Contrast Nephropathy and Nitrates
Phase: PHASE4
Conditions: Contrast Induced Nephropathy
Sponsor: Mt. Sinai Medical Center, Miami

 
 
 
 
 
Date  
 
 
: 
 April 14, 2015 
 
Version 
 
 
: 
 5 
Test drug 
 
 
: 
Intravenous Nitroglycerin (NTG) 
Title  
 
 
: 
Contrast Nephropathy and Nitrates (CoNaN) 
Principal Investigator 
: 
Gervasio A. Lamas MD 
Co-Principal Investigator 
: 
Julio G. Peguero MD 
Co-Principal Investigator 
: 
Paul Kurlansky MD 
 
 
 
Confidentiality Statement 
The information contained in this document, especially unpublished data, is the property of 
Mount Sinai Medical Center and is therefore provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board/Independent Ethics Committee.  
 
 
 
 
 
 
 
 
 

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Table of Contents 
1.0 
EXECUTIVE SUMMARY............................................................................................................. 4 
2.0 
BACKGROUND ............................................................................................................................. 5 
2.1 
INTRODUCTION ....................................................................................................................... 5 
2.2 
CONTRAST-INDUCED NEPHROPATHY AND NITRIC OXIDE ..................................... 5 
2.3 
NITROGLICERYN TO PREVENT CONTRAST INDUCED NEPHROPATHY .............. 7 
3.0 
INVESTIGATORS AND FACILITIES ........................................................................................ 7 
3.1 
STUDY LOCATION .................................................................................................................. 7 
3.2 
STUDY MANAGEMENT .......................................................................................................... 7 
3.2.1 
SUB-INVESTIGATORS .................................................................................................... 7 
3.2.2 
STATISTICIAN .................................................................................................................. 7 
3.2.3 
INDEPENDENT DATA AND SAFETY MONITORING COMMITTE ...................... 8 
4.0 
CONAN TRIAL DESIGN .............................................................................................................. 8 
4.1 
PRIMARY ENDPOINT ............................................................................................................. 8 
4.1.1 
GLOMERULAR FILTRATION RATE ........................................................................... 8 
4.2 
SECONDARY ENDPOINTS ..................................................................................................... 8 
4.2.1 
MEHRAN SCORE .............................................................................................................. 9 
4.3 
SAMPLE AND METHODOLOGY .......................................................................................... 9 
5.0 
RESEARCH DESIGN AND METHODS ................................................................................... 10 
5.1 
SAMPLE SIZE .......................................................................................................................... 10 
5.2 
STUDY POPULATION ........................................................................................................... 10 
5.2.1 
PATIENT RECRUITMENT ........................................................................................... 10 
5.2.2 
INCLUSION CRITERIA ................................................................................................. 10 
5.2.3 
EXCLUSION CRITERIA ................................................................................................ 10 
5.2.4 
SCREENING AND BASELINE EVALUATION .......................................................... 11 
5.2.5 
RANDOMIZATION ......................................................................................................... 11 
5.3 
STUDY ALGORYTHM ........................................................................................................... 11 
5.4 
TREATMENT REGIMENS .................................................................................................... 12 
5.4.1 
NITROGLYCERIN PHARMACOLOGY ..................................................................... 12 
5.4.1.1 
NITROGLYCERIN HUMAN TOXICITY ................................................................ 12 
5.4.1.2 
SEVERE HYPOTENSION .......................................................................................... 12 

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5.4.1.3 
METHEMOGLOBINEMIA ........................................................................................ 13 
6.0 
THE USE OF NITRATES FOR THE PREVENTION OF CIN .............................................. 14 
7.0 
BUDGET ........................................................................................................................................ 15 
8.0 
REFERENCES .............................................................................................................................. 15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1.0 EXECUTIVE SUMMARY 
  
Study Design 
This is a placebo controlled study in 400 patients, testing the hypothesis that pre-treatment use of 
intravenous nitroglycerin will decrease the incidence of renal insufficiency after percutaneous  
angiography, cardiac or lower extremity 
 
Intervention 
Patients undergoing  percutaneous angiography will be randomly assigned to receive intravenous 
nitroglycerin (5 mcg/min, titrated up to 50mcg/min for at least 1 hour, maintaining systolic blood 
pressure (BP) > 100 mmHg, before and 3 hours after the procedure) or a normal saline placebo in 
a 1:1 ratio. 
  
Enrollment period   
The patients will be enrolled during a 2 year period. 
 
Rationale for this study 
 
Animal models suggest that the impaired synthesis of nitric oxide is one important contributor to 
the pathogenesis of the vasoconstriction caused by exposure to contrast-media. Our previous, 
retrospective, pilot study supported the hypothesis that the administration of nitrates, particularly 
intravenous nitroglycerin, before PCI, may decrease the incidence of contrast induced 
nephropathy (CIN).  
 
Primary Endpoint:  
 
1- The primary endpoint will be the change in estimated glomerular filtration rate (eGFR) 
assessed by modification of diet for renal disease formula, after percutaneous 
angiography. 
 
Secondary Endpoints:  
 
1- CIN will be defined as an increase in serum creatinine of 25% or ≥ 0.5 mg/dl post-
percutaneous angiography.  
2- Safety profile of the intervention including volume overload, hypotension, headache, the 
need for hemodialysis, intra-aortic balloon pump, endotracheal intubation or the use of 
pressors.  
3- Analysis and comparison to a CIN predictive score calculator (Mehran Score).  
 
 
 
 
 

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2.0 BACKGROUND 
 
2.1 INTRODUCTION 
CIN is a complication of percutaneous angiography that, when it occurs, usually begins shortly 
after the administration of contrast media (1-3).  The incidence has been reported in the range of 
0 to 50%, depending on comorbidities and risk factors (4-8).  CIN usually resolves 
spontaneously, but it has been associated with an increased risk of morbidity, in-hospital death, 
and late mortality (9-10). There is no specific management for renal insufficiency after the 
development of CIN.  Therefore, there is interest in finding preventive strategies.  Available 
evidence supports the use of hydration, sodium bicarbonate, and reduction of contrast volume 
administered to patients at risk (22). Statin use for prevention of CIN is still controversial (30-
32), with a recent publication showing promising results (33). A hydration system was proposed 
by Briguori et al. (34) that showed CIN preventive effects. Further studies are needed to support 
these findings. Other agents, such as N-acetylcysteine, fenoldopam, nifedipine, captopril, 
prostaglandins and aminophylline have been evaluated in the prevention of CIN with varying 
results (23-29).  
 
Animal models suggest that the impaired synthesis of nitric oxide is one important contributor to 
the pathogenesis of the vasoconstriction that may lead to CIN (11-13). We plan to investigate 
whether the use of intravenous nitroglycerin before exposure to contrast media reverses this 
vasoconstriction, and therefore, prevents the development of CIN. 
 
The present manuscript describes the background, rationale, study design, safety monitoring, and 
analysis plan for the proposed contrast nephropathy and nitrates trial (CoNaN).  
 
2.2 CONTRAST-INDUCED NEPHROPATHY AND NITRIC OXIDE 
 
The pathophysiology behind CIN is not well understood.  Different mechanisms have been 
proposed to explain the decrease in glomerular filtration rate after exposure to contrast media.  
The two major theories for the development of CIN are renal vasoconstriction resulting in 
medullary hypoxemia, and direct cytotoxic effects of the contrast agents (14-18).  
 
Devrim et al, performed a randomized animal model trial, exposing rat kidneys to contrast media 
and measuring nitric oxide (NO) levels after exposure. They suggested that non-ionic low 
osmolar contrast medium administration leads to accelerated oxidant reactions and decreased NO 
level in rat kidney tissues. (13) 
 
In another animal model completed by Brezis et al. they exposed anesthetized rats to the 
inhibitor of NO formation, L-NG-monomethylarginine (LNMMA). While increasing blood 
pressure and reducing renal blood flow they measured a decline in oxygen tension. These 
responses were promptly reversed by L-arginine, a NO donor, which bypasses the LNMMA 
blockade. They concluded that vasodilatation by nitroglycerin may participate in the balance of 

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renal medullary oxygenation and play an important role in the prevention of medullary hypoxic 
injury. (19) 
 
Agmon et al, produced a simple model of radiocontrast induced nephropathy. Rats were 
pretreated with indomethacin (prostaglandin blocker) and N omega-nitro-L-arginine methyl ester 
(L-NAME, to inhibit nitric oxide synthesis) and then exposed to a contrast agent. Acute renal 
failure consistently developed, with a decline in creatinine clearance. Pretreatment with L-
NAME or indomethacin reduced basal medullary blood flow. It was concluded that prostanoids 
and nitric oxide have an important protective role in the renal response to radiocontrast material, 
and reduced synthesis of these vasoactive substances in renal/vascular diseases may predispose 
patients to radiocontrast nephropathy. (11) 
 
The mechanism by which N-acetylcysteine and other antioxidants have been proposed to confer 
renal protection in some animal models and human trials is through stimulation of nitric oxide 
synthase (NOS) to increase the endothelial production of NO. (17) 
 
Nitroglycerin exerts its effects by bypassing the NOS mechanism and forming nitric oxide.  In 
smooth muscle, nitric oxide activates guanylate cyclase which increases guanosine 3’5’ 
monophosphate (cGMP) leading to dephosphorylation of myosin light chains and smooth muscle 
relaxation.  It produces a vasodilating effect on the peripheral veins and arteries, with more 
prominent effects on veins than arteries. (20)   
 
In the study of Efrati et al, the administration N-acetylcysteine was associated with maintenance 
of higher urinary NO levels after exposure to contrast media in comparison to the placebo group, 
were it was associated with a decrease of NO urinary levels after exposure to the toxin. They 
explained that “contrast media agents can cause a direct tubular injury, leading to the generation 
of oxygen free radicals, which in turn react with nitric oxide to produce peroxynitrite. 
Peroxynitrite is a potent oxidant that further decreases nitric oxide bioavailability and results in 
more tissue injury. Patients with chronic renal failure, diabetes mellitus, and heart failure have 
impaired nitric oxide activity, which could account for their susceptibility to develop contrast 
media nephrotoxicity”. (17) 
 
We recently completed a small retrospective study at our institution (exhibit A). We sought to 
investigate whether the use of nitrates before PCI reduces the incidence of CIN. We evaluated 
patients that were admitted to the hospital after PCI and had repeat serum creatinine measured. 
We measured the effects of pre-procedure nitrate use on post-PCI renal function in patients who 
received nitrates within 24 hours before the procedure and compared it with that of those who 
did not receive nitrates. Multivariable logistic regression analysis demonstrated that the use of 
nitrates correlated with a decrease incidence of CIN. Intravenous nitroglycerin infusion was 
associated with a lower risk of CIN compared with other means of administering nitrates. We 
concluded that the study supported the hypothesis that the administration of pre-PCI nitrates, 
particularly intravenous nitroglycerin, may decrease nephrotoxicity caused by contrast-media. 
But prospective, randomized-controlled trials are warranted to support or refute this hypothesis. 
 

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The mechanistic hypothesis of the CoNaN trial is that by pre-treating with intravenous 
nitroglycerin and exposing the renal vasculature to nitric oxide donor (NO), the damage caused 
by renal vasoconstriction and hypoxia due to radiographic contrast agent will be ameliorated, 
thus reducing the incidence of CIN. 
 
2.3 NITROGLICERYN TO PREVENT CONTRAST INDUCED NEPHROPATHY 
 
Experimental animal studies provide evidence that NO plays a role in CIN. The clinical 
information on the use of intravenous nitroglycerin to prevent CIN is limited to one retrospective 
study. Our hypothesis that pre-PCI exposure to intravenous nitroglycerin could prevent CIN has 
a favorable theoretical basis. The reality of our premise is still uncertain.  
 
Our proposal for a randomized clinical trial will answer a simple clinical question. It will help to 
demonstrate a correlation or not, between experimental results obtained in animal models and 
human subjects. It will also contribute to clarify the role of NO donors in the renal vasculature. 
 
 
3.0 INVESTIGATORS AND FACILITIES 
 
 
3.1 STUDY LOCATION 
The CoNaN trial will be performed at Mount Sinai Medical Center in Miami Beach, Florida. The 
Departments involved in the developing of the trial include: the Columbia University Division of 
Cardiology, the Division of Nephrology and the Department of Medicine. 
3.2 STUDY MANAGEMENT 
The trial will be coordinated by the CoNan Trial research teams that consist of the principal and 
co-principal investigators, sub-investigators, and a study coordinator. The study coordinator will 
evaluate eligibility; obtain consent, schedule subject’s follow-up visits, data collection and 
maintenance of study documentation.  Handling of investigational products will be the 
responsibility of an onsite pharmacist as well as the assistant investigators.  
 
3.2.1 SUB-INVESTIGATORS 
Vertilio Cornielle MD, Sabas I. Gomez MD, Orlando Santana MD, Robert Goldzer MD, Javier 
Reyna MD, Carlos Podesta MD, Hany Elmahdy MD, Omar Issa MD. 
 
3.2.2 STATISTICIAN   

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Statistical consultation will be provided by Helen Parise PhD, Chief Statistician for the 
Cardiovascular Research Foundation. 
 
3.2.3 INDEPENDENT DATA AND SAFETY MONITORING 
COMMITTE 
The DSMB will be composed of experts not associated with the trial.  The Chair and members 
are:  Esteban Escolar MD (Chair), Juan Carlos Brenes MD and Ayman Layka MD 
(Nephrologist).  They will review unblinded data, and obtain statistical consultation as needed. 
The first data monitoring will occur once 100 patients have been enrolled. After the first visit has 
been completed, monitoring visits frequency will be every 12 months, depending on enrollment 
 
4.0 CONAN TRIAL DESIGN 
 
The Contrast Nephropathy and Nitrates trial (CoNaN) is a single center, randomized, 1 x 1 
factorial clinical trial designed to test the effects of intravenous nitroglycerin infusion in renal 
function given prior to angiography.  
 
Specific aims for this trial include: 
 
 To determine whether the intravenous nitrates have any effect on the glomerular filtration 
rate (GFR) after the exposure to contrast media. 
 To determine if intravenous nitroglycerin will decrease the incidence of CIN. 
 
4.1 PRIMARY ENDPOINT 
 
The primary endpoint for this trial will be to determine the change in glomerular filtration rate 
after exposure to contrast media.  We will compare the change in GFR before and after 
percutaneous angiography of the group that received intravenous nitroglycerin with the change in 
GFR before and after percutaneous angiography of the group that did not receive intravenous 
nitroglycerin. 
 
4.1.1 GLOMERULAR FILTRATION RATE 
 
We will estimate the GFR using the modification of diet in renal disease (MDRD) formula: 
 
GFR = 175 x SerumCr-1.154 * age-0.203 * 1.212 (if patient is African American) * 0.742 (if female)   
 
4.2 SECONDARY ENDPOINTS 
 
Major secondary endpoints will include:  

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1- Incidence of CIN, defined as an increase in baseline serum creatinine of 25% or ≥ 0.5 
mg/dl 48 to 72 hours post-percutaneous angiography  
2- Safety profile of the interventions including volume overload, hypotension, headache, 
medication interaction, the need for hemodialysis, intra-aortic balloon pump, 
endotracheal intubation or the use of vasopressors.  
3- Analysis and comparison to a CIN predictive score calculator (Mehran Score).  
 
 
4.2.1 MEHRAN SCORE 
 
According to a validated score proposed by Mehran et al. patients with a score equal or greater 
than 6, has a 14% chances or more of developing CIN (21). We will use this value to recruit 
patients with a high probability of developing CIN. The score will be calculated using the 
following variables:  hypotension (5 points for BP <80/60mmHg), intra-aortic balloon pump use 
before during or after the procedure (5 points),  congestive heart failure (5 points for New york 
Heart Association Class II-III, history of pulmonary edema or an ejection fraction <40%)  age > 
75 years (4 points), anemia (3 points for hematocrit <39% for men and <35% for women), 
diabetes mellitus (3 points),  serum creatinine > 1.5 (4 points), GFR <60 (2 points for 41-60; 4 
points for 21-40 and 6 points for <20) and contrast volume used (1 for each 100 cc). 
 
 
4.3 SAMPLE AND METHODOLOGY 
We will enroll 400 patients with a Mehran score of 6 or more that have a pre-procedural 
creatinine measured. Following baseline assessments, patients will be randomly assigned to 
receive intravenous infusion nitroglycerine plus intravenous normal saline or normal saline only.  
 
 
 
 
 
 
 
 
ALL PATIENTS 
(400) 
Intravenous Nitroglycerin  
Intravenous Fluids 
(200) 
Intravenous Fluids 
(200) 

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5.0 RESEARCH DESIGN AND METHODS 
 
5.1 SAMPLE SIZE 
NOT A CASE CONTROL STUDY.  This is a randomized, placebo-controlled clinical trial with 
a 1:1 randomization of active therapy to placebo.  Prior data from our retrospective study 
indicate that the failure rate among controls is 0.3.  If the true relative risk of failure for 
experimental subjects relative to controls is 0.5, we will need to study 161 experimental subjects 
and 161 control subjects to be able to reject the null hypothesis that this relative risk equals 1 
with probability (power) 0.9.   The Type I error probability associated with this test of this null 
hypothesis is 0.05.   
5.2 STUDY POPULATION 
 
5.2.1 PATIENT RECRUITMENT 
The recruitment strategies for CoNaN trial are targeted to specific groups in order to meet study 
goals with respect to patient enrollment and demographics.  Meeting these goals, which results in 
a study population that reflects the typical patient population with the disease/health 
characteristics of interest, is necessary for making informed conclusions based on data collected 
during the study. 
 
CoNaN trial will randomize 400 patients with a Mehran score ≥ 6 in a 1 x 1 trial of intravenous 
nitroglycerin versus intravenous saline only. All patients must complete informed consent 
process prior to being randomized into the trial. 
 
Patients will be recruited primarily from 2 different sites. (1) Mount Sinai Emergency 
department, once they are evaluated by cardiology and scheduled for a non-emergent 
catheterization. (2) Directly from the Mount Sinai Medical Center catheterization Laboratory. 
 
5.2.2 INCLUSION CRITERIA 
All of the following inclusion criteria must be present for the patient to be enrolled in the trial. 
1- Patient must be scheduled for percutaneous angiography, defined as diagnostic cardiac 
catheterization, or lower extremity or aortic iodinated contrast angiography.  
2- Patients must have a Mehran score of at least 6 before the procedure.  
3- Patients must have baseline creatinine and hemoblogin drawn before the procedure. 
4- Signed informed consent. 
 
5.2.3 EXCLUSION CRITERIA 
None of the following exclusion criteria must be present for the patient to be enrolled in the trial 

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1- Patients on renal replacement therapy before randomization, will be excluded. 
2- Being exposed to any types of nitrates 48 hours prior to randomization,  
3- History of allergic reaction to any of the components of intravenous nitroglycerin. 
4- Exposure to contrast media 4 days prior randomization. 
5- Planned revascularization in the next 24 to 48 hours of the first PCI procedure. 
6- The patient is hypotensive (<90/60mmHg) at the time of randomization. 
7- Patients exposed to phosphodiesterase inhibitors 48 hours prior to randomization 
 
 
5.2.4 SCREENING AND BASELINE EVALUATION 
Potentially eligible patients will undergo an initial evaluation in which eligibility will be 
confirmed and the trial protocol explained in detail. All willing and eligible patients providing 
informed consent will have baseline data obtained including relevant history and use of all 
conventional and alternative therapies. Baseline laboratory tests will be performed and 
information on quality of life will be obtained. 
 
The following variables will be obtained for all patients included in the trial: age, gender, weight, 
height, body mass index, blood pressure, left ventricular ejection fraction, hypertension, diabetes 
mellitus, peripheral vascular disease, medication use (angiotensin converting enzyme inhibitors, 
calcium channel blockers, beta blockers, statins, ascorbic acid, acetylcysteine, angiotensin 
receptor blockers, diuretics, aspirin), PCI (number of vessels) smoking status, amount of 
contrast, type of contrast, amount of hydration, serum hemoglobin, serum sodium, serum 
potassium, baseline creatinine and post procedure creatinine, glomerular filtration rate. 
 
 
5.2.5 RANDOMIZATION 
After inclusion and exclusion criteria verification, coordinator will complete the randomization 
screen, in the system. The patients will be randomly assigned to one of the two treatment arms. 
The coordinator will order the treatment in the patient’s chart and start the pre-stocked infusion. 
The infusions will consist in intravenous nitroglycerin in addition to Intravenous Saline or 
Intravenous saline. 
We will randomize using a computer generated pre-set list. The computer program will randomly 
assign a letter (A or B) to each individual case up to 400 cases.  The trial coordinator and the 
pharmacist will be the only un-blinded persons that will have access to the randomization list. In 
case that for safety reasons an investigator must know if the patient is receiving the experimental 
therapy or not, a copy of the randomization list will be held at the coordinator’s office.  
 
5.3 STUDY ALGORYTHM 

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To achieve our primary and secondary end-points we will (1) screen patients in the 
catheterization lab and/or emergency department of Mount Sinai Medical Center. (2) After 
inclusion and exclusion criteria’s are verified, informed consent will be signed by the patient. (3) 
a case report form will be completed. (4) The research staff will order a treatment protocol to be 
administered. (5) Laboratory studies will be performed if needed. (6) The patients will receive an 
intravenous infusion of nitroglycerin and/or saline for at least 1 hour. (7) Coronary angiography 
will be performed and another screening for exclusion criteria will be done by the coordinator 
and assistant investigators. (8) Variables such as volume of contrast and number of vessels 
stented will be obtained. (9) Patients will go to recovery area and another infusion will be started 
for another 3 hours. (10) 48 hours later patient will be contacted to come to the hospital for 
another set of laboratory studies or patients that stayed in the hospital will be contacted and all 
the information needed will be completed.  
 
5.4 TREATMENT REGIMENS 
Continuous intravenous infusion of nitroglycerin 5 mcg/min will be started and titrated every 3-5 
minutes for a maximum of 100 mcg/minute if tolerated by blood pressure (>100/60mmHg), at 
least 1 hour before and 3 hours after the procedure. The nitroglycerin for infusion comes in a pre-
mixed 250 ml bottle, with a concentration of 200 mcg/ml. 
Intravenous sodium chloride 0.9%, will be administered at 1ml/kg/hr at least 1 hours before the 
procedure and at least 3 hours after for both treatment arms. If the ejection fraction is known to 
be less than 40% or patient have signs and symptoms of volume overload, a 0.5 ml/kg/hr 
regimen will be utilized. If the patient is in acute congestive heart failure, no intravenous fluids 
will be given. 
5.4.1 NITROGLYCERIN PHARMACOLOGY 
Nitroglycerin is a vasodilator and antianginal agent, that can be administer intravenously, orally, 
intra-anal, as a topical agent, as a patch, sublingual and as a translingual spray.  In our study it 
will be administered via intravenous infusion as previously specified by the protocol.  
 
5.4.1.1 NITROGLYCERIN HUMAN TOXICITY 
Nitroglycerin serious adverse reactions include severe hypotension, nitrates tolerance, 
bradycardia, anaphylactoid reactions, and methemoglobinemia. Other common reactions include 
headaches, lightheadedness, dizziness, flushing, orthostatic hypotension, reflex tachycardia, 
edema, burning oral sensation (sublingual use) and tingling oral sensation (sublingual use).  
 
 
5.4.1.2 SEVERE HYPOTENSION 

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The most common adverse effect of Nitroglycerin is hypotension. Nitroglycerin forms free 
radical nitric oxide. In smooth muscle, nitric oxide activates guanylate cyclase which increases 
guanosine 3’5’ monophosphate (cGMP) leading to dephosphorylation of myosin light chains and 
smooth muscle relaxation. This produces a vasodilator effect on the peripheral veins and arteries 
with more prominent effects on the veins, decrease preload (left ventricular end-diastolic 
pressure); may modestly reduce afterload. This can lead to severe hypotension and paradoxical 
bradycardia and increased angina pectoris can accompany hypotension.  
5.4.1.3 METHEMOGLOBINEMIA 
Methemoglobinemia is an uncommon side effect of nitroglycerin use.  Methemoglobin is an 
oxidized form of hemoglobin that has a decreased affinity for oxygen, resulting in an increased 
affinity of oxygen to other heme sites and overall reduced ability to release oxygen to tissues. 
The oxygen-hemoglobin dissociation curve is therefore shifted to the left when it’s present. 
When methemoglobin concentration is elevated in red blood cells, tissue hypoxia can occur. The 
protective enzyme systems normally present in red blood cells maintain methemoglobin levels at 
less than one percent of the total hemoglobin in healthy people. Exposure to exogenous oxidizing 
drugs and their metabolites such is nitrates may accelerate the rate of formation of 
methemoglobin up to one-thousand fold, overwhelming the protective enzyme systems and 
acutely increasing methemoglobin levels. 
 
5.4.1.4 NITROGLYCERIN DRUG TO DRUG INTERACTIONS 
Nitroglycerin is relatively save medication. Some medications can cause severe or fatal adverse 
reactions. Interaction risk stratification is done following the following classification:  
 
A - No known interaction 
B - No action needed 
C - Monitor therapy 
D - Consider therapy modification 
X - Avoid combination 
 
 
 Alfuzosin: May enhance the hypotensive effect of Nitroglycerin. Risk C: Monitor 
therapy 
 Alteplase: Nitroglycerin may decrease the serum concentration of Alteplase. Risk 
C: Monitor therapy 

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 Ergot Derivatives: May diminish the vasodilatory effect of Nitroglycerin. This is 
of particular concern in patients being treated for angina. Nitroglycerin may 
increase the serum concentration of Ergot Derivatives. Risk X: Avoid combination 
 Heparin: Nitroglycerin may diminish the anticoagulant effect of Heparin. 
Nitroglycerin may decrease the serum concentration of Heparin. Risk C: Monitor 
therapy 
 Hypotensive Agents: May enhance the adverse/toxic effect of other Hypotensive 
Agents. Risk C: Monitor therapy 
 Phosphodiesterase 5 Inhibitors: May enhance the vasodilatory effect of 
Vasodilators (Organic Nitrates). Risk X: Avoid combination 
 Prilocaine: 
Methemoglobinemia 
Associated 
Agents 
may 
enhance 
the 
adverse/toxic effect of Prilocaine. Combinations of these agents may increase the 
likelihood of significant methemoglobinemia. Management: Monitor patients for 
signs of methemoglobinemia (e.g., hypoxia, cyanosis) when prilocaine is used in 
combination 
with 
other 
agents 
associated 
with 
development 
of 
methemoglobinemia. Avoid lidocaine/prilocaine in infants receiving such agents. 
Risk C: Monitor therapy 
 Rosiglitazone: Vasodilators (Organic Nitrates) may enhance the adverse/toxic 
effect of Rosiglitazone. Specifically, a greater risk of myocardial ischemia was 
reported for users of this combination in a meta-analysis. Management: Consider 
alternatives to this combination when possible. Rosiglitazone prescribing 
information states that the combination of rosiglitazone and a nitrate is not 
recommended. Risk D: Consider therapy modification 
 Ethanol: Avoid ethanol (may increase the hypotensive effects of nitroglycerin). 
Monitor. 
 
Herb/Nutraceutical: Avoid bayberry, blue cohosh, cayenne, ephedra, ginger, 
ginseng (American), kola; licorice (may worsen hypertension). Avoid black 
cohosh, California poppy, coleus, golden seal, hawthorn, mistletoe, periwinkle, 
quinine, shepherd's purse (may cause hypotension).  
 
 
6.0 THE USE OF NITRATES FOR THE PREVENTION OF CIN 
See retrospective study attached - Exhibit A 

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7.0 BUDGET  
 
See Budget proposal attached- Exhibit B 
 
 
 
8.0 REFERENCES 
(1) Katholi RE, Taylor GJ, McCann WP, et al. Nephrotoxicity from contrast media attenuation 
with theophylline. Radiology 1995;195:17-22. 
 
(2) Manske CL, Sprafka JM, Strony JT, Wang Y. Contrast nephropathy in azotemic diabetic 
patients undergoing coronary angiography. Am J Med 1990;89:615-620.  
 
(3) Barrett BJ. Contrast nephrotoxicity. J Am Soc Nephrol 1994;5:125-137.  
 
(4) Parfrey PS, Griffiths SM, Barrett BJ, et al. Contrast material-induced renal failure in 
patients with diabetes mellitus, renal insufficiency, or both. A prospective controlled study. 
N Engl J Med 1989;320:143-149.  
 
(5) Cigarroa RG, Lange RA, Williams RH, Hillis LD. Dosing of contrast material to prevent 
contrast nephropathy in patients with renal disease. Am J Med 1989;86:649-652.  
 
(6) Lautin EM, Freeman NJ, Schoenfeld AH, et al. Radiocontrast-associated renal dysfunction: 
incidence and risk factors. Am J Roentgenol 1991;157:49-58. 
 
(7) Barrett BJ, Parfrey PS, Vavasour HM, et al. Contrast nephropathy in patients with impaired 
renal function: high versus low osmolar media. Kidney Int 1992;41:1274-1279.  
 
(8) Weinrauch LA, Healy RW, Leland OS Jr, et al. Coronary angiography and acute renal 
failure in diabetic azotemic nephropathy. Ann Intern Med 1977;86:56-59. 
 
(9) Zhang T, Shen LH, Hu LH, He B. Statins for the prevention of contrast-induced 
nephropathy: a systematic review and meta-analysis. Am J Nephrol 2011;33:344-351. 
 
(10) McCullough PA, Wolyn R, Rocher LL, et al. Acute renal failure after coronary intervention: 
incidence, risk factors, and relationship to mortality. Am J Med 1997;103:368-375. 
 
(11) Agmon Y, Peleg H, Greenfeld Z, et al. Nitric oxide and prostanoids protect the renal outer 
medulla from radiocontrast toxicity in the rat. J Clin Invest 1994; 94:1069-1075.  
 
(12) Heyman SN, Rosenberger C, Rosen S. Regional alterations in renal haemodynamics and 
oxygenation: a role in contrast medium-induced nephropathy. Nephrol Dial Transplant 
2005; 20:i6-i11. 

 [CONAN TRIAL] 
Version  5 April 14, 2015 
 
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16 
 
(13) Devrim E, Cetin M, Namuslu M, et al. Oxidant stress due to non ionic low osmolar contrast 
medium in rat kidney. Indian J Med Res 2009; 130:433-436. 
 
(14) Rudnick M, Tumlin J. Pathogenesis, clinical features, and diagnosis of contrast-induced 
nephropathy. In: www.uptodate.com, Basow, DS (Ed), UpToDate, Waltham, MA, 2011. 
 
(15) Persson PB, Hansell P, Liss P. Pathophysiology of contrast medium-induced nephropathy. 
Kidney Int 2005;68:14-22. 
 
(16) Heyman SN, Rosenberger C, Rosen S. Regional alterations in renal haemodynamics and 
oxygenation: a role in contrast medium-induced nephropathy. Nephrol Dial Transplant 
2005; 20:i6-i11. 
 
(17) Efrati S, Dishy V, Averbukh M, et al. The effect of N-acetylcysteine on renal function, nitric 
oxide, and oxidative stress after angiography. Kidney Int 2003; 64:2182-2187. 
 
(18) Efrati S, Berman S, Ilgiyeav I, et al. Differential effects of N-acetylcysteine, theophylline or 
bicarbonate on contrast-induced rat renal vasoconstriction. Am J Nephrol 2009;29:181-191. 
 
(19) Brezis M, Heyman SN, Dinour D, et al. Role of nitric oxide in renal medullary oxygenation. 
Studies in isolated and intact rat kidneys. J Clin Invest 1991; 88:390-395.  
 
(20) Corwin S, Reiffel JA. Nitrate therapy for angina pectoris. Current concepts about 
mechanism of action and evaluation of currently available preparations. Arch Intern Med 
1985; 145:538-543.  
 
(21) Mehran R, Aymong ED, Nikolsky E, et al. A simple risk score for prediction of contrast-
induced nephropathy after percutaneous coronary intervention: development and initial 
validation. J Am Coll Cardiol 2004; 44:1393-1399. 
 
(22) Pannu N, Wiebe N, Tonelli M. Alberta Kidney Disease Network. Prophylaxis strategies for 
contrast-induced nephropathy.  JAMA 2006;295:2765-2779. 
 
(23) Kshirsagar AV, Poole C, Mottl A, et al. N-acetylcysteine for the prevention of radiocontrast 
induced nephropathy: a meta-analysis of prospective controlled trials. J Am Soc Nephrol 
2004;15:761-769.  
 
(24) Fishbane S. N-acetylcysteine in the prevention of contrast-induced nephropathy. Clin J Am 
Soc Nephrol 2008;3:281-287.  
 
(25) Efrati S, Berman S, Ilgiyeav I, et al. Differential effects of N-acetylcysteine, theophylline or 
bicarbonate on contrast-induced rat renal vasoconstriction. Am J Nephrol 2009;29:181-191. 
 

 [CONAN TRIAL] 
Version  5 April 14, 2015 
 
MOUNT SINAI MEDICAL CENTER | CoNaN Trial 
17 
 
(26) Hamsuddin AA, Kowalik KJ, Bjarnason H, et al. Using a dopamine type 1A receptor 
agonist in high-risk patients to ameliorate contrast-associated nephropathy. AJR Am J 
Roentgenol 2002; 179:591-596. 
 
(27) Russo D, Minutolo R, Cianciaruso B, et al. Early effects of contrast media on renal 
hemodynamics and tubular function in chronic renal failure. J Am Soc Nephrol 
1995;6:1451-1458.  
 
(28) Spargias K, Adreanides E, Demerouti E, et al. Iloprost prevents contrast-induced 
nephropathy in patients with renal dysfunction undergoing coronary angiography or 
intervention. Circulation 2009; 120:1793-1799.  
 
(29) Ix JH, McCulloch CE, Chertow GM. Theophylline for the prevention of radiocontrast 
nephropathy: a meta-analysis. Nephrol Dial Transplant 2004; 19:2747-2753.  
 
(30) Xinwei J, Xianghua F, Jing Z, Xinshun G, Ling X, Weize F, et al. Comparison of usefulness 
of simvastatin 20 mg versus 80 mg in preventing contrast-induced nephropathy in patients 
with acute coronary syndrome undergoing percutaneous coronary intervention. Am J 
Cardiol 2009: 104(4):519-24. 
 
(31) Patti G, Ricottini E, Nusca A, Colonna G, Pasceri V, D'Ambrosio A, et al. Short-term, high-
dose Atorvastatin pretreatment to prevent contrast-induced nephropathy in patients with 
acute coronary syndromes undergoing percutaneous coronary intervention (from the 
ARMYDA-CIN [atorvastatin for reduction of myocardial damage during angioplasty--
contrast-induced nephropathy] trial. Am J Cardiol 2011: 108(1):1-7. 
 
(32) Toso A, Maioli M, Leoncini M, Gallopin M, Tedeschi D, Micheletti C, et al. Usefulness of 
atorvastatin (80 mg) in prevention of contrast-induced nephropathy in patients with chronic 
renal disease. Am J Cardiol 2010: 105(3):288-92.  
 
(33) Quintavalle C, Fiore D, De Micco F, Visconti G, Focaccio A, Golia B, et al. Impact of a 
High Loading Dose of Atorvastatin on Contrast-Induced Acute Kidney Injury. Circulation 
2012: Nov 12.  
 
(34) Briguori C, Visconti G, Focaccio A, Airoldi F, Valgimigli M, Sangiorgi GM, et al. Renal 
Insufficiency After Contrast Media Administration Trial II (REMEDIAL II): RenalGuard 
System in high-risk patients for contrast-induced acute kidney injury. Circulation 2011: 
124(11):1260-9.