Clinical trial NCT01815957
Conditions: Coronary Microcirculation Coronary Artery Disease Myocardial Disease Ischemia
Keywords: coronary microcirculation coronary artery disease myocardial disease ischemia
Sponsor: University of New Mexico
Start date: 2012-05-01; Completion date: 2016-03-01
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is being done to determine if Ranolazine treatment improves coronary microcirculation function among patients with coronary microcirculation dysfunction. We are also looking to learn if symptomatic improvement of chest pain during treatment with Ranalozine is related to improved coronary microcirculation function.

Detailed description:

Arms: arm 1: After enrollment in the study, participants will initiate Ranolazine for 4 weeks. The participant's usual anti-anginal medication regimen will be continued unchanged throughout study duration. Patients will receive Ranolazine 500 mg orally twice daily for 1 week, and the dose will be increased to 1,000 mg twice daily for an additional 3 weeks if tolerated.
Interventions: intervention 1: Rnalozine
Intervention descriptions: intervention 1: . After enrollment in the study, participants will initiate Ranolazine for 4 weeks. The participant's usual anti-anginal medication regimen will be continued unchanged throughout study duration. Patients will receive Ranolazine 500 mg orally twice daily for 1 week, and the dose will be increased to 1,000 mg twice daily for an additional 3 weeks if tolerated.

Protocol documents:
ICF_001.pdf: 
 
Page 1 of 8 
Updated 3/27/2015 
 
The University of New Mexico Health Sciences Center 
Consent to Participate in Research 
3/27/2015 
 
Study title:  Impact of Ranolazine on Coronary Microcirculatory Resistance- A prospective single 
center study to evaluate the effect of Ranolazine on microcirculatory resistance. 
 
Introduction 
You are being asked to participate in a research study that is being done by Bina Ahmed, MD, who is 
the Principal Investigator and associates from the Department of Internal Medicine, Cardiology.  This 
research is studying the effect of the drug Ranolazine (Ranexa) on patients with chest pain due to 
abnormal function of small heart arteries (microvessels) without blockages in the main heart arteries.  
Participants enrolled in this study will have already had a heart catheterization prior to enrollment. 
Participants will undergo a follow up heart catheterization four weeks after enrollment. This is not 
done as standard of care but is part of the research study to re-assess small vessel function after the 
four week treatment with Ranexa.  Although the idea for this study is solely Dr. Ahmed’s, the study is 
being ‘sponsored’ by the company which makes Ranexa (Gilead Pharmaceuticals). 
 
Background 
The heart has small blood vessels which are essential and play a complex role in regulating blood flow 
to the heart muscle. Patients who have abnormal function of the small heart arteries without having 
blockages in the main arteries have  chest pain which brings them to the hospital recurrently.  These 
patients are at risk for dying from heart related issues later in life compared to patients who don’t have 
this dysfunction.   
 
To date, there are limited therapies known to treat small vessel dysfunction.  Ranexa is a medication 
that has been shown to improve symptoms of chest pain in these patients but whether this is actually 
related to improving small vessel dysfunction remains unknown.  Our study is looking to see what 
happens to abnormal small vessel function after treatment with Ranexa.    
 
You are being asked to participate in this study because you have been told you have small vessel 
dysfunction in your heart arteries without having blockages in your main heart arteries.  We are going 
to ask 20 people to take part in this study at the University of New Mexico.  
 
This form will explain the research study, and will also explain the possible risks as well as the 
possible benefits to you. We encourage you to talk with your family and friends before you decide to 
take part in this research study. If you have any questions, please ask one of the study investigators.     
 
What will happen if I decide to participate?  
If you agree to participate, the following things will happen:
Enrollment visit 
Once you are diagnosed with small vessel dysfunction in your heart arteries and are willing to 
participate, you will be enrolled into the study.  You will have to do the following during the 
enrollment visit:   


 
Page 2 of 8 
Updated 3/27/2015 
 
1:  Pregnancy testing:  If you are a female with the possibility of being pregnant, your urine will be 
tested to see if you are pregnant.  You will not be eligible to participate if you are pregnant, 
2:  Questionnaires:  You will be asked to fill out a questionnaire that evaluates your activity level and 
the quality and quantity of your chest pain episodes.  
3:  ECG (electrocardiogram):  We will perform an ECG if not already done.   An ECG takes recordings 
of the electrical activity of your heart from small, sticky patches called electrodes attached to the chest, 
arms and legs.  This test does not carry any risks to you and is done routinely. 
4:  History:  We will ask your permission to obtain your past medical history including demographic, 
medication and social history. 
5:  Treatment with Ranexa:  You will be started on the study medication, Ranexa.  This is a drug that is 
approved to treat chest pain symptoms.  You will take the drug twice a day for a total of 4 weeks.  The 
first week you will take 500 mg tablets twice a day followed by 1000 mg tablets twice a day for 3 
additional weeks. 
   
It is very important that you take the study medication as instructed throughout the study. Do not miss 
any tablets. If at any time you experience any problems or decide you no longer wish to continue to 
take study medication you should not stop taking the study medication without first contacting the 
study nurse or the study doctor. 
 
Your study doctor will discuss with you medications that you may or may not take during the study 
because there are certain medicines that you should not take in addition to the trial medication. It is 
very important that at each visit you tell your study doctor about all medications that you are presently 
taking. This includes prescriptions drugs, over-the-counter medicines and vitamins. It is very important 
that you take the study drug given to you just as the doctor tells you to.    
 
You will also not be able to start any new medications or change any of your old medications during 
the 4 week study period. If you must start a new medication while in the study, please tell the study 
staff before taking it. They will decide if it conflicts with the study drug. You may be removed from 
the study if the study doctor feels it would be in your best interest. It is essential that all medication 
related questions be discussed with the study team prior to starting, stopping or changing any doses.    
 
Please inform your study doctor if you receive additional medicine from another doctor for the 
treatment of any diseases at any time during your participation in the study. Please tell your study 
doctor or study staff if you have any unusual symptoms at any time during the study. 
 
It is very important that you return all unused study medication at every study visit. The study 
medication must be taken only by the person for whom it has been prescribed and it must be kept out 
of the reach of children or persons with limited capacity to read or understand. 
 
Phone Follow-up: 
 
At the end of the first week after you have started Ranexa, a member of our study team will contact 
you by phone.  You will be asked about any side-effects that you are experiencing.  At this time if you 
are tolerating the medication, you will be asked to increase the dose to 1000 mg twice a day for the 
three additional weeks.  You will then be contacted every week for two additional weeks to ensure that 
you are doing well on the therapy.   


 
Page 3 of 8 
Updated 3/27/2015 
 
Follow-Up Visit: 
 
At the end of four weeks of treatment with Ranexa, you will be scheduled to return to undergo another 
heart catheterization to re-assess small vessel function.  This test will be a shorter version of the heart 
catheterization you had four weeks prior to the study. We will use the wrist or leg artery to get access 
into the arterial system.  This is done after application of sufficient local anesthetic and insertion of a 
hollow tube similar to an IV line.  First we will pass a catheter into the pumping chamber of the heart 
and measure pressures inside.  
 
We will then use a different catheter to engage your heart artery (most likely the left main artery) and 
inject dye to see what the artery looks like using XRAY.  We will then place a very small wire in your 
heart artery and measure the function of your small heart arteries.  During this test, we give you a 
medication called adenosine which may make you feel flushed transiently while we assess the effect of 
Ranexa on the small vessels via the small wire in your heart arteries. 
 
Once we are done, we will remove our equipment.  You will be monitored afterwards for 3-5 hours 
prior to being discharge home.  You will be given further instruction about care of the access site either 
in your wrist or leg. You will be asked to not lift anything greater than 10lbs for about 5 days as your 
access artery heals. 
 
During the follow-up visit, we will ask you to fill out the two questionnaires that you filled out at the 
screening visit regarding your activity level and the quality and quantity of your chest pain episodes.    
 
How long will I be in this study? 
Once you agree to enroll, you will be in the study for a total of four weeks.  The study involves 1 
additional visit over a period of 4 weeks and a phone follow-up at 1,2 and 3 weeks.   The visit for the f/u 
heart catheterization will require you to be in the hospital for possibly 8-12 hours.  After the procedure, 
you will be advised not to lift anything heavier than 10 pounds for 5 days and if your leg artery was used, 
to not engage in prolonged climbing for 5-7 days.   
 
What are the risks or side effects of being in this study? 
There are several possible risks and side effects you may experience from participating in this clinical 
study.  
 
1:  Risks and side effects of  Ranexa 
Minor side effects (5-10 out of a 100 people):   
• 
feeling like you might pass out; 
• 
swelling in your hands, ankles, or feet; 
• 
slow, fast, or pounding heartbeats; 
• 
tremors or shaking; 
• 
blood in your urine; 
• 
urinating less than usual or not at all; 
• 
shortness of breath; 
• 
constipation 


 
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Serious side effects (less than 1 out of a100 people): 
• Prolonged QT interval:  You may develop a long electrical interval (called prolonged QT 
interval) and a dangerous fast heartbeat.  This happens in less than 1% of people.  We will 
check your QT interval on an ECG which will be done at the time of enrollment to make sure 
you are not at risk for this.     
• Liver failure:  Ranexa does not cause liver failure but patients with liver failure should not be 
on Ranexa as they will not be able to metabolize the drug.  
• Ranexa should not be taken with certain medications that may alter its metabolism.  The study 
team will carefully review all your medications to make sure there are no concerning 
interactions.  In addition, you should not begin any medications for the duration of study 
without discussing it with the study team. 
2:  Risks of Study procedures 
 
Risks of heart catheterization: 
a. Bruising around catheter in your artery (approximately 1-2 out of 100 patients)   
b. Major Bleeding which may require blood transfusion (less than 1 out of 400 patients) 
c. Serious reaction or rash to contrast dye  (less than 2 out of 1000 patients) 
d. Contrast dye induced kidney failure (less than 2 out of a 100 patients) 
e. spasm of your access artery  (2-4 out of 400 patients) 
f. Access artery perforation (0.5-1 out of 100 patients) 
g.  Local nerve damage (less than2 out of 1000 patients) 
h. Infection (less than1 out of 400 patients) 
i. Stroke, heart attack or death (less than2 out of 1000 patients) 
 
 Risk of small vessel testing: 
Bleeding: We will give you medicines which thin your blood during the procedure.  These are given 
for heart catheterization. On average, risk of having a major bleeding problem which requires blood 
transfusion is less than 1 in 400 patients. We monitor the extent of how thin your blood is very 
carefully during the procedure. 
Risks of placing a small wire in your heart arteries: Because we will be placing a small wire into your 
heart artery, there is a very small risk of causing trauma and a tear in the artery. On average, the risk of 
causing a tear or spasm of your artery is less than 2 in a 1000. If spasm does develop, will treat this 
with giving nitroglycerin down your heart arteries to release the spasm. Death resulting from tearing of 
the heart artery is extremely rare but possible (less than 2 in 1000 patients).   
Risk of Adenosine infusion:  
We will administer Adenosine through your IV line in your arm while we perform small vessel 
function testing.  The drug will be administered for about 5 minutes.  Adenosine is the same 
medication given to patients who undergo a chemical stress test. We will use the same weight based 
dose. Adenosine can cause temporary slowing of your heart rate (less than1 in 100 patients), give you 


 
Page 5 of 8 
Updated 3/27/2015 
 
temporary chest pain (1 out of 5 patients), flushing (15 out of 100 patients), shortness of breath (5-10 
out of 100 patients). Because the medication is in your system for seconds, the effects do not last long. 
Other potential risks: 
 
There is the possible risk of physical stress, emotional distress, inconvenience and possible loss of 
privacy and confidentiality associated with participating in a research study.  
 
Follow-up cardiac catheterization will be associated with additional radiation exposure.  This will be 
less than that received during the initial heart catheterization.  Efforts will be made to limit total 
exposure and we anticipate 2-5 minutes of additional xray exposure will be used.  There will be 
exposure to different organs but centered around your chest and abdominal areas.  This may amount to 
a years worth of natural background radiation that an average person receives.  
 
Risk of placing an IV line:  Risk associated with this are minimal but include site infection and bleeding.  
Both of these are extremely rare and careful septic precautions are strictly adhered to.   
For more information about risks and side effects, ask the investigator.  
What are the benefits to being in this study? 
There may or may not be direct benefit to you from participating in this study. But if you have been 
diagnosed with small vessel dysfunction, the findings of this study may help you if the study drug is 
shown to improve this function.  Similarly, if the drug is shown not to improve small vessel function 
specifically for you, than the drug can stopped and other treatments pursued.  This is the purpose of the 
study is to show that there is actual improvement in function on treatment with Ranolazine.  It is hoped 
that information gained from this study will help in the treatment of future patients with small vessel 
dysfunction.  Receiving a second cardiac catheterization is not routinely done to assess response to drug.  
It is only being done because of this study protocol.  The follow-up cardiac catheterization along with 
all associated risks is purely for research to understand the effects of Ranexa on small vessel dysfunction.      
 
What other choices do I have if I do not want to be in this study? 
You do not have to participate in this study to receive treatment for your condition. You can receive 
this drug without participating in this study.  Also, there are other medicines available for the treatment 
of small vessel dysfunction . Participation in this study is not a substitute for your usual ongoing 
medical care by your regular doctor or specialist. The study doctor will tell you more about the risks 
and benefits of participating in this study as compared to the risks and benefits of alternative 
treatments.  
 
How will my information be kept confidential? 
We will take measures to protect your privacy and the security of all your personal information, but we 
cannot guarantee confidentiality of all study data.   
Information contained in your study records is used by study staff, and it will be shared with the 
sponsor of the study, Gilead Pharmaceuticals. The University of New Mexico Health Sciences Center 
Human Research Review Committee (HRRC) that oversees human subject research, and the Food and 


 
Page 6 of 8 
Updated 3/27/2015 
 
Drug Administration and/or other entities that may have access will be permitted to access your 
records.   
There may be times when we are required by law to share your information.  However, your name will 
not be used in any published reports about this study. A copy of this consent form will be kept in your 
medical record. 
 
Information (without your name) will be entered into a computer database/locked file cabinet in the 
research nurse’s office. Data will be stored for 1-2 years, and then will be destroyed.   
 
Medical information created by this study will become part of your hospital medical record since it 
will be used to treat you. 
   
What are the costs of taking part in this study? 
You (and/or your insurance company) will not be responsible for the costs of the follow-up heart 
catheterization or the cost of Ranexa taken during the four weeks.  However if you agree to participate 
there may be cost of personal time necessary to attend study visits, time missed from work, parking or 
other transportation fees.  If the drug is found to be making improvements to your condition, we will 
recommend it be continued.  But the drug sponsor will not cover the cost of the drug after the study is 
completed in four weeks.  At this time, if we decided to continue your treatment, the cost will have to 
be covered by you or your insurance company.   
You will still be responsible for the cost of your usual ongoing medical care, including procedures 
and/or non-study medications that your study doctor or regular doctor requires during this study as part 
of your usual medical care.  
 
 
What will happen if I am injured or become sick because I took part in this study? 
If you require medical care as a result of a complication specifically resulting from the study procedure 
or study drug, UNMHSC will provide you with emergency treatment. This will be billed to your 
insurance company.  No commitment is made by the University of New Mexico Health Sciences 
Center (UNMHSC) to provide free medical care or money for injuries to participants in this study.  
Reimbursement for all related costs of care will be sought from your insurer, managed care plan, or 
other benefits program. If you do not have insurance, you may be responsible for these costs. You will also 
be responsible for any associated co-payments or deductibles required by your insurance. It is important 
for you to tell your study doctor immediately if you have been injured or become sick because of 
taking part in this study. If you have any questions about these issues, or believe that you have been 
treated carelessly in the study, please contact the Human Research Review Committee (HRRC) at the 
University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131, (505) 272-1129 
for more information.   
 
Will I be paid for taking part in this study? 
You will be not be paid to participate in this study 


 
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Updated 3/27/2015 
 
How will I know if you learn something new that may change my mind about 
participating? 
You will be informed in a timely manner of any significant new information pertaining to your safety 
that may influence your willingness to continue participation in the study. If new scientific information 
is obtained about any of the study medications during the course of the study, your study doctor or 
study staff will provide this information to you. This will be done so you can decide whether or not 
you wish to continue to participate in the study. 
 
Can I stop being in the study once I begin? 
Your participation in this study is completely voluntary. You have the right to choose not to participate 
or to withdraw your participation at any point in this study without affecting your future health care or 
other services to which you are entitled.   
The study doctor may remove you from this study if: 
• Staying in the study would be harmful. 
• You need treatment not allowed in this study. 
• You fail to follow instructions. 
• You become pregnant. 
• The study is cancelled. 
In addition, you may be taken out of the study if for any reason your doctor feels it would be in your 
best interest for you to stop participating. If you should decide to leave the study you should tell the 
study doctor or study staff.  They will make sure that proper procedures are followed and a final visit is 
made for your safety. If you leave the study early, you must return all unused study medication.  You 
may be asked questions about your experience while you were in the study.  You may be asked to have 
follow-up evaluations such as laboratory tests or a physical examination to help your withdrawal from 
the study happen safely. 
 
Whom can I call with questions or complaints about this study? 
If you have any questions, concerns or complaints at any time about the research study, Bina Ahmed, 
MD or her associates will be glad to answer them at 505-272-9223, Monday through Friday from 8:30 
AM to 5:00 PM.  If you need to contact someone after business hours or on weekends, please call 505-
272-1720 and ask for the cardiology interventionalist on call. If you would like to speak with someone 
other than the research team, you may call the UNMHSC HRRC at (505) 272-1129.   
   
Whom can I call with questions about my rights as a research subject? 
If you have questions regarding your rights as a research subject, you may call the UNMHSC HRRC at 
(505) 272-1129. The HRRC is a group of people from UNM and the community who provide 
independent oversight of safety and ethical issues related to research involving human subjects. For 
more information, you may also access the HRRC website at http://hsc.unm.edu/som/research/hrrc/. 
 


 
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CONSENT 
You are making a decision whether to in this study. Your signature below indicates that you have read 
the information provided (or the information was read to you). By signing this consent form, you are 
not waiving any of your legal rights as a research subject. 
 
I have had an opportunity to ask questions and all questions have been answered to my satisfaction.  
By signing this consent form, I agree to participate in this study. A copy of this consent form will be 
provided to you. 
 
____________________________     
____________________________            ___________  
Name of Adult Subject (print)  
 
Signature of Adult Subject  
 
         Date 
 
 
INVESTIGATOR SIGNATURE 
I have explained the research to the subject or his/her legal representative and answered all of his/her 
questions. I believe that he/she understands the information described in this consent form and freely 
consents to participate. 
 
_________________________________________________ 
Name of Investigator/ Research Team Member (type or print) 
 
_________________________________________________            ___________________ 
(Signature of Investigator/ Research Team Member)                        Date 

Prot_000.pdf: 
v5/27/2014 
1 
Impact of Ranolazine on Coronary Microcirculatory Resistance (MICRO Study) 
Bina Ahmed MD, Yasmin Hamirani MD, Allon Rafael MD, Wyatt Voyles MD, Mark Sheldon MD, Mark 
Ricciardi MD, Noel Bairey Merz MD 
I.  Background: 
The coronary microcirculation (CMC) plays an essential and complex role in regulating coronary blood 
flow and myocardial perfusion.  Recent clinical classification of CMC dysfunction by Camici et al includes 
a heterogeneous group of patients including those with CMC dysfunction without evidence of 
obstructive epicardial coronary artery disease (CAD) or myocardial disease (Type I); CMC dysfunction in 
the presence of myocardial diseases such as primary and secondary cardiomyopathies (Type II); CMC 
dysfunction in the presence of obstructive CAD (Type III) and iatrogenic CMC dysfunction (Type IV) 1.  
Unlike epicardial CAD, where the link between ischemia and angiographic coronary anatomy lends a 
target for therapy, the study and treatment of the disorders of the CMC are still in evolution.  However, 
over the last two decades our understanding of CMC has broadened and our ability to study CMC 
function has evolved.  
Importance of the Coronary Microcirculation:   CMC function is adversely effected by various forms of 
myocardial diseases 2-4 and both endothelial dependant and independent CMC dysfunction can increase 
long-term risk of adverse cardiovascular events among patients with all types of CMC dysfunction5, 6. 
Assessment of Coronary Microcirculation:  In the absence of direct visualization, there are several 
approaches to indirectly measuring CMC function.   Non-invasive tools have included perfusion cardiac 
MRI, positron emission topography and myocardial contrast echocardiography based measurement of 
microcirculatory blood flow 7-10.  However, requirements for dedicated software programs, lack of 
uniform definition of findings and inferior reproducibility strongly limit non-invasive assessment of the 
CMC.  Currently, the gold standard for measuring CMC function involves invasive measurement using 
Doppler or thermodilution methods to quantify coronary blood flow and vasoreactivity in response to 
vasoactive stimuli 11, 12.  Historically, the more accurate invasive method of measurement has been 
limited by complicated protocols which mandate pre-procedural mixing of restricted medications such 
as acetylcholine; the need to withhold chronic medications and the lack of reproducibility of the 
measurements obtained.  
A simpler and more reproducible method of measuring global coronary microcirculatory resistance has 
recently been validated13-16.  The index of microcirculatory resistance (IMR) is based on the premise that 
at peak hyperemia, variability of resting vascular tone and hemodynamics is reduced to give an accurate 
assessment of minimum microvascular resistance.  It is defined as distal coronary pressure divided by 
the inverse of the hyperemic mean transit time (a correlate to absolute flow), measured simultaneously 
using a temperature sensor/ pressure tipped guidewire.  Compared  to traditional Doppler based 
coronary flow measurements,  IMR is easier to use, allows quantification of blood flow and pressure 
measurements while reducing the impact of basal flow conditions to provide superior reproducibility 
and less hemodynamic variability compared to doppler based measurements 15.   An IMR measurement 
of <20u is associated with normal CMC function. 
 
Treatment of Coronary Microcirculatory Dysfunction:  Treatment of patients with CMC dysfunction has 
focused on reducing atherosclerotic burden and symptom relief.  There is a paucity of data evaluating 
the impact of drug therapy on CMC function.  Ranolazine is a late sodium current inhibitor thought to 


v5/27/2014 
2 
decrease left ventricular compressive forces resulting in increased myocardial blood flow and 
improvement in signs and symptoms of angina 17-23.  In a porcine model, Ranolazine was also shown to 
cause transient increase in epicardial coronary blood flow and decrease in coronary vascular resistance 
via alpha-1 blockade24.  Direct impact of Ranolazine on the microcirculation remains unknown. 
Clinically, among patients with Type I CMC dysfunction (CMC dysfunction in the absence of obstructive 
CAD or myocardial disease), Ranolazine has been shown to improve symptoms of angina and cardiac 
MRI based perfusion compared to treatment with placebo 25.  Whether this symptomatic improvement 
is due to actual improvement in CMC function remains unknown.    
 
II:  Specific Aims 
1:  Does Ranolazine treatment improve CMC function among patients with Type I CMC dysfunction?   
2:  Is symptomatic improvement in chest pain with Ranolazine related to improved CMC function? 
 
III:  Design and Methods 
This single center, prospective study is designed as a pilot proposal evaluating the effect of Ranolazine 
among patients with Type I CMC dysfunction.   
Inclusion Criteria: 
-  Patients with subjective symptoms of ischemia without flow limiting angiographic CAD (<50% 
epicardial coronary stenosis) and abnormal IMR (>20 U).  
- Definition of ischemia (any one): 
• 
chest pain with dynamic ischemic ECG changes (t wave inversions or > 1 mm ST 
depressions  
• 
Exercise treadmill testing induced chest pain with ≥1 mm of downsloping or flat 
ST segment depression during exercise or recovery; ≥2 mm of ischemic ST 
depression at a low workload (stage 2 or less or ≤130 beats/min); early onset 
(stage 1) or prolonged duration (>5 min) of ST depression; multiple leads (>5) 
with ST depression 
• 
Nuclear stress perfusion defect > 10% 
• 
Stress echocardiogram with stress induced wall motion abnormality 
 Exclusion Criteria: 
- Age < 18 yrs 
- Flow Limiting epicardial CAD >50% 
- Life expectancy < 6 months 
- Recent (<1 week) myocardial infarction or positive biomarkers 
- Severe aortic stenosis  
- Contraindications to IMR testing including inability to utilize antithrombotic therapy and/or 
intravenous adenosine 
- Contraindications to Ranolazine therapy: 
-Patients with known hepatic insufficiency, prolonged QT or renal failure (GFR < 60) 
-use of drugs that inhibit CYP3A such as diltiazem, verapamil, ketoconazole, macrolides and HIV 
protease inhibitors 
- Pregnancy, breastfeeding  
- Patients taking drugs which prolong QT interval 
 
Study Flow: 
Patients meeting entry criteria will undergo detailed history regarding demographics, cardiovascular risk 
profile, clinical presentation, laboratory analysis and current medical therapy.  After enrollment in the 
study, participants will initiate Ranolazine for 4 weeks.  The participant’s usual anti-anginal medication 


v5/27/2014 
3 
regimen will be continued unchanged throughout study duration.  Patients will receive Ranolazine 500 
mg orally twice daily for 1 week, and the dose will be increased to 1,000 mg twice daily for an additional 
3 weeks if tolerated.   
-All participants will complete baseline Seattle Angina Questionnaire (SAQ) and Duke Activity Status 
Index (DASI). 
-1 week:  Patients will undergo phone f/u and if tolerated, drug dose will be increased to 1000 mg twice 
daily.    
- 4 weeks:  Patients will be scheduled to return for a follow-up cardiac catheterization and IMR at no 
charge.  Patients will be asked to complete SAQ and DASI questionnaires.  
 
Procedures: 
 
Coronary Angiogram and left heart catheterization:  Patients will undergo an initial clinically indicated 
coronary angiogram and left heart catheterization with IMR testing and then undergo post Ranolazine 
follow-up coronary angiogram and left heart catheterization using standard technique by one of three 
experienced interventional cardiologists (B.A, M.S or M.R). The study sponsor will pay for the follow –up 
cardiac catheterization and IMR. 
Assessment of Coronary Microvascular Function:  Coronary physiologic indexes will be measured in a 
stenosis free area of the left anterior descending coronary artery when possible, or in the left circumflex 
artery as a secondary choice.  Appropriate coronary guide catheter will be used to engage left main 
coronary artery.  After adequate heparinization, a temperature sensor/ pressure tipped guidewire (Radi 
pressure wire, St Jude Medical Systems) will be advanced through the guide catheter and placed and 
secured at least 3 cm distal to guide catheter in the coronary artery and secured.   After injecting 3 cc of 
room temperature normal saline, proximal and distal temperature sensors on guidewire will calculate 
mean transit time using thermodilution.  This is repeated three times to obtain an average baseline 
transit time.  Next, intravenous adenosine (140 μg per kilogram of body weight per minute through a 
central vein) is used to induce hyperemia.  We then inject 3 cc of room temp normal saline and calculate 
hyperemic transit time.  This is performed at 120, 150 and 180 seconds after initiation of intravenous 
adenosine and averaged to obtain a mean hyperemic transit time.  In addition, simultaneous hyperemic 
pressure gradient is measured in the proximal and distal vessel.   Once data is obtained, the following 
calculations are made: 
1:  Index of Microvascular Resistance (IMR):  IMR is defined as hyperemic distal coronary pressure 
divided by the inverse of hyperemic mean transit time.  IMR is based on the assumption that at peak 
hyperemia the variability of resting vascular tone and hemodynamics will be eliminated, and the 
minimum microvascular resistance will be achieved.  Studies have correlated IMR value <20 to normal 
microvascular resistance 13, 16, 26.   
 
IV:  Data and Analysis  
Sample Size:  The sample size of 20 patients is not powered for a specific end point as this is a pilot 
exploratory analysis meant to determine the effect of Ranolazine on IMR.  It is our intention to use this 
data to determine feasibility and power of an appropriately sized multicenter randomized clinical trial. 
Feasibility:   The historic incidence of CMC dysfunction can vary depending on the patient population 
being studied.  The estimated historical incidence of Type I CMC dysfunction is approximated to be 20-
30% 27.  At the University of New Mexico, we anticipate performing approximately 400 cardiac 
catheterizations for the indication of objective ischemia (as outlined in entry criteria).  Of these, we 
estimate that 50% have non-obstructive CAD.  Current data from the IMR patient registry at UNM shows 


v5/27/2014 
4 
that approximately 50% of patients with ischemia and non-obstructive CAD have IMR >20 U (mean 26.7 
± 13.1). We conservatively approximate 40 patients per year who meet entry criteria for the study at 
University of New Mexico.  
Data Safety: Data will be monitored by Dr. Abinash Achrekar. 
Primary Endpoint:   
1:  Relative change in IMR before and after Ranolazine therapy.  Mean change between the groups will 
be analyzed using a paired t test. 
Secondary endpoints: 
1:  Absolute change in SAQ and DASI scores before and after Ranolazine therapy.  Mean change between 
the groups will be analyzed using a paired t test. 
2:  Compare relative change in IMR among patients with and without symptomatic improvement in 
angina burden based on SAQ and DASI scores. 
V:  Scientific Focus 
CMC dysfunction continues to be a disease entity with limited therapeutic targets.  More recently, 
therapeutic trials, including those using Ranolazine, have shown improvement in angina burden and 
myocardial perfusion among patients with CMC dysfunction 25, 28 but no study has evaluated mechanism 
for this therapeutic effect.   
The primary purpose of our study is to obtain pilot data showing mechanistic effect of Ranolazine on 
microcirculatory resistance.  Our project meets the scientific focus put forth and explores a novel 
diagnostic and therapeutic strategy among patients with coronary microvascular ischemic heart disease.  
We hope to help elucidate the mechanism of effect of Ranolazine among patients with CMC dysfunction 
and to correlate invasively measured microvascular resistance with subjective burden of angina.  If 
shown to improve CMC function, Ranolazine would represent a therapeutic strategy among patients 
with CMC dysfunction and support a larger scale multi-center trial.     
VI:  Potential Challenges 
1:  Study Feasibility:  There may be two potential limitations to recruitment.  One may be due to 
insufficient patients meeting entry criteria.  The true prevalence of Type I CMC dysfunction is 
speculative.  Review of the literature shows a varied rate between 10-30% of patient with chest pain and 
no epicardial CAD.  Buchthal et al. studied 35 women with ischemic chest pain and no flow limiting CAD 
and found that 20% had abnormal metabolic response to exercise most likely due to CMC dysfunction 27.  
We used a similar estimate to calculate annual number of patients who would meet entry criteria for 
our study.  It is conceivable that the true prevalence of Type I CMC dysfunction is lower making 
feasibility more difficult.  I 
2:  Evidence of true hyperemia:  Use of intravenous Adenosine is well validated for the induction of 
coronary hyperemia.  Literature review suggests that mean time to maximal hyperemia using 
intravenous adenosine is 84±46 seconds (range, 23-125 seconds) and time from discontinuation of 
infusion to return of coronary flow to basal levels is 145±67 seconds 29.  To ensure standardized IMR 
measurement under maximal hyperemia, all cases will undergo three measurements at 120 seconds, 
Formatted: Font: Italic, Underline


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5 
150 seconds and 180 seconds after initiation of intravenous adenosine (140 μg per kilogram of body 
weight per minute through a central vein). 
 
VII:  Relevant Contributions 
 
At the University of New Mexico, we have implemented IMR into clinical practice among patients 
meeting criteria for evaluation of CMC function.  Our protocol adheres to meticulous technique and a 
standardized protocol.  In addition to the proposed study, we are currently evaluating the role of CMC 
dysfunction among patients with ACS and no angiographic culprit.  As a clinical fellow, I worked with Dr. 
Noel Bairey Merz and the WISE study group to develop a protocol for doppler based coronary 
microvascular testing among women with chest pain and normal coronary arteries at Cedars Sinai 
Medical Center.  In addition, at the University of Vermont, I was an investigator in a pilot project 
comparing quantitative measures of myocardial blood flow on first-pass CT imaging with microsphere-
derived absolute values in an animal model of regional coronary ischemia and hyperemia.     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6 
 
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