Effects of Sublingual and Transdermal Administration of Nitroglycerin for Coronary CT Angiography on Image Quality
Phase: PHASE4
Conditions: Coronary Artery Disease
Sponsor: Massachusetts General Hospital

Effects of Sublingual and Transdermal Administration of 
Nitroglycerin for Coronary CT Angiography on Image Quality 
 
NCT#: NCT02961946 
 
 
 
Study protocol and statistical analysis plan 
October 14, 2018 
 

Methods  
This study had a prospective, randomized controlled design conducted at a single, 
academic hospital and was approved by our institution’s review board, which required 
signed consent. The study was HIPAA compliant and registered at the Clinical Trials 
Registry (#NCT02961946) with the title “Effects of Sublingual and Transdermal 
Administration of Nitroglycerin for Coronary CT Angiography on Image Quality”. 
Based on prior literature, we hypothesized that mean coronary artery diameter before and 
after nitroglycerin application would be 2.86 mm and 3.26 mm, respectively, with 13.8% 
vasodilation (13). We assumed an equivalence range of 3% and determined a type-I error 
of (0.05/3=0.017) for a 3-group comparison with 80% power. In total, 198 individuals and 
66 individuals per arm were necessary for a 3-group comparison.  
Coronary artery vasodilation was the primary outcome. Secondary outcomes included 
changes in vital signs and frequency of side effects after nitroglycerin application. The 
dependent variable was the method of nitroglycerin delivery which could be lingual, 
sublingual, or transdermal. 
Patient Selection 
We identified potential subjects from our clinical cardiac CT schedule and included those 
whose study required an ECG-gated non-contrast CT followed by CCTA acquisitions. 
Subjects with a history of coronary revascularization were included. Exclusion criteria 
were age under 18 years, known hypersensitivity to nitroglycerin, closed-angle glaucoma, 
use of phosphodiesterase type 5 inhibitors within 72 hours prior to the study, conditions 
associated with elevated intracranial pressure, hemodynamic instability, critical aortic 

stenosis, systolic blood pressure below 90 mmHg, pregnancy or lactating female, women 
with a positive urine pregnancy test, and subjects unwilling or unable to consent to 
participation.  
Study Workflow 
The physician enrolling the subject to the study was blinded to the method of nitroglycerin 
administration. After obtaining informed consent, subjects were randomized (block 
randomization, block size=198) to one of three nitroglycerin delivery methods: (1) 
sublingual as a tablet (2x0.4 mg, Nitrostat, Pfizer Inc., NY), (2) lingual as a spray (2x0.4 
mg, Nitrolingual, Pohl-Boskamp, Hohenlockstedt, Germany), or (3) transdermal as a 
patch (2x0.4 mg/h, Nitro-Dur, Merck&Co Inc., NJ). After assessing initial vital signs (heart 
rate, rhythm, and blood pressure), non-contrast CT was acquired. Subsequently, 
nitroglycerin was administered. Patches were placed on the upper chest, taking care to 
avoid body hair. The transdermal delivery method required an application time of at least 
45 minutes, while lingual and sublingual nitroglycerin required 5 minutes application time 
before CCTA acquisition (Figure 1). After CCTA, the patches were removed, and the 
location was inspected for skin reaction, while spray and tablets did not require further 
interaction. Next, we remeasured vital signs and asked for symptoms of allergic-type 
reactions and if sublingual tablets had completely dissolved. Systolic blood pressure >180 
mmHg or a drop of >10 mmHg compared to initial values required observation and follow-
up until normalization. Finally, patients filled out a query asking about side effects during 
the exam. 

Image Acquisition 
All individuals were scanned on a 128-slice dual-source CT (Somatom Definition Flash, 
Siemens Healthineers, Forchheim, Germany). Scan length was from carina to diaphragm 
and was extended if necessary. Scan parameters were as follows: non-contrast CT 
(prospectively-ECG-triggered at 350ms after the R wave, fixed 120kV, mA adjusted to 
body size, with a reference of 80 mAs [CareDose4D, Siemens Healthineers], 64x0.6mm 
collimation), CCTA (prospectively-ECG-triggered for heart rates <85 bpm, ≥85 bpm 
retrospectively-ECG-gated, with an acquisition window in late systole to early diastole 
(220-400 msec after the R-wave), 80-120kV with optimal kV [CarekV, Siemens 
Healthineers] and automatic mA selection based on the scout scan, reference 280 mAs, 
64x0.6mm collimation). No beta-blocker was administered, as per our standard site 
practice.  
Images were reconstructed using iterative reconstruction algorithm (strength level 3/5, 
Admire, Siemens Healthineers) with 0.6 mm slice thickness at 350ms for non-contrast 
images and 220-440ms (20ms intervals) for CCTA images. All studies were blinded as to 
the nitroglycerin delivery method. Coronary calcium scores (Agatston method) and 
severity of any coronary artery disease were assessed from the radiology reports. 
Quantitative Analysis 
A 
cardiovascular 
imaging-trained 
radiologist 
with 
six 
years 
of 
experience 
(X.X.)(anonymized) measured coronary diameters at seven locations (Figure 2) using a 
3D-workstation (Aquarius v.4.4.12, Terarecon Inc., Foster City, CA). These locations 
were predetermined as: (1) proximal right coronary artery (RCA) 1.5 cm distal from the 
ostium; (2) mid RCA 1.0 cm proximal of the acute marginal branch; (3) distal RCA 1.0 cm 

proximal of the bifurcation into posterior descending artery and right postero-lateral 
branch; (4) middle of the left main (LM); (5) proximal left anterior descending artery (LAD) 
1.0 cm after LM bifurcation or, if less distance to the 1st diagonal branch, in the middle of 
the proximal LAD; (6) mid LAD 2.0 cm distal of 1st diagonal branch or if less distance to 
the 2nd diagonal branch, in the middle of mid LAD; and (7) left circumflex coronary artery 
2.0 cm distal of the LM bifurcation. Positions were located in the non-contrast images and 
reaffirmed on CCTA images using a corresponding phase of the cardiac cycle. Locations 
with non-calcified or calcified plaques or unclear depiction of the coronary artery due to 
adjacent structures such as veins were avoided, and in those segments, the location of 
measurement was moved distally up to 1.0 cm from the original position while staying in 
the same coronary segment and avoiding bifurcations. If coronary diameters could not be 
measured at any of these positions, the location was excluded. We excluded stented or 
bypassed locations from measurements. All coronary diameters were measured twice at 
each location using short-axis views in an enlarged field-of-view and averaged using 
window width and level of 350 HU and 50 HU for non-contrast and 800 HU and 200 HU 
for CCTA images (Figure 2). Window settings were set based on preliminary 
measurements in 20 patients who underwent CCTA without nitroglycerin and therefore 
no diameter differences in non-contrast and CCTA images. Locations #1, #4, and #5 were 
defined as proximal-, locations #2 #6, and #7 as mid-, and location #3 as distal coronary 
segments.  

Safety 
By query, side effects were evaluated, including headache, dizziness, and nausea during 
the exam. The severity of headache was quantified on a 10-point scale ranging from 1 
minimal- to 10 maximal-intensity.  
 
Statistical Analysis 
Demographic and scan parameter summaries were calculated for the entire subject 
cohort and by nitroglycerin administration method. Categorical variables were 
summarized using frequencies and percentages, while continuous variables were 
summarized as means and standard deviations, or as median and interquartile range 
(25th and 75th percentiles) if the distribution of the variables were skewed. Differences in 
continuous variables by treatment were assessed using the Kruskal-Wallis test, and 
differences in categorical variables were assessed using either the Pearson χ2 test, or 
Fisher’s exact test.  Changes of vital parameters pre- and posttreatment were compared 
using paired t-test.   
A linear quantile (median) mixed-effects model was constructed to quantify the 
unadjusted association between treatment and vasodilation (contrast diameter/non-
contrast diameter x 100) while accounting for dependencies within the data set due to 
multiple observations per subject. This modeling approach permitted the estimation of the 
median vasodilation as a function of covariates while avoiding the parametric modeling 
assumptions that are typically associated with linear mixed models. Estimates of fixed-
effects, and their 95% Wald-type confidence intervals, were computed for all model 

parameters. Linear combinations of these parameters were used to estimate overall 
effects, and effects by treatment.  
Two additional models were constructed where we hierarchically accounted for patient 
demographics (i.e., age, gender, BMI and height) and then by patient demographics and 
disease severity measure (i.e., CA score). A subgroup analysis was performed where 
model parameters were estimated by proximal, mid and distal regions. Due to the 
explorative nature of this subgroup analysis, p-values were not adjusted for multiple 
comparisons. 
All analyses were performed using R 3.4.3 (R-Core Team, 2017, Vienna, Austria)  (20) 
and the lqmm R library (21).