Clinical trial NCT02147067
Conditions: Microvascular Angina
Keywords: microvascular angina coronary microvascular disease coronary physiology ranolazine
Sponsor: Emory University
Start date: 2014-09-01; Completion date: 2018-06-01
Enrollment: 26 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to look at the effects of the drug Ranolazine compared to Placebo on symptoms of chest pain or chest tightness (known as angina), exercise endurance and ability, and changes in blood flow to the very small arteries of the heart (known as coronary microvascular function) in patients who do not have significant blockages in their major heart arteries. Ranolazine is a drug that is already approved by the FDA for angina, but it may be particularly effective in people with disease in their tiny heart vessels (known as coronary microvascular disease).

This trial aims to enroll 50 patients with angina who undergo baseline bicycle exercise testing with monitoring of the heart's electrical activity and oxygen consumption (known as cardiopulmonary exercise test) and coronary angiogram (taking pictures of the heart arteries through small hollow tubes placed through the wrist or groin). If severe blockages in the main arteries are not found then testing for coronary microvascular function will be performed. Subsequently, participants will then be randomized 50/50 to either Ranolazine or Placebo. After taking the study drug for 12 weeks, they will then repeat the cardiopulmonary exercise test and the coronary angiogram with testing for microvascular function.

Detailed description:
Heart disease is the most common cause of death in the world. Most of our understanding of heart disease has involved the large heart arteries (epicardial arteries); however, disease of the very small heart arteries (coronary microvasculature) likely precedes the development of epicardial disease and represents the "base of the iceberg" of cardiovascular disease. Yet, we do not understand how dysfunctional microvasculature leads to reduced blood flow, symptoms and adverse outcomes.

Coronary microvascular disease results from a combination of structural and functional abnormalities, so it is important to have reliable diagnostic tools that do not rely solely on imaging. The gold-standard for testing involves hemodynamic (blood circulation) measurements such as coronary flow reserve (CFR) and hyperemic microcirculatory resistance (HMR) that take place in the cardiac catheterization laboratory.

Ranolazine is a relatively new U.S Food and Drug Administration-approved medicine to help with angina (chest pain). There are no publications on the effect of Ranolazine on HMR.

Arms: arm 1: Ranolazine 1,000 mg twice daily arm 2: Placebo twice daily
Interventions: intervention 1: Ranolazine intervention 2: Placebo
Intervention descriptions: intervention 1: Ranolazine 1,000 mg twice daily intervention 2: Placebo

Protocol documents:
Prot_SAP_000.pdf: 
MARINA Study Proposal 
Version 1.1 
Amended 11/2/2016 
 
Microvascular Assessment of Ranolazine in 
Non-Obstructive Atherosclerosis (MARINA) 
 
Protocol version date: November 2, 2016 
 
NCT02147067 
 
 
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MARINA Study Proposal 
Version 1.1 
Amended 11/2/2016 
 
 
 
 
 
 
 
 
Microvascular Assessment of Ranolazine in 
Non-Obstructive Atherosclerosis (MARINA) 
 
 
CONFIDENTIAL 
NOT FOR DISSEMINATION 
 
 
 
 
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MARINA Study Proposal 
Version 1.1 
Amended 11/2/2016 
Study centers:  Emory University Hospital Clifton Campus, Emory University Hospital Midtown, Emory 
University Hospital John’s Creek, St. Joseph’s Hospital of Atlanta 
 
 
Investigators 
Principal Investigator: 
Habib Samady, M.D., F.A.C.C., F.S.C.A.I. 
Professor of Medicine 
Director, Cardiac Catheterization Laboratory 
Emory University Hospital 
Director, Interventional Cardiology 
Emory University School of Medicine 
1364 Clifton Road, Suite F606  
Atlanta, GA 30322 
Tel: (404) 778 1237 
Fax: (404) 712 7102 
Email: hsamady@emory.edu 
 
 
 
 
Co-Investigators: 
Olivia Y. Hung, M.D., Ph.D. 
Cardiology Fellow  
Division of Cardiology 
Emory University School of Medicine, Atlanta, GA  
Tel: (404) 712-0991 
Email: ohung@emory.edu 
 
Michael C. McDaniel, M.D. 
Assistant Professor of Medicine 
Division of Cardiology 
Emory University School of Medicine, Atlanta, GA  
Tel: (404) 778-7667 
Email: mmcdan2@emory.edu 
 
Laurence Sperling, M.D. F.A.C.C., F.A.H.A., F.A.C.P. 
Professor of Medicine 
Medical Director of Preventive Cardiology 
The Emory Clinic 
Division of Cardiology 
Emory University School of Medicine, Atlanta, GA  
Tel: (404) 778-2746 
Email: lsperli@emory.edu 
 
Gina P. Lundberg, M.D., F.A.C.C. 
Assistant Professor of Medicine 
Medical Director of the Heart Center for Women  
Saint Joseph's Hospital 
Division of Cardiology 
Emory University School of Medicine, Atlanta, GA 
Tel: (678) 843-9601 
Email: gina.lundberg@emory.edu 
Arshed A. Quyyumi, M.D., F.A.C.C., F.R.C.P. 
Professor of Medicine 
Division of Cardiology 
Co-director, Emory Clinical Cardiovascular 
Research Institute (ECCRI) 
Emory University School of Medicine, Atlanta, GA  
Tel: (404) 727-3655 
Email: aquyyum@emory.edu 
 
Leslee Shaw, Ph.D., F.A.C.C., F.A.S.N.C., F.A.H.A. 
Professor of Medicine 
Division of Cardiology 
Co-director, Emory Clinical Cardiovascular 
Research Institute (ECCRI) 
Emory University School of Medicine, Atlanta, GA  
Tel: (404) 712-0282 
Email: lshaw3@emory.edu 
 
Susmita Parashar, M.D., M.P.H., M.Sc. 
Assistant Professor of Medicine 
Division of Cardiology 
Emory University School of Medicine, Atlanta, GA 
Tel: (404) 778-2746 
Email: susmita.parashar@emory.edu 
 
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MARINA Study Proposal 
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I. 
Objectives 
The goal of this proposal is to evaluate the effects of Ranolazine compared to Placebo on 
anginal symptoms, exercise tolerance, and coronary microvascular function in patients with mild to 
moderate non-obstructive atherosclerosis.  
 
II. 
Scientific Rationale, Background and Significance 
While it is well known that cardiovascular disease is the most common cause of morbidity 
and mortality in the developed nations and is rapidly becoming so in the developing countries, what 
is less recognized is that both epicardial and microvascular disease contribute to these devastating 
sequelae. In fact, coronary microvascular disease likely precedes the development of epicardial 
disease and represents the “base of the iceberg” of cardiovascular disease. Yet, much of the 
diagnostic and therapeutic focus has been limited to epicardial disease, neglecting the contribution 
of dysfunctional microvasculature towards ischemic symptoms and adverse outcomes.1-6 Coronary 
microvascular disease results from a combination of structural and functional abnormalities, so it 
is important to have reliable diagnostic tools that do not rely solely on imaging. Although there has 
been substantial interest in the development of non-invasive functional assessments, the gold-
standard for testing continues to involve invasive hemodynamic measurements such as coronary 
flow reserve (CFR) and hyperemic microcirculatory resistance (HMR).1  
Ranolazine is a relatively new U.S Food and Drug Administration-approved anti-anginal 
agent.7-10 The anti-anginal mechanism of Ranolazine has not been fully elucidated yet but the 
leading hypothesis is that Ranolazine inhibits the late inward sodium channels, a factor in ion 
homeostasis and myocardial contractility.11-13 Ranolazine appears to positively impact on the 
subjective assessment of angina as measured by the Seattle Angina Questionnaire (SAQ) in patients 
with coronary microvascular disease;14,15 however, there are no publications on the effect of 
Ranolazine on CFR or HMR. 
 
III. 
Our Research Group 
Our research specializes in assessing structural and functional aspects of the coronary 
vasculature with a focus on studying the effects of pharmacological interventions on coronary 
epicardial and microvascular function as well as wall shear stress using computational fluid 
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dynamic models created in collaboration with researchers at the Georgia Institute of Technology 
and the Department of Mathematics and Computer Science at Emory University.  
 
IV. 
Hypotheses 
1. Ranolazine therapy, as compared to placebo, improves weekly angina frequency and 
nitroglycerin consumption in patients who have non-obstructive atherosclerosis, have 
persistent stable angina, and are already on disease-modifying medical therapy (DMT).  
2. Ranolazine therapy, as compared to placebo, improves peak VO2 in patients who have non-
obstructive atherosclerosis, have persistent stable angina, and are already on DMT.  
3. Ranolazine therapy, as compared to placebo, improves microvascular function, resulting in 
increased CFR and decreased HMR. 
 
V. 
Specific Aims 
Primary Aims:  
In patients with stable angina already on DMT and angiographically normal or near normal 
coronary arteries, Ranolazine 1000 mg twice daily, as compared to placebo, after 12 weeks, 
improves patients’ weekly angina frequency and nitroglycerin consumption (SAQ angina frequency 
dimension). 
 
Secondary Aims: 
In patients with stable angina already on DMT and angiographically normal or near normal 
coronary arteries, Ranolazine 1000 mg twice daily, as compared to placebo, after 12 weeks: 
1. Improves patients’ SAQ subscores regarding physical limitation, angina stability, treatment 
satisfaction, and disease perception. 
2. Improves patients’ peak VO2, exercise duration, and time to angina, as evaluated by 
cardiopulmonary exercise testing (CPET). 
3. Increases CFR as measured by velocity Doppler wires 
4. Decreases HMR as measured by pressure and velocity Doppler wires 
 
 
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VI. 
Study Design 
 
A. Description 
       
Patients with persistent stable angina and on DMT (ASA, statin) will be recruited from 
multiple centers throughout Atlanta, GA. They will undergo baseline evaluation of their angina using 
SAQ, CPET, and cardiac catheterization with coronary microvascular function assessment with 
combined pressure and flow wire system (ComboMap® Pressure and Flow System, Volcano 
Therapeutics, Inc.).   
 
Subsequently, patients will be randomized to treatment with DMT plus Ranolazine twice 
daily versus DMT plus Placebo twice daily for 12 weeks. Initially, patients will be on 
Ranolazine/placebo 500 mg twice daily, and the dose will be increased one week later as tolerated 
to Ranolazine/placebo 1,000 mg twice daily. Ranolazine has been FDA approved and is prescribed 
in the same dosages that this study uses. Therefore, it is noteworthy to mention that we are not 
studying a new drug in this study, but rather investigating whether this drug has new implications. 
Enrolled patients will be treated with Ranolazine/placebo 1,000 mg twice daily for 12±3 weeks.  
 
On follow-up, patients will again be evaluated with SAQ, CPET, and angiography with 
coronary physiology assessment. Subjective angina improvement, exercise capacity, and 
microvascular function will be compared to baseline measurements in both arms.  While Ranolazine 
has previously been shown to improve both angina and exercise capacity,8,9 there are no published 
randomized controlled trials with regards to the effects of Ranolazine on CFR or HMR. As the gold-
standard for evaluation of coronary microvascular disease continues to involve these invasive 
hemodynamic measurements, a follow-up cardiac catheterization is necessary to assess the changes 
in CFR and HMR, objective evidence in the evaluation of coronary microvascular disease in patients.  
 
B. Inclusion criteria 
1) History of typical angina or effort-induced anginal symptoms and are currently experiencing 
angina at least once per week; 
2) Abnormal stress ECG, exercise stress imaging, or pharmacological stress imaging; 
3) Non-obstructive coronary artery disease as defined by lesion stenosis ≤ 50% in any artery (left 
main, LAD, circumflex, diagonals, marginals, RCA, PDA, and posterior lateral) as visualized by 
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diagnostic angiography  
 
C. Exclusion criteria: 
1) Inability to provide informed consent; 
2) Active Myocardial Infarction (STEMI or NSTEMI);  
3) History of CABG; 
4) Diagnosis of other specific cardiac disease such as severe valvular heart disease, 
cardiomyopathy, or variant angina; 
5) Left Ventricular Ejection Fraction (LVEF) < 30%; 
6) Known renal insufficiency (CrCl < 30 mL/min) or on dialysis; 
7) Contraindications to the use of Ranolazine, including patients on CYP3A4 inducers/potent 
inhibitors, and patients with liver cirrhosis. 
 
Note: 
The following scenarios are not exclusions but do warrant monitoring or dose modifications: 
1) Limit dose of Ranolazine to 500mg BID in patients who are currently on diltiazem or verapamil 
2) Limit concurrent simvastatin to a maximum dose of 20 mg/day 
3) Limit concurrent metformin to a maximum dose of 1,700 mg/day 
4) Monitor for QT interval on ECG in patients with history of QT interval prolongation (familial, 
congenital, or acquired) or who are concurrently on QT interval-prolonging medications  
5) Monitor renal function in patients with Cr < 60 mL/min. 
 
D. Study Protocol: 
 
Baseline CPET (Visit 1a): 
-Consent form for study participation will be signed in person or by mail. Consent form may be 
mailed to the patient to be signed if patient’s commute to Emory is limited (e.g. patients who live far 
from Emory campus). 
-Stop all β-blockers and calcium channel blockers ≥48 hours prior to CPET 
-Stop long-acting nitrates ≥24 hours prior to CPET 
-Schedule appointments for follow-up CPET and angiography 
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-SAQ 
-CPET within 1 week of angiography, ideally the day before angiography 
 
Baseline angiography (Visit 1b): 
-Coronary angiography with physiology and reactivity testing within 1 week of CPET, ideally the 
day after CPET 
-Stop all β-blockers and calcium channel blockers ≥48 hours prior to catheterization 
-Stop long-acting nitrates ≥24 hours prior to catheterization 
-Laboratory measurements if not already obtained within the past 2 weeks (CBC, BMP, troponin, 
Hgb A1c, fasting lipid panel) 
 
Once CPET and cardiac catheterization are performed, patients will then be randomized to either 
Ranolazine or Placebo in addition to current medical therapy 
 
4 weeks follow-up:  
-ECG 
-SAQ 
 
12-week follow-up CPET (Visit 2a): 
-Stop all β-blockers and calcium channel blockers ≥48 hours prior to CPET 
-Stop long-acting nitrates ≥24 hours prior to CPET 
-SAQ 
-CPET within 1 week of angiography, ideally day before angiography 
 
12-week follow-up angiography (Visit 2b, scheduled separately from CPET): 
-Coronary angiography with pressure and flow measurements within 1 week of CPET, ideally the 
day after CPET 
-Stop all β-blockers and calcium channel blockers ≥48 hours prior to catheterization 
-Stop long-acting nitrates ≥24 hours prior to catheterization 
-Laboratory measurements (CBC, BMP, troponin, fasting lipid panel) 
 
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E. Study Chart 
 
Baseline 
4 weeks 
12 weeks 
Informed consent 
X 
 
 
Medical history 
X 
 
 
CPET 
X 
 
X 
Cardiac Catheterization with Reactivity Testing 
X 
 
X 
SAQ (full) 
X 
X 
X 
Current Medications 
X 
X 
X 
Study Medication Adjustment (if needed) 
 
X 
 
 
 
VIII. Methodology 
 
A. Cardiopulmonary Exercise Testing (CPET) 
In order to standardize exercise stress testing, CPET will be performed under the guidance 
of the MET-TEST CPET network in Atlanta, led by Dr. Sundeep Chaudhry. The MET-TEST was 
created in 2003 and is a high-precision stress test with detailed physiological assessment, allowing 
accurate and reproducible measurements of peak VO2. Individuals may demonstrate an abnormal 
CPET response before they develop symptoms or present with cardiac events,16,17 and abnormal 
CPET results are strong predictors of future adverse outcomes.18 Having performed over 65,000 
tests and participated in studies since its inception, the MET-TEST CPET network will help ensure 
the quality of the collected data. Peak VO2, exercise duration, and time to angina will be obtained at 
baseline and at follow-up, thus determining changes in peak VO2, exercise duration, and time to 
angina (secondary endpoints).  
 
B. Angiography with Coronary Physiology and Reactivity Testing 
 
After routine coronary biplane angiography, the microvascular function of each coronary 
artery will be assessed using intravenous infusion of adenosine at 140 micrograms/kg/minute for 
3 minutes to achieve maximal hyperemia. Continuous recordings of aortic pressure and 
electrocardiogram are done during baseline and during drug infusion periods. A 0.014-inch 
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combined pressure and Doppler flow velocity monitoring guidewire (ComboWire® XT Pressure 
and Flow Wire, Volcano Therapeutics, Inc.) is advanced into the target vessel chosen to make 
Doppler and hemodynamic recordings. It is important to note that adenosine is the drug of choice 
to induce hyperemia and that its role in coronary physiology assessment differs from its role in 
pharmacological stress testing.  
 
CFR is defined as the ratio of average peak velocity (APV) at maximal hyperemia to baseline. 
HMR is defined as the ratio of hyperemic distal pressure to APV.19 CFR and HMR will be calculated 
at baseline and 12-week post-Ranolazine therapy, thus determining change in CFR and HMR value 
(secondary endpoints).  
 
Coronary endothelial function will also be evaluated by measurement of coronary blood flow 
during infusion of intracoronary acetylcholine. Coronary blood flow (CBF) is defined as diameter 
(D)2 x APV / 8.  Percent change in CBF (%ΔCBF) is calculated by (CBFACh – CBFbaseline) / CBFbaseline x 
100%, where a >50% increase in CBF in response to acetylcholine is considered normal.20 The effect 
of Ranolazine vs. placebo on endothelial function between baseline and follow-up will also be 
assessed (secondary endpoint).   
 
C. Patient Population 
A minimum of 50 patients will be enrolled into this double-blind study and randomized in a 
1:1 ratio to receive Ranolazine twice daily versus placebo twice daily while on DMT. Patients will 
be called one week after randomization for study medication dose adjustment, with the goal of 
Ranolazine/placebo 1,000 mg twice daily during the study period as tolerated. We expect to conduct 
12-week follow-up evaluation on a total of at least 40 patients accounting for 20% drop out rate due 
to the invasive nature. 
 
D. Endpoints 
Primary Endpoint: Change in weekly angina frequency and nitroglycerin consumption (SAQ angina 
frequency dimension) after 12 weeks therapy with Ranolazine compared with placebo. 
 
Secondary Endpoints: 
1. Change in SAQ score (composite and individual dimensions) after 12 weeks therapy with 
Ranolazine compared with placebo. 
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2. Change in peak VO2, time to angina, and exercise duration as measured by CPET after 12 weeks 
therapy with Ranolazine compared with placebo.  
3. Change in CFR after 12 weeks therapy with Ranolazine compared with placebo.  
4. Change in HMR after 12 weeks therapy with Ranolazine compared with placebo.  
5. Change in %ΔCBF after 12 weeks therapy with Ranolazine compared with placebo. 
 
E. Statistical Methods 
The power calculations for this study are informed by other published studies on Ranolazine. 
In the CARISA trial (3-group parallel arms, n=823), Chaitman et al. reported mean weekly angina 
frequency decreased from 4.5 attacks per week to 3.3 ± 0.3 for Placebo and 2.1 ± 0.2 for Ranolazine 
1,000mg (P<0.001). In the ERICA trial (n=565), Stone et al. reported mean weekly angina frequency 
decreased from 5.7 to 3.3 attacks per week for Placebo and from 5.6 to 2.9 attacks per week for 
Ranolazine 1,000mg (P=0.028). Sample size calculations for these two trials suggest a minimum of 
36 patients for 99% 2-sided confidence interval, 95% power, and 1:1 ratio. In a more recent study 
evaluating the impact of Ranolazine in 20 women with angina and non-obstructive CAD, Mehta et 
al. showed that, compared to Placebo, Ranolazine improved angina stability (p=0.008), physical 
functioning (p=0.046) and quality of life (p=0.021) as measured on the SAQ.14 Taken together, we 
believe that 50 patients should provide adequate power to detect changes in the SAQ.  
For an invasive evaluation of patients with coronary microvascular disease (secondary 
endpoint), there are no trials regarding the effects of Ranolazine on measurements such as CFR or 
HMR, so this study will generate data to determine the need for future larger studies and/or future 
sample size calculations. The closest published study found in the literature was by Mehta et al., in 
which the investigators measured myocardial perfusion reserve index (MPRI) scores by cardiac 
magnetic resonance (CMR), which is not the gold standard invasively measured indices as 
performed in this trial. MPRI can be a surrogate for invasive coronary hemodynamic measurements 
but is not as well validated. Patients in this study had MPRI scores of 2.4 ± 0.4 while on Ranolazine, 
compared with 2.1 ± 0.4 while on Placebo.14 Using these results, we estimate that the study, with a 
power of 80%, 1:1 ratio, and two-sided confidence interval of 85%, will require a sample size of 38 
patients. Assuming 20-25% drop-out due to the invasive nature of the study, we anticipate enrolling 
50 patients. 
For biostatistical data analysis, continuous variables will be reported as mean and standard 
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deviation (1 SD), and a t-test or U-test will be employed depending on whether or not the variables 
are normally distributed and the standards of deviations are the same. Analysis of variables at the 
level of patient, treatment arm, and lesion will be performed using multilevel regression models. 
Chi-square test or Fisher’s exact test will be used, as appropriate, to compare categorical variables. 
All statistical analyses will be carried out using the Statistical Package for Social Sciences (SPSS) 
software (SPSS, Inc., Chicago, IL) or Statistical Analysis System (SAS) software (SAS Institute Inc., 
Cary, NC). A two-sided p-value of <0.05 will be considered statistically significant. 
  
F. Data Management 
All documents and subsequent versions related to this study will be identifiable, traceable 
and appropriately stored to provide a complete history of the clinical study. The principal 
investigator is responsible for the accuracy, legibility, and security of all clinical study data, 
documents, and subject records at the investigator’s participating medical site. Designated study 
staff (principal investigator, co-investigators, clinical coordinators, and other appropriately trained 
personnel) is responsible for entering the data and access to the database will be limited to these 
persons.  
All data and information concerning subjects collected during the course of this study will be 
kept strictly confidential according to applicable laws and regulations. The informed consent form 
shall be signed and dated by the principal investigator or his authorized designee(s). This form and 
all other source documents will be maintained by the research team throughout the clinical study 
in subject specific folders in a locked filing cabinet. All coronary angiography and physiology data 
will be recorded on compatible compact discs (CD-ROM or DVD) and stored in a locked filing 
cabinet. Electronic information will be kept on password-protected computers and secured access 
network drives. All records and reports prepared in connection with this study will be maintained 
in a secure location for a minimum period of 15 years post approval or longer as may be otherwise 
required by law. 
All public reporting of the results of the study will eliminate identifiable references to the 
subjects. The results of this clinical study will be submitted for publication following study 
completion and data analysis. Study data published in medical journals and/or presented at 
scientific conferences will not allow the identification of study subjects.  
 
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G. Monitoring and Reporting 
Processes to ensure site record keeping, data entry, and reporting are well-defined to ensure 
timely access to clinical trial data and supporting documentation. Investigators are required to keep 
records on all relevant observations, including records concerning adverse effects, whether 
anticipated or unanticipated. All adverse events will be captured on an adverse event case report 
form, tracked from time of study enrollment until completion of follow-up, and promptly reported 
to the IRB and Gilead Sciences. The investigator will also notify the IRB regarding new and 
significant safety information and any event that requires expedited reporting as serious, 
unexpected, and related to the clinical study drug. The principal investigator, IRB or a regulatory 
authority may suspend or prematurely terminate participation in this clinical study if suspicion of 
an unacceptable risk to subjects arises during the study. The study shall be terminated if an 
unacceptable risk is confirmed. 
 
H. Duration of study and Follow Up 
It is estimated that it will take 1 year to enroll patients and collect baseline data and 4 months 
for follow-up data collection. 
 
 
 
 
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Johnson BD, Shaw LJ, Buchthal SD, et al. Prognosis in women with myocardial ischemia in the absence of obstructive 
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Pepine CJ, Anderson RD, Sharaf BL, et al. Coronary microvascular reactivity to adenosine predicts adverse outcome 
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Sicari R, Rigo F, Cortigiani L, Gherardi S, Galderisi M, Picano E. Additive prognostic value of coronary flow reserve 
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Chaitman BR. Ranolazine for the treatment of chronic angina and potential use in other cardiovascular conditions. 
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Chaitman BR, Skettino SL, Parker JO, et al. Anti-ischemic effects and long-term survival during ranolazine 
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10. Stone PH, Gratsiansky NA, Blokhin A, Huang IZ, Meng L. Antianginal efficacy of ranolazine when added to treatment 
with amlodipine: the ERICA (Efficacy of Ranolazine in Chronic Angina) trial. J Am Coll Cardiol 2006;48:566-75. 
11. Belardinelli L, Shryock JC, Fraser H. Inhibition of the late sodium current as a potential cardioprotective principle: 
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12. Nash DT, Nash SD. Ranolazine for chronic stable angina. Lancet 2008;372:1335-41. 
13. Lovelock JD, Monasky MM, Jeong EM, et al. Ranolazine improves cardiac diastolic dysfunction through modulation 
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15. Villano A, Di Franco A, Nerla R, et al. Effects of ivabradine and ranolazine in patients with microvascular angina 
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16. Balady GJ, Arena R, Sietsema K, et al. Clinician's Guide to cardiopulmonary exercise testing in adults: a scientific 
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17. Chaudhry S, Arena R, Wasserman K, et al. Exercise-induced myocardial ischemia detected by cardiopulmonary 
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19. Eshtehardi P, Luke J, McDaniel MC, Samady H. Intravascular imaging tools in the cardiac catheterization laboratory: 
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