also review the 
occurrence of any thrombotic event as early as feasible after it occurs.  The 
Committee shall have the power and authority to direct changes in, or termination of, 
the study.  The study shall be terminated, if at anytime, while patients are maintained 
on LD therapy, the rates of thrombotic and bleeding events exceed either the rate in 
the control group, the expected rate from the sample size calculation, or  twice the 
aggregate rate of such events reported for other bileaflet valves in the peer reviewed 
literature, as determined by meta-analysis.
Changes to the plan can only occur with concurrence of the Data Safety Monitoring 
Committee and ethics committees.
The committee shall initially consist of:
1. Dr. Sidney Levitsky
Professor of Surgery
Beth Israel Deaconess Hospital
Harvard University
Boston, Massachusetts
2. Dr. Jean Dumesnil

25
Professor of Cardiology
Hopital Laval,
Ste-Foy, Quebec, Canada
3. Dr. A. Graham Turpie
Professor of Hematology
McMaster University
Hamilton, Ontario, Canada
4. Jay Herson, Ph.D.
Adjunct Faculty, Biostatistics
Johns Hopkins University
Baltimore, Maryland
H. Data Analysis
Data will be analyzed using Kaplan-Meier life tables and linearized rates.  Although 
randomization does not occur until month 3, early postoperative data (PRQWKV
postoperative) will be analyzed to examine potential differences between test and 
control groups using regular percentage comparisons.  Data will be stratified by risk 
factors including age and others as appropriate.  Data forms will be completed 
preoperatively, operatively and at each follow-up.  This can be done on paper or 
electronically at the mutual choice of the center and the study monitor.  
Case Report Forms –
Example Case Report Forms are provided in Appendix A. A forms notebook or
electronic database for each patient will be provided by the sponsor. The notebook is 
designed to make keeping the records for the study more organized and to reduce the 
potential for mixing up data. An electronic database may also be used for this 
purpose.  Extra forms will be provided on request, or as needed.
I. Reports
Summary reports of the study shall be produced annually by the sponsor and monitor,
and be provided to each investigator, Data Safety Monitoring Committee member and 
ethics committee chairperson.
IV.
Device Description and Risk Analysis
The On-X prosthesis is a bileaflet mechanical heart valve prosthesis.  The housing 
consists of On-X pyrolytic carbon coating on a graphite substrate.
Two radiopaque leaflets are constrained by pivots in the housing walls.  The leaflets are 
On-X pyrolytic carbon deposited on a graphite substrate which is mixed with 10 weight 
% tungsten to allow for radiographic visualization.  In the closed position, the occluders 
rest at 40q within the valve orifice.  The valve design permits maximum leaflet opening 
angles of 90q from the plane of the housing, a position that follows flow.   The pivot 
design includes features that enhance and ensure closure response to reverse flow and 
opening response to forward flow.
The rotatable sewing ring is made from polytetrafluoroethylene (PTFE) fabric attached to 
the valve housing by means of titanium retaining rings and 5-0 suture material.  The 

26
retaining rings positively attach the sewing ring to the valve housing by straddling a
flange on the housing OD.  They also provide the means for radiographic visualization 
and identification.  There are no coatings or treatments on the fabric, although black 
orientation marks are included on the ring fabric.  The sewing rings are supra-annular and 
allow the tissue annulus to abut the pyrolytic carbon housing directly, except in sizes 
larger than 25 mm, where the sewing rings become intra-annular to allow the 25 mm 
housing (largest size made) to fit properly into larger tissue annuli.
Valves are packaged on a valve holder with a separately packaged, removable handle to 
facilitate insertion and in situ orientation, and to provide protection during shipment and 
handling.  The package is designed for shipment protection as well as handling ease. 
Valves are surgically clean and have been sterilized.  The instructions for use packaged 
with the valve describe the handling of the valve during surgery in detail.  Adhere to all 
instructions, warnings and precautions in the labeling.  
A review of the literature on Coumadin anticoagulation of mechanical heart valve 
prostheses is inconclusive on the preferable therapy for various valves.  Various groups 
have struggled with the lack of information on the subject of anticoagulation; yet have 
crafted recommendations based on information available.  These include the ACCP (3)
and AHA/ACC (4) recommendations.  Butchart(5) in a review of embolism in prosthetic 
heart valves concluded that valves vary in susceptibility to thrombosis due to subtle 
design differences, that optimal INR range is often uncertain, and that further research is 
needed.
Many studies of various mechanical valves have attempted to examine low intensity 
Coumadin therapy, Coumadin plus aspirin, aspirin alone and even no anticoagulation.  
These studies have had mixed results.  Horstkotte (6) suggested that INR levels of 3.0 to 
4.5 are too high for the St. Jude valve, but that a prospective trial is needed to show the 
proper level.  Cannegieter (7) in the first detailed study of optimum anticoagulation 
suggested the target of 3.0 to 4.5 initially.
Others have studied and suggested lower INR targets (8-12) in the range of 2.0 to 3.0.  
These studies resulted in the lower recommendation of ACCP and ACC.
Still other groups have examined lower Coumadin in combination with antiplatelet 
agents, such as aspirin or dipyridamole.  Starting with the work of Turpie, et al (13)
various groups have shown a benefit of adding aspirin or dipyridamole, to Coumadin (14-
15).  But some mixed results indicating a possible increase in bleeding occurred with 
addition of aspirin (16-17).  Three separate meta-analyses (18-20) support the addition of low-
dose aspirin or dipyridamole to Coumadin.
Another strategy for reducing thrombotic and bleeding events from Coumadin therapy is 
to control the therapy better with clinic or home monitoring.  These studies have 
uniformly shown better results with better control (21-23).  Yet still bleeding and 
thrombosis rates are considered suboptimal for mechanical valves, even though a 
background rate for these events exists that becomes about 2% per year at 80 years old 
(24).
As mechanical valves have long been known for their durability, they have also been 
thought to require long-term Coumadin anticoagulation to prevent thrombotic events.  
This requirement subjects patients to an increased risk of bleeding events and has been 

27
the major shortcoming in the performance of mechanical valves.  It is, therefore, 
desirable to reduce or eliminate Coumadin anticoagulation.
The valve selected for this trial must also be shown to perform better than existing 
mechanical valves in terms of adverse events and other surrogate endpoints that indicate 
possible reduction of events based on the effects of valve design.  These endpoints 
include adverse event rates, (especially in relation to the degree of anticoagulation 
actually achieved in a study), hemodynamics and hemolysis.
The On-X aortic valve has been shown to achieve low adverse event rates [25,26],
especially in the face of sporadic anticoagulation [27].  This is true also when compared to 
a similar contemporary study [28].  The hemodynamics of the valve are superior to other 
mechanical valves [26,29] indicating a reduction in turbulence which can effect blood 
damage and thrombotic events.  The valve also produces very little hemolysis in the 
aortic or mitral position [30], which also indicates a potential for reduced thrombotic 
complications.  
A study of the valve in sheep in a model designed to predict resistance to thrombosis, 
performed by Flameng (31), found that the On-X valve statistically outperformed both the 
SJM and CMI valves. The first thrombosis of an On-X valve occurred at 6 weeks 
compared to 2 weeks for the others.  Additionally, 2 of 6 test valves survived the test 
without thrombosis compared to 0 of 7 for the others.  
In an ongoing clinical trial in South Africa (32), 200 On-X valves have been implanted 
with 100% follow-up out to about 3 years.  About 40% of these patients are not 
anticoagulated due to the social conditions in South Africa, yet there has been only one
thrombosis event in the mitral position in the study.  Given the valve’s clinical 
performance to date, it is an ideal candidate for a study using lower dose Coumadin.
V.
Monitoring Procedures
The monitor of the study shall be a professional staff member of the Clinical Studies 
Department of the sponsor.  Monitoring of the clinical trial will be a continuous process 
to ensure that high quality data are obtained through compliance with the investigational 
plan. Case report forms or electronic data will be reviewed for accuracy, completeness, 
and conformity with requirements. Particular attention will be paid to complication 
reporting. Frequent communication will be maintained with each clinical center to keep 
both the center and the sponsor informed and aware of the clinical trial progress.
On-site monitoring of all study centers will occur at least annually to ensure continued 
acceptability of the center by assessing compliance to the investigational plan., adherence 
to data collection procedures, verification of the accuracy of submitted clinical data to the 
patient’s source documents, maintenance of clinical trial records, verification of informed 
consent, and verification of control of test articles. Reports of each center’s audits will be 
provided to the investigator and sponsor, and if necessary, appropriate corrective action 
will be taken to ensure compliance to the investigation plan.
Preinvestigation Visit:

28
Preinvestigation visits will be conducted by the clinical trial monitor to review the 
investigational plan and discuss the report of previous investigations with the investigator 
and staff to assure that they:
x
Understand the investigation of the device and the requirements for its accountability.
x
Understand the nature of the investigational plan including record, reports and 
recruitment of patients.
x
Understand the requirement for an adequate, well controlled clinical trial.
x
Understand and accept the obligation to conduct the clinical investigation in 
accordance with applicable national regulations.
x
Understand and accept the obligation to obtain Ethics Committee or Institutional 
Review Board (IRB) review and approval before the clinical trial may be initiated, 
ensure continuing review of the trail by the Ethics Committee or IRB and keep the 
sponsor informed of any actions by the Ethics Committee or IRB that concern the 
clinical trial.
x
Have access to an adequate number of suitable patients to conduct the investigation.
x
Have adequate facilities and staffing to conduct the investigation.
x
Have sufficient time from other obligations to fulfill the responsibilities of the 
investigation.
Particular attention will be given complication reporting.
Annual Center Visit and Audit:
Following the preinvestigation visit, on-site monitoring visits will be conducted at least 
annually.
On-site monitoring visits will assess the progress of the clinical trial and identify any 
concerns that result from device performance and review of the investigator’s clinical 
trial records, study management documents and patient consent forms. This review 
includes adherence to the investigational plan, Ethics Committee or IRB review of the 
clinical trial and its progress and maintenance of records and reports.
To assure the integrity of the clinical trial data, individual patient records and other 
source documents are compared to reports from the investigator to determine that:
x
The information recorded in the case report forms and/or reports is accurate, complete 
and legible.
x
There are no omissions in the case report forms  of specific data (e.g., development of 
an intercurrent illness)
x
Missing follow-up visits are documented in the reports.
x
Patients failing to complete the clinical trial and the reason for failure are noted in the 
reports.
x
Informed consent has been documented.

29
A record of the monitor’s findings will be maintained by the sponsor and investigator and 
will contain the following information:
x
The date(s) of the visit.
x
The name(s) of the monitor(s) who conducted the visit.
x
The name(s) and address of the investigator(s) and other center staff who were 
visited.
x
A statement of the findings, conclusions and any actions taken to correct deficiencies 
observed during the audit.
Resolution of concerns and completion of assigned tasks will be documented by the 
monitor.
Interim Visits:
Interim visits to the study centers will be conducted as deemed to be necessary, typically 
only when circumstances require additional training or assistance as determined by the 
monitor.
Final Center Visit:
A final visit to the study center may be made by the monitor, if necessary. Any ongoing 
responsibilities that will continue after the final visit will be discussed with the 
investigator and the study center coordinator. A final monitoring report, which includes 
device inventory verification and disposition of unused devices, will be prepared by the 
monitor.
Regular Reports:
The monitor will provide regular at least quarterly summary reports of the clinical 
investigation to all investigators and the sponsor. The contents of these reports will be 
determined by the monitor and sponsor jointly.
The sponsor or monitor will provide reports to each investigator based on individual 
requests for data. Each investigator will also get at least a quarterly update of the required 
activities for the study at his/her center.
VI.
Legal/Ethical Considerations
The study will be conducted under the rules of the local country or the Declaration of 
Helsinki whichever provides more patient protection.  Where governmental approval is 
required (FDA, competent authority or Health Canada), it will be obtained prior to 
starting the study at any center in such country.  All centers will have the approval of 
their local ethics committee before beginning patient enrollment.  All patients will be
given adequate written informed consent.  The patient must agree to, and understand, the 
drug therapy regime and the follow-up requirements.  Informed consent shall include all 
elements of information required by international standards, and shall notify the patient 
that data will be shared with government regulatory bodies as needed. See the example in 
Appendix C.
Sponsors must be able to verify to regulatory agencies, e.g., the Food and Drug 
Administration, that this clinical investigation has been conducted in accordance with 

30
ethical principles. The Investigational Device Exemption (IDE) regulation applies to the 
United States.  At each center investigators are required to:
x
Obtain informed consent from patients involved in the clinical trial
x
Obtain Institutional Review Board approval prior to starting the clinical trial at their 
institution.
Copies of the presently approved labeling for the device are contained in Appendix D. A
list of all IRB and Investigator Information in included in Appendix E.

31
VII.
References
1. Draft Replacement Heart Valve Guidance, U.S. Food and Drug Administration, 
October 14, 1994.
2. Edmunds LH, Clark RE, Cohn LE, et al. Guidelines for Reporting Morbidity and 
Mortality after Cardiac Valvular Operations.  Ann Thor Surg 1996; 62:932-5.
3. Stein Paul D, Bussey Henry I, Dalen James E, Turpie Alexander GG. 
Antithrombotic Therapy in Patients With Mechanical and Biological Prosthetic 
Heart Valves.  Chest. January 2001; 119(1): 220S-227S.
4. Bonow Robert O, Carabelo Blasé, de Leon Jr. Antonio C, et al.  ACC/AHA 
Pocket Guidelines for Management of Patients With Valvular Heart Disease.  
ACC/AHATask Force on Practice Guidelines Report July 2000; 4-48.
5. Butchart Eric G.  Prosthetic Heart Valves. Cardiovascular Thrombosis: 
Thrombocardiology and Thromboneurology, Second Edition, M. Verstraete, V. 
Fuster, E.J. Topol, ed., Lippencott-Raven, Philadelphia; 1998; 395-413.
6. Horstkotte Dieter, Schulte Hagen D, Bircks Wolfgang, Strauer Bodo E.  Lower 
intensity anticoagulation therapy results in lower complication rates with the St. 
Jude Medical prosthesis.  J Thorac Cardiovasc Surg 1994;107:1136-45.
7. Cannegieter SC, Rosendaal FR, Wintzen AR, et al. Optimal Oral Anticoagulant 
Therapy In Patients With Mechanical Heart Valves.  N Engl J Med 1995;333:11-
17.
8. Butchart Eric G, Lewis Peter A, Grunkemeier Gary L, Kulatilake Nihal, 
Breckenridge Iain M.  Low Risk of Thrombosis and Serious Embolic Events 
Despite Low-Intensity Anticoagulation Experience With 1,004 Medtronic Hall 
Valves.  Circulation 1988;78(suppl I):I-66--I-77.
9. Horstkotte Dieter, Schulte Hagen D, Bircks Wolfgang, Stauer Bodo E.  Lower 
Intensity anticoagulation therapy results in lower complication rates with the St. 
Jude Medical prosthesis.  J Thorac Cardiovasc Surg 1994;107:1136-45.
10. Anderson Per V, Aagaard Jan.  Low-Dose Warfarin In Patients With 
Carbomedics Heart Valve Prostheses.  Asian Cardiovasc Thorac Ann 2000;8:11-
14
11. Kontozis Loizos, Skudicky Daniel, Hopley Mark J, Sareli Pinhas.  Long-Term 
Follow-Up of St. Jude Medical Prosthesis in a Young Rheumatic Population 
Using Low-Level Warfarin Anticoagulation:  An Analysis of the Temporal 
Distribution of Causes of Death.  Am J. Cardiol 1998;81:736-739.
12. Acar Jean, Iung Bernard, Boissel Jean Pierre, et al.  AREVA: Multicenter 
Randomized Comparison of Low-Dose Bersus Standard-Dose Anticoagulation in 
Patients With Mechanical Prosthetic Heart Valves. Circulation 1996;94:2107-
2112.
13. Turpie Alexander GG, Gent Michael, Laupagcis Andreas, et at.  A Comparison 
Of Aspirin with Placebo In Patients Treated With Warfarin After Heart-Valve 
Replacement. N Engl J. Med 1993;329:524-529.
14. Skudicky Daniel, Essop Mohammed R, Wisenbaugh Thomas, et al.  Frequency of 
Prosthetic Valve-Related Complications with Very Low Level Warfarin 
Anticoagulation Combined with Dipyridamole After Valve Replacement Using 
St. Jude Medical Prostheses.  Am J Cardiol 1994; 74:1137-1141.
15. Yamak Birol, Iscan Zafer, Mavitas Binali, et al.  Low-dose Oral Anticoagulation 
and Antiplatelet Therapy with St. Jude Medical Heart Valve Prosthesis.  J Heart 
Valve Disease 1999;8:665-673.

32
16. Albertal Jorge, Sutton Marcela, Pereyra Daniel, et al.  Experience With Moderate 
Intensity Anticoagulation and Aspirin After Mechanical Valve Replacement.  A 
Retrospective, Non-randomized Study. J of Heart Valve Dis 1993;2:302-307.
17. Altman Raúl, Rouvier Jorge, Gurfinkel Enrique, Scazziota Alejandra, Turpie 
Alexander GG.  Circulation 1996;94:2113-2116
18. Cappelleri Joseph C, Fiore Louis D, Brophy Mary T, Deykin Daniel, Lau Joseph.  
Efficacy and safety of combined anticoagulant and antiplatelet therapy versus 
anticoagulant monotherapy after mechanical heart-valve replacement:  A 
metaanalysis.  Am Heart J 1995;130:547-552.
19. Massel David, Little Stephen H.  Risks and Benefits of Adding Anti-Platelet 
Therapy to Warfarin Among Patients With Prosthetic Heart Valves:  A Meta-
Analysis.  J Am Coll Cardiol 2001;37:569-578.
20. Pauleur Hubert, Buyse Marc.  Effects Of Dipyridamole In Combination With 
Anticoagulant Therapy On Survival And Thromboembolic Events In Patients 
With Prosthetic Heart Valves.  J Thorac Cardiovasc Surg 1995;110:463-472.
21. Jamieson WR Eric, Miyagishima Robert T, Tyers Frank O, et al.  Bileaflet 
Mechanical Prostheses in Mitral and Multiple Valve Replacement Surgery.  
Circulation 1997;96[suppl II]:II-134-II-139.
22. Körtke Heinric, Körfer Reiner.  International Normalized Ratio Self-Management 
After Mechanical Heart Valve Replacement:  Is an Early Start Advantageous?.  
Ann Thorac Surg 2001;72:44-48.
23. Butchart Eric G, Payne Nicola, Li Hui-Hua, et al.  Better anticoagulation control 
improves survival after valve replacement.  J Thorac Cardiovasc Surg
2002;123:715-723.
24. Bamford J, Warlow CP.  Stroke and TIA in the general population.  In:  Butchart 
EG, Bodnar E (eds).  Current Issues in Heart Valve Disease:  Thrombosis, 
Embolism and Bleeding.  London:ICR, 1992;3-15.
25. Laczkovics A, Heidt M, Oerlert H, et al.  “Early Clinical Experience with the On-
X Prosthetic Heart Valve.  J. Heart Vlv Dis 2001;10:94-99.
26. Summary of Safety and Effectiveness Data, On-X Prosthetic Heart Valve, FDA, 
May 30, 2001.
27. Pomar JL, Laczkovics A, Birnbaum D, et al.  “Anticoagulant Compliance in a 
Multicenter Prospective Heart Valve Study without Home Monitoring.”  
Presented at Society for Heart Valve Disease, First Biannual Meeting, London, 
England, June 15-18, 2001.
28. The On-X Experience, Medical Carbon Research Institute, August 2001; 3(2) 2-7.
29. Chambers J, Ely J.  “Early Postoperative Hemodynamic Performance of the On-X
Prosthetic Heart Valve: A Multicenter Study.” J Heart Vlv Dis 1998;7:569-573.
30. Birnbaum D, Laczkovics A, Heidt M, et al.  “Examination of Hemolytic Potential 
with the On-X Prosthetic Heart Valve.”  J Heart Vlv Dis 2000;9:142-5.
31. Flameng W, Meuris B.  Performance of Bileaflet Heart Valve Prosthesis in an 
Animal Model of Heart Valve Thrombosis, 6th Annual Hilton Head Workshop on 
Prosthetic Heart Valves, March 6-10, 2002, Hilton Head, South Carolina.
32. Williams MA, Crause L, Van Riet S. “A Comparison of Mechanical valve 
Performance in a Poorly Anticoagulated Community.” J Card Surg 2004;19:410-
4.

33
Appendix A
Case Report Forms

34
Institution:
Investigator:
MCRI On-X®
Low Dose 
Anticoagulation Study
CRF 1 (p1 of 2)
Preoperative Data
Patient Initials
Patient No.                -
Visit Date (m/d/y):  ______/______/_______  
Date of Birth (m/d/y):  ______/_______/______                Sex:          Male          Female
1.  Patient has met Inclusion/Exclusion criteria.      Yes        No   (If No, attach explanation)
2.  Informed Consent has been given.                      Yes        No   (If No, follow notification procedure.)
Date (m/d/y):  ______/______/______  (Keep signed Informed Consent in patient study file.)
3.  NYHA Functional Class:              I                 II                   III                 IV              Unknown 
4.  Cardiac Rhythm:
Sinus            Atrial Fibrillation
                                           Paced           Other, specify: ______________________________________________
5.  Disease Etiology:         Rheumatic
Calcific                           Pros. Valve Dysfunction
             Congenital
Endocarditis                   Degenerative/Myxomatous
             Other, specify:  __________________________________________________________
6.  Valvular Lesions:
Aortic
Mitral
Stenosis
Regurgitation
Mixed
Other, specify:  ______________________
7.  Previous cardiac surgery:        Yes           No                 CAB 
                                                     (If yes, specify)
                                                                                            Valve          A           M           T        P
                                                                                             ASD
                                                                                             VSD
                                                                                      
PPM /ICD
                                                                                             PTCA/Stent
                                                                                      
Other: _________________________________________
8.  Pre-operative Anticoagulation         Yes        No
Heparin         Warfarin/Coumadin
Clopidogrel              Aspirin            Indandione derivatives
INR:  ____________  INR Target Range:______________  Date (m/d/y): ___________________

35
Institution:
Investigator:
MCRI On-X®
Low Dose
Anticoagulation Study
CRF 1 (p2 of 2)
Preoperative Data
Patient Initials
Patient No.                -
9.    Preoperative risk characteristics
Ejection fraction (%0 ___________________
Left atrial systolic dimension (mm) ________
Spontaneous echo contrasts ____Yes ____No
Ventricular aneurysm ____Yes ____No
Vascular pathology ____Yes ____No
Neurological events ____Yes ____No
Estrogen replacement therapy ____Yes ____No
10.   Preoperative blood test results (AVR only)
Factor V Leiden Mutation _____________________
Prothrombin Mutation
_____________________
AT-III Activity
_____________________
Protein C Activity
_____________________
Protein S Activity 
_____________________
Factor VIII Activity
_____________________
Lipoproteins
_____________________
Serum Thromboxane B2
_____________________
Urine Thromboxane B2
_____________________
Endogenous Thrombin Potential  ________________
P2Y 12
_____________________
11.  Patient Qualifies for Group - I) Low Risk Aortic _____,  II) High Risk Aortic _____,  III) Mitral _____
Investigator Signature:  _______________________________________  Date (m/d/y):  _______/_______/_______

36
Institution:
Investigator:
MCRI On-X®
Low Dose 
Anticoagulation Study
CRF 2
Operative Data
Patient Initials
Patient No.                -
Surgery Date (m/d/y):  _____/_____/_____   Surgeon:_________________________Emergency      Yes   No
Valve Information:     Aortic                  Size:  __________________mm    Serial #:  _____________________
                                      Mitral                  Size:  __________________mm    Serial #:   _____________________
Concomitant         CAB                                                                    Aneurysm         Aortic              Abdominal
Cardiovascular                                                                                                             Ventricular       Arch
Procedures:            Valve         A        M        T        P
                                                                                                           Other, specify: ___________________________
                                ASD                                                                    _______________________________________
                                VSD                                                                     None
Suture                           Interrupted                Pledgeted                Everting Mattress               Noneverting
Technique:
                                      Continuous               Other, specify: ____________________________________________________
Crossclamp time:  _______________Minutes
Cardioplegia:
Cold              Warm             Both                 
Antegrade               Retrograde           Both
Intraoperative Drugs:
Heparin       Yes        No    
Aprotinin        Yes        No    
Intraoperative Adverse Events:        Yes            No     (If Yes, complete below.)
Prolonged Hypotension           Yes        No                         Difficulty Restarting Rhythm             Yes        No
Excessive Bleeding                  Yes        No                        Difficulty Weaning from Bypass        Yes        No
Cardiac Tamponade                 Yes        No                        Study Valve Explanted                        Yes      No
Cardiac Arrest                          Yes        No                         Death                                                  Yes        No
Other                                        Yes         No     If Yes, explain:___________________________________________
Valve Orientation:  Check the most accurate valve orientation description below based upon the direction of the valve axis.
Mitral:        Anatomical           Antanatomical         Other, describe: _______________________________________
Aortic:         LC/RC commissure        RC/NC commissure           NC/LC commissure
                    Other, describe:  _____________________________________________________________________
Investigator Signature:  _____________________________________  Date (m/d/y):  _______/_______/________ 

37
Institution:
Investigator:
MCRI On-X®
Low Dose
Anticoagulation Study
CRF 3
Follow Up
Patient Initials
Patient No.                -
Visit Date (m/d/y)  ______/______/______
          Early PostOperative/Discharge
          Interim (3___ or 6___ month)
          Annual (__________year)  (12 + 2 month interval)
          Off Schedule
Group:______     Randomized to:
Treatment _______
Control ________
Patient Status                          Missed Follow Up Visit.  Reason, _________________________________________
(If follow up                            Lost to Follow Up:
Off Schedule)                               Efforts to Contact and Results:_________________________________________
                                                 Adverse Event    (Complete Complications Form CRF 4)
Type of Examination:       Office/Outpatient        Hospital        Telephone         Other _________________________
NYHA Class:                 I                II                   III                  IV                 Unknown
Cardiac Rhythm:                          Sinus                                  Regular 
                                                     Paced                                  Irregular 
                                                     Atrial Fibrillation               Other, specify:_______________________________
Anticoagulant                               None                                  Warfarin/Coumadin
Therapy:
                                                     Clopidogrel                        Heparin
                                                     Aspirin                                Other ______________________________________
INR  _________________    Blood Collection Date (m/d/y): ______/______/______ (closest to date of visit)
New Complications:  (Since last follow up)              Yes              No       (Complete complication form, CRF 4)
Echo Completed (m/d/y)_______________ Attach CRF 6 and send echo, applicable only at 1, 3 and 5 yr follow-up.
Investigator Signature:  _____________________________________ Date (m/d/y):   ______/______/________

38
Institution:
Investigator:
MCRI On-X®
Low Dose
Anticoagulation Study
CRF 4
Complications 1 of 2
Patient Initials
Patient No.                -
Start Date (m/d/y):  ______/______/________        Stop Date (m/d/y):  ______/______/______ or         Ongoing
Duration:  _____________            Weeks              Days              Hours            Minutes
Etiology: ____________________________________________________________________________________ 
Complication Type (check all that apply)
Complication number:  ________
1.           Thromboembolism         Neurologic:      TIA            Peripheral:       Major        Cardiac: MI         Unknown
                                                                               RIND                                 Minor
                                                                               CVA                                   Fatal
2
Valve Thrombosis
3.
Bleeding Event
            Major            Minor
                     Cerebral            Cardiac         Ocular              GI              Nosebleed        Hematoma           Other
4.
Prosthetic Endocarditis (Organism:  _______________________)
Risk Factor:             Dental Work               IV Drug Use               Recent Infection                Other
5.           Prosthetic Valve Dysfunction
                         Nonstructural                        (Type: _________________________________)
                         Structural                              (Type: _________________________________)
                         Paravalvular Leak                (       Minor                   Major)
6.           Hemolysis (conduct blood tests)
7.           Hemolytic Anemia (conduct blood tests)       Primary        Secondary to: ________________________
8.           Congestive Heart Failure                            Valve Related                     Not Valve Related
9.           Reoperation                                                 Repair                     Explant
10.
Other Valve Related                                    Explain: ____________________________________________
11.         Death  - Primary Cause:           Valve related           Other cardiac             Other             Unknown
(continues next page……………..)

39
Institution:
Investigator:
MCRI On-X®
Low Dose
Anticoagulation Study
CRF 4
Complications 2 of 2
Patient Initials
Patient No.                -
Complication number: _____________
Treatment:           None            Medication           Hospitalization               Surgery (Complete CRF5)
Patient Condition at Time of Event
Cardiac Rhythm                Sinus                        Paced                   Atrial Fibrillation
                                                 Other
NYHA Class              I                     II                  III                  IV                 Unknown
Anticoagulant Therapy             Warfarin              Clopidogrel                  Heparin
INR:  ___________            Aspirin                 None                           Other ____________________________
Outcome:
                     Event Fully Resolved
                     Permanent Impairment (Specify: __________________________________________)
                     Event Ongoing
                     Death Date (d/m/y):  ______/______/______
                              Autopsy                     Yes               No
                              Explant                      Yes               No        (If yes, complete CRF-5)
Relationship to Device:
               Valve Related:                  Yes                       No
Lab Test Results for Hemolysis, as needed:
Plasma Free Hemoglobin ________________ Lab Upper Normal ____________
SLDH
_______ Lab Upper Normal ________ (LD1 ____, LD2 _____, LD3 _____, LD4 ______, LD5 ______)
Reticulocyte Count _____________ Lab Upper Normal _______________
Serum Haptoglobin ____________ Lab Lower Normal _______________
Investigator Signature:  ____________________________________ Date (m/d/y):  ______/______/________

40
Institution:
Investigator:
MCRI On-X®
Low Dose
Anticoagulation Study
CRF 5
Reoperative Data
Patient Initials
Patient No.                -
Reoperative Procedure:      Procedure Date (m/d/y):  ______/______/______
                                                                         Aortic      Replacement Valve Mfg: _________________________
Study Valve Replacement
           (complete Explant data below)             Mitral      Size: ___________mm  Type: _____________________
                                                           Aortic       Specify:______________________________________________
Study Valve Repair
                                                           Mitral        ____________________________________________________
CABG
Pacer Implantation
Aneurysm Repair
                                                                                 Position: _________________________________________
                                                Replacement             Procedure: ________________________________________
Non Study Valve
                                                Repair                       Replacement Valve Mfg: _____________________________
                                                                                 Size: ___________mm  Type:__________________________
Explant Condition:              Reop             Autopsy              Explant Date (m/d/y):  ______/______/______
(check all that apply)
Pannus Overgrowth
PVL
Thrombus
Vegetation            Organism:   ______________________________________________________________
Other                     Specify:  ________________________________________________________________
Valves Returned:                Yes      Date Returned (m/d/y):  ______/______/______
                                             No      If No, Explain, __________________________________________________
Investigator Signature: _____________________________________  Date (m/d/y):  ______/______/________

41
1.
ECHO DATE (m/d/y):  __________/__________/__________
2.
VALVE  Position___________ Size ___________ Serial Number _____________
3.
PHYSICAL ASSESSMENT:
________________________________________ bpm  heart rate
_______________________________________ cm  height
________________________________________ kg  weight
________________________________________ m2 BSA
4.
CARDIAC RHYTHM:                 Normal sinus
                                                      Atrial fibrillation
                                                      Atrial flutter
                                                      Heart block:  degree  __________________________________________________
                                                      Paced
                                                      Other:  _____________________________________________________________
5.
IMAGING:      ________________________________________ cm     LVOT diameter systole
6.
SUBAORTIC WAVEFORM:
________________________________________ m/s  Peak velocity
________________________________________ mmHg  Mean gradient
________________________________________ cm  Velocity time integral
Investigator Names:
Center:   
         
MCRI On-X
Low Dose Anticoagulation Study
CRF  6
Echocardiography Data (page 1 of 2)
Patient Initals:
Study No.:

42
Date of Echo (m/d/y) __________________________
7.
RECORD ONLY DATA AS APPLICABLE TO VALVE EXAMINED:
7a.
TRANSAORTIC  WAVEFORM (FOR AVR):    _________________________________ m/s          Peak velocity
        _________________________________ mmHg    Mean gradient
        _________________________________ cm          Velocity time integral
7b.
TRANSMITRAL WAVEFORM (FOR MVR):    _________________________________ m/s          Peak velocity
       _________________________________ mmHg    Mean gradient
       _________________________________ cm          Velocity time integral
       _________________________________ ms          Pressure half-time
8.         REGURGITATION:                No                          Yes, please complete amount and location below:
Through          Paravalvular         Uncertain
     
                                                                                                      None
                                                                                    +1 Trivial/trace
                                                                                    +2 Mild
                                                                                    +3 Moderate
                                                                                 
            +4 Severe
9.           LEFT VENTRICULAR FUNCTION:               Normal (EF>50%)
                   Mild impairment (EF40-50%)
                           
                   Moderate impairment (EF30-40%)
                   Severe impairment (EF<30%)
10.
VALVE THROMBUS: ________ No _________ Yes.  If yes, specify location and amount: _________________________________
11.
OTHER ABNORMALITIES:  Describe:  _________________________________________________________________________
Investigator’s Signature:  _______________________________________      Date (m/d/y): ______/______/______
Investigator Names:
Center:   
         
MCRI On-X
LOW DOSE ANTICOAGULATION STUDY
CRF  6
Echocardiography Data (page 2 of 2)
Patient Initals:
Study No.:

43
APPENDIX B
MCRI
INVESTIGATOR AGREEMENT FOR ON-X£ PROSTHETIC HEART VALVE 
Clinical Trial of the On-X® Valve Using Low Dose Anticoagulation
I wish to participate in the supplemental clinical investigation of the On-X Prosthetic Heart 
Valve using low dose anticoagulation. I understand that this is a commercially available 
prosthesis which is manufactured by MCRI and is planned for testing for optimum 
anticoagulation in a clinical trial.
I am familiar with the intent of the investigation of this product, including the objective of the 
proposed clinical trial and the proposed trial procedures. I believe that, because of my training 
and experience and available patient population, I am qualified to investigate the product 
performance under the proposed Clinical Investigation Plan. I agree to conduct the clinical 
investigation under the purview of an appropriate Institutional Review Board (IRB) or Ethics 
Committee.
I specifically, and further, agree that:
1. I will conduct the clinical investigation in accordance with the Investigator 
Agreement, the Clinical Investigation Plan, any applicable regulations and any 
condition of approval imposed by any hospital or other reviewing authority. I will 
obtain all preoperative and operative data and complete follow-up data for each 
valve implant, as defined in the Clinical Investigation Plan.
2. Information concerning the product and the study must be provided to each 
patient participating in this clinical investigation. Written informed consent must 
be obtained from each patient who participates in this clinical investigation.
3. All information which I hereafter obtain from MCRI or any other person acting 
on behalf of MCRI about or relating to this study of the prosthesis, and all 
information which I have or will obtain under or concerning this study is 
considered by MCRI to be proprietary and confidential to MCRI. I will maintain 
all such information in confidence and will not use such confidential information, 
or release, reveal or disclose such confidential information to anyone without the 
written consent of MCRI or prior public disclosure by MCRI.  I will also assure 
that any and all co-investigators listed here and reporting to me will maintain 
confidentiality as described above.
4. I will notify MCRI, in writing, when approval for this investigational study is 
obtained from the Institutional Review Board (IRB) or Ethics Committee.
5. I have never participated in an investigational study which has been terminated 
for reasons of noncompliance.
6. Additional investigators participating in this study and reporting to me are:
_______________________           ______________________________________
Name (Surgeon)                                                             
Address
_______________________           ______________________________________
Name (Surgeon)                                                                    Address                                    

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_______________________           ______________________________________
Name (Surgeon)                                                                     Address
_______________________           ______________________________________
Name (Surgeon)                    
Address
_______________________          ______________________________________
Name (Surgeon)                                                                     Address
_______________________
______________________________________
Name (Surgeon)                                                                     Address
_______________________           ______________________________________
Name (Surgeon)                                      
Address
The study coordinator currently participating in the study under my direct supervision is:
______________________        _______________________________________
Name                                                  
Address
________________________________________
___________________________
Signature of Investigator
Type or Print Name
________________________________________
___________________________
Institution
Address
________________________________________
___________________________
City/State/Country
Telephone
________________________________________
___________________________
FAX
Date

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APPENDIX C
Clinical Trial of the On-X® Valve Using Low Dose Anticoagulation
Example Patient Informed Consent Form
Statement of Research
You are being invited to participate in a clinical trial (research study) as described below.
Please read the following explanation and ask your physician any and all questions that you have 
before agreeing to participate in this study which will involve the On-X Prosthetic Heart Valve.
Information about the Research
The On-X heart valve consists of an On-X pyrolytic carbon housing and leaflets with a titanium 
alloy ring around the housing. There is a sewing ring made of knitted polytetrafluoroethylene 
attached to the housing with two titanium rings and suture material. I understand these materials 
have a long history of use in cardiac prostheses.
The On-X heart valve, (the Prosthesis), is intended for treatment of patients who have been 
diagnosed with disease of a heart valve, and require replacement of their natural aortic or mitral 
valve, or previously implanted mechanical or tissue aortic or mitral valve.
The purpose of this study is to define the lowest level of required antithrombotic (anti-blood clot) 
therapy for the Prosthesis.  It is a randomized trial of three different antithrombotic drug 
therapies.  The therapies include three treatment groups for patients with: 1.) low risk of clotting 
having an aortic valve replacement, 2.) higher risk of clotting having an aortic valve 
replacement, and 3.) a mitral valve replacement.  Your doctor can tell you to which group you 
belong.  To belong to a group you may be required to have certain blood and urine tests done.  
These require the collection of about 3 tablespoons of blood and a urine sample.  Each treatment 
group will have a control group that uses the presently recommended antithrombotic drug 
therapy of the American Heart Association using Coumadin® and aspirin.  You will be randomly 
assigned to the treatment or the control group that goes with your group.  The treatment drug 
therapy for the low risk aortic valve replacement group is a combination of two presently used 
drugs – aspirin and Plavix®.  The treatment drug therapy for the high risk aortic valve 
replacement group and the mitral valve replacement is a reduced dose of Coumadin and aspirin.
The Prosthesis is a device with about 11 years of clinical experience which have indicated that 
the valve is safe and effective in standard use. The valve has governmental approval for sale 
throughout the world wherever such approval is required.  Particularly the valve is approved for 
sale in the United States under a premarket approval application with FDA numbered P000037.  
This clinical study will involve approximately 1200 patients. All patients will follow the same 
procedures and follow-up schedule except that each patient will be placed into a particular 
anticoagulation drug therapy randomly. Once enrolled a patient will be followed in the study for 
up to 8 years, and the overall study is expected to take up to 11 years to complete.  When the 
information has been collected, it will be submitted to the appropriate regulatory authorities for 
approval to modify the recommendations contained in the labeling regarding appropriate long-
term drug therapy for the valve.

46
Patients who have valvular heart disease and require replacement of their heart valve are being 
invited to participate in this study. Your treatment will be similar to that provided to patients who 
have their heart valves replaced with any other commercially available prosthetic heart valve.
Before surgery, you will have routine diagnostic tests to assess the status of your heart valves. 
You will then have surgery with implantation of the Prosthesis. Your progress will be closely 
monitored and recorded at the following times: discharge (or within 30 days following surgery), 
three and six months after surgery, and 12 months following surgery. After the 12-month visit, 
you will see your doctor on a yearly basis for at least 1 and up to 8 years. At your 3 month visit 
you will be randomly assigned to one of two anticoagulation drug therapies depending upon the 
type of implant you receive and your general health apart from the valve.  These two therapies 
are the standard anticoagulant therapy now used based on the recommendations of the American 
Heart Association or a therapy with a reduced dose of anticoagulation.  Laboratory blood 
samples will be drawn and other diagnostic tests will be done according to the requirements of 
the protocol during the appropriate preoperative and follow-up visits. The results of these tests 
may result in your removal from the study if you are found to be more likely to clot than most 
people or if you are found to not respond to the drug therapy.  You will be informed of this 
before your 3 month visit should it occur. The diagnostic tests will include echocardiograms 
(sound wave studies of the heart) at 1, 3 and 5 years following surgery.  The drug therapy you
will be placed on may require frequent laboratory blood tests.  The understanding of the use of 
the medications you are assigned to is important to the success of this study. Autopsies are 
requested should death occur during the study period to confirm any potential complication 
related to the study.
Risks and Discomforts
The primary risk of this study if you are in a low dose treatment group is that the drug therapy 
you are given may not be as effective in controlling blood clots on or around your new valve as 
the normal therapy is with mechanical valves.  Specifically, patients in the low dose treatment 
groups may have a higher risk of blood clots, called thrombi, on or around the new valve and a
higher risk of blood clots breaking off the valve, called thromboemboli, traveling through the 
blood stream.  These blood clots can possibly cause mini-strokes, major strokes, heart attacks, 
limb injuries or amputations or death.
Certain general risks are associated with any surgical procedure. General surgical risks include 
anesthesia complications, drug reactions, and infection. The primary risk associated with the 
Prosthesis is similar to that of other commercially available heart valves, that is, failure to restore 
function. Specifically, this might involve structural failure of the valve, blood leak around the 
valve, clotting on or around the valve, or infection. As with any other prosthetic valve, the 
complications that may occur with the Prosthesis can result in minor to severe consequences, 
including permanent disability, reoperation or death. 
The general risks of anticoagulant therapy include bleeding if anticoagulation is too strong and 
blood clotting if anticoagulation is too weak.  These risks can be minimized by strict adherence 
to the timing and amounts of medicines prescribed by your doctor and by regular routine 
monitoring of your anticoagulation state.  They can also be minimized when taking Coumadin by 
adhering to a diet low in vitamin K containing foods such as leafy green vegetables (spinach and 
the like), liver and cranberry juice.  Additionally no prescription or over-the-counter medications 
should be taken without prior approval of your doctor.

47
Foreseeable risks and discomforts will be minimized by thorough preoperative evaluation and 
close intraoperative and postoperative monitoring of your condition, but unforeseeable risks may 
occur.
Benefits
It is generally believed that lowering the dose of anticoagulation will reduce the chance of 
suffering a bleeding event, but will increase the chance of suffering a blood clotting event.  If a 
valve is less likely to have a clotting event, then reducing anticoagulation should not 
significantly increase the risk of blood clotting events.  If assigned to the group using aspirin and 
Plavix, a further benefit will be not requiring monthly bleeding tests.  Thus, the primary benefit 
of the study is restored function of the heart valve and restored general health with less chance of 
problems.  Another benefit will be that your progress and health status will be carefully 
monitored.  Those patients on Coumadin will be monitored by weekly home testing which is 
shown to significantly reduce adverse events for these patients.  Any complication that might
arise may be detected and treated (if necessary) at an early stage, decreasing the potential for 
more serious problems.  Also, knowledge that is gained by your participation may be of potential 
benefit to other patients.
Alternative Methods of Treatment
Alternatives to heart valve replacement with the Prosthesis include replacement of your mitral or 
aortic valve with a different commercially available mechanical or tissue heart valve; or repair 
your native heart valve. Another alternative is that you may decide not to undergo any surgical 
treatment, and remain cared for with medications.
Confidentiality
Confidentiality of your medical records will be maintained at all times by those associated with 
this research study. Regulatory authorities (those responsible for the well-being of patients 
involved in research studies) and the sponsor On-X Life Technologies, Inc., and monitor of the 
study may inspect and perhaps copy the medical research records, if necessary, to ensure the 
validity of the information. Knowledge that is gained from the study may be published in
scientific journals; however, no patient will be identified.
Research Related Injuries
If physical injury occurs due to involvement in the research, medical treatment will be available, 
but you (or your insurance company) should be responsible for payment for the cost of treatment. 
Compensation for lost wages and/or direct or indirect losses will not be available. Further 
information about research-related injuries is available from the hospital (telephone: ________-
_________-__________).
Your participation in this study does not waive any legal rights or release the hospital or its 
agents from liability for negligence.
Questions about the Research
Nothing in this document is intended to limit the authority of the doctor to provide emergency 
medical care to the extent that the doctor is permitted to do so under applicable local laws.

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If you have questions about the research or develop a study-related problem, you should contact 
Dr. _____________________________________________________ at the following telephone 
number: __________- ___________ - ______________. During nonbusiness hours, you should 
contact the on-call doctor at _________________ - ____________ - _____________.
If you have any questions about your rights as a research subject, you should contact the Ethics 
Committee Chairperson (Name): ____________________________________ at _________ -
__________ - __________.
Voluntary Participation
Your participation in this research study is voluntary. Your refusal to participate will not 
jeopardize your future treatment or benefits at (Name of Hospital or Institution) -
___________________________________________.
You are free to discontinue participation in this study at any time without fear of penalty or loss 
of medical care. Your surgeon may also withdraw you from the study for just cause without 
your prior consent, but will inform you if this action is taken.
Progress of the Study
As the study progresses and information is collected, your doctor will inform you of any new and 
significant findings related to the Prosthesis or the procedures associated with its use.
Costs
There will be no additional cost to you beyond the usual customary costs associated with heart 
valve replacement. However, neither On-X Life Technologies nor (Name of Hospital or 
Institution) is responsible for compensation in the event of any physical injury that might occur 
as a result of your participation in this study. Information (tests, physical examinations, x-rays, 
etc.) that is gathered purely for the purposes of this research study (that is, not part of the usual 
medical intervention for heart valve replacement) will be provided to the patient free of charge. 
Signature
You are making a decision whether or not to participate in this study.  Your signature indicates 
that you have read the information provided, have discussed this study with your doctor and his 
or her staff, and have decided to take part. Again, you may withdraw from the study at any time, 
or choose not to participate without any prejudice to you. You will receive a copy of this form 
for your personal records.
____________                                                 ___________________________________
Date                                                                                        Patient Signature
Reason, if patient did not sign: 
______________________________________________________________________________
______________________________________________________________________________
_____________________________________________________________________
______________                                                ___________________________________
Date                                               
Witness Signature

49
I have fully explained this research study to the participant, and in my opinion, and his/hers, 
there was sufficient information regarding the risks and benefits to make an informed decision. I 
will inform the participant in a timely manner of any changes in the procedure or the risks and 
benefits if any occur.
_________________                          __________________________________________
Date                                                                             Investigator Signature

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Appendix D
Labeling

51
Appendix E
IRB and Investigator Information

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Institutional Information On-X Low Dose Anticoagulation Study
Institution
Investigator
Investigator’s Address and Phone 
Number
IRB Chairman
IRB Address and Phone Number
Emory University, Atlanta, GA
John Puskas, MD
550 Peachtree St. NE, Ste 7700
Atlanta, GA 30365
(404) 686-2513
Dr James W. Keller
Emory University
Institutional Review Board
1256 Briarcliff Road, NE
Briarcliff Campus, Bldg A, 307-N
Atlanta, Georgia 30306-2656
404-712-0720
Additional Centers to be Added

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Appendix F
MCRI On-X LOW DOSE ANTICOAGULATION STUDY
ECHOCARDIOGRAPHIC PROCEDURES
1.
General – interobserver and intraobserver variability
1.1
At each center, no more than two operators should perform studies.
1.2
At each center, one or at most two machines will be used for the study.  Velocity data will be calibrated 
using a string phantom or equivalent device.
2.
Exclusions
2.1
Poor echocardiographic window
3.
Recording studies
3.1
Unless impossible, every study will include the following standard imaging views: parasternal long-axis, 
parasternal short-axis, apical 4-chamber, apical 2-chamber, apical long-axis and subcostal.  Off-axis views 
as appropriate will also be necessary particularly to look for paraprosthetic regurgitation.
3.2
Doppler recordings will be made with a stand-alone continuous wave probe from apical views and for 
valves in the aortic position from additional right intercostals or suprasternal views.  Both orthograde 
waveforms and, if present, regurgitant jets will be recorded.
3.3
Subaortic pulsed recordings will be made in the apical 5-chamber view with the sample placed just below 
the level at which significant flow acceleration occurs.
3.4
Recordings should be made with the scale set to maximize signal size and with the maximum 
available sweep speed.
3.5
All images and waveforms used for calculating information will be recorded on electronic media.
4.
Data collected
4.1
Heart rate (BPM), height (cm) and weight (kg) are collected by the most convenient measure at the time of 
the echo exam.  Body surface area (BSA) is determined from the standard nomogram or standard equation 
below.  Geometric orifice area (GOA) is given by valve size in Table 8 of the On-X valve instructions for 
use.  BSA (m2) = (Wt(kg)0.425 X Ht(cm)0.725) X 0.007184.
4.2
Diameter of the left ventricular outflow tract measured on three parasternal long-axis frames frozen in 
systole.  Diameters will be measured from the trailing edge of the left septal echo to the leading edge of the 
anterior mitral leaflet echo.  The maximum dimension will be taken.  If there is reverberation artifact 
from calcium, the leading edge to leading edge convention will be used; if this artifact is excessive, the 
measurement will not be made.  The best measurement (usually at the preoperative examination) will 
be assumed to remain constant throughout the study.
4.3
From the subaortic waveform (for prostheses in mitral or aortic positions):  peak velocity (v1), mean 
pressure drop (p1), velocity integral (VTI1).
4.4
From the transaortic waveform (prostheses in the aortic position only):  peak velocity (v2), mean pressure 
drop (p2), velocity integral (VTI2).
4.5
From the mitral waveform (prostheses in the mitral position only):  Pressure half-time (PHT), mean 
pressure drop, peak instantaneous early velocity (vm), diastolic velocity integral (DVI).

54
4.6
Doppler measurements will be made over 3 cycles in sinus rhythm or over 5 to 10 cycles in atrial 
fibrillation (depending on clinical judgment).  These will then be averaged.
5.
Calculations
The data collected will be entered on a database and the following calculations will be performed at the 
central laboratory:
5.1
Effective area by the continuity equation (EOA) in the aortic position:
EOA = CSA x VTI1 / VTI2
[1]
where CSA is left ventricular outflow cross-sectional area in cm2 calculated from the diameter assuming 
circular cross-section; VTI1 is subaortic velocity integral in cm and VTI2 is aortic velocity integral in cm.
5.2
Effective area by the continuity equation (MOA) in the mitral position:
MOA =  CSA x VTI1 / DVI
[2]
where DVI is diastolic velocity integral in cm
5.3
Effective area by the pressure half-time method (MOA1/2) in the mitral 
position:
MOA1/2 = 220/PHT
[3]
5.4
Peak pressure drop across the aortic valve:
Peak ¨3 Y2
2 – v1
2)
[4]
5.5
Mean pressured difference across the aortic valve:
Mean ¨3 S1 – p2
[5]
5.6
Peak pressure drop across the mitral valve:
3HDNǻ3 Ym
2
[6]
5.7
Cardiac Output:
CO = CSA x VTI1 x BPM  [7]
5.8
Indexed effective orifice areas (EOAI), and cardiac index (CI):
EOAI = EOA/BSA  [8]; CI = CO/BSA  [9]
5.9
Performance Index (PI):
PI = EOA/GOA  [10]
6.
Other analyses
6.1
For valves in the aortic position, mean and standard deviation values will be calculated for the following 
parameters: peak transaortic velocity, mean transaortic velocity, mean pressure difference, peak pressure 
difference, effective orifice area, cardiac output and all indices.
6.2
For valves in the mitral position, mean and standard deviation values will be calculated for the following 
parameters:  peak transmitral velocity, peak transmitral pressure difference, mean transmitral pressure 
difference, effective orifice area by continuity equation, pressure half-time and effective orifice area by 
pressure half-time, cardiac output and all indices.
6.3
The site and severity of aortic regurgitation and mitral regurgitation will be assessed.
6.4
The presence, site and size of any thrombus will be assessed.