Nitroglycerin prevents radial artery occlusion: the NORAO study

1. Post-Procedural/Pre-Hemostasis
Intra-Arterial Nitroglycerin:
A Prospective, Randomized Trial
Evaluating Intra-Sheath
Nitroglycerin to Improve Arterial
Patency After Transradial
Catheterization
(ClinicalTrials.gov Identifier: NCT02105493)
Surya Dharma*, MD, PhD, Sasko Kedev, MD, PhD, Tejas
Patel, MD, Ferdinand Kiemeneij, MD, PhD, Ian Gilchrist, MD
*Department of Cardiology and Vascular Medicine
Faculty of Medicine, University of Indonesia
National Cardiovascular Center Harapan Kita
Jakarta, Indonesia

2. Disclosure Statement of Financial Interest
I, Surya Dharma, DO NOT have a financial
interest/arrangement or affiliation with one or more
organizations that could be perceived as a real or apparent
conflict of interest in the context of the subject of this
presentation.

3. Introduction
• Despite trans-radial access (TRA) increasing
acceptance, radial artery occlusion (RAO)
continues to be one of the limitations of TRA
and potentially limits the radial artery as an
access site in the future.
• Currently, there is no data whether vasoactive
pharmacological therapy such as
nitroglycerin administered intra-arterially at
the end of the procedure may reduce the
incidence of RAO.

4. Main objective
• To evaluate whether administration of
nitroglycerin at the end of a trans-radial
procedure may preserve the patency of the
radial artery.
• Hypothesis: The addition of nitroglycerin
(nitric oxide donor) at the end of a TRA
procedure may preserve the patency of the
radial artery, thereby reduce the incidence of
RAO.

5. All patients undergoing trans-radial catheterization (N=1762)
Cocktail Administration
Catheterization procedure :
PCI, N =707
Coronary Angiography, N =1047
Others, N =8
Post procedure
56 pts were excluded due to:
-Hemodynamic Instability (25 pts)
-Nitrates intolerance (18 pts)
-Refuse to participate (13 pts)
Randomization
Figure 1. Flow Chart
Study design:
Multi-center, prospective,
randomized, placebo-controlled
trial involving three
experienced radial centers in
Indonesia, India, and
Macedonia
Each of the centers has
extensive experience in trans-radial
procedures (>80% TRA)

6. 500 μg NTG intra sheath
N =853
Placebo (saline) intra sheath
N =853
Randomization
Post Administration
Hemostasis Compression
One day Duplex ultrasonography of the arm:
Anterograde flow of the radial artery
Primary outcome:
The incidence of RAO
as confirmed by
absence of antegrade
flow at one day after
the trans-radial
procedure evaluated by
duplex ultrasound of
the radial artery
Figure 1. Flow Chart

7. Figure 2. Sheath position (A) and Doppler
evaluation (B)

8. Results
Table 1. Baseline clinical characteristics.
Variables All patients
n = 1706
Nitroglycerin
group
n = 853
Placebo
group
n = 853
P
Value
Age, years 59.27±10.37 59.15±10.53 59.38±10.23 0.654
Male gender, N (%) 1167 (68%) 589 (69%) 578 (68%) 0.567
Height, cm 168 (136-198) 167.81 ± 9.18 167.50±9.19 0.485
Weight, kg 75 (39-145) 75 (39-135) 74 (44-145) 0.737
Body Mass Index, kg/m2 26 (15-30) 26 (15-45) 26 (16-50) 0.685
Diabetes mellitus, N (%) 413 (24%) 212 (25%) 201 (23%) 0.534
Acute Coronary Syndrome, N (%) 486 (28%) 241 (28%) 245 (29%) 0.830
Glycoprotein IIb/IIIa inhibitor use, N (%) 3 (0.2%) 1 (0.1%) 2 (0.2%) 1.000
Procedure, N (%)
Coronary angiography 1025 (60%) 515 (60%) 510 (59%)
PCI 677 (39%) 337 (39%) 340 (39%) 0.582
Others 4 (0.2%) 1 (0.1%) 3 (0.3%)
Continuous data are presented as mean ± SD or median (min–max).
PCI=percutaneous coronary intervention.

9. Table 2. Procedural Characteristics.
Variables All patients
n = 1706
Nitroglycerin
group
n = 853
Placebo
group
n = 853
P
Value
Right radial artery access, N(%) 1684 (98%) 840 (98%) 844 (99%) 0.391
First radial procedure, N (%) 1375 (81%) 685 (80%) 690 (81%) 0.760
Repeated radial access, N (%) 331 (19%) 168 (20%) 163 (19%) 0.760
Radial puncture attempt, N(%)
Single puncture 1499 (88%) 750 (88%) 749 (88%) 0.941
Puncture technique, N (%)
Counter-puncture 548 (32%) 299 (35%) 249 (29%) 0.01
Sheath size, N (%)
5F 496 (29%) 257 (30%) 239 (28%) 0.337
6F 1207 (71%) 595 (70%) 612 (72%) 0.311
7F 2 (0.1%) 0 2 (0.2%) 0.500
8F 1 (0.05%) 1 (0.1%) 0 1.000
Heparin dose, IU 5000 (2500-
17,000)
5000 (2500-
17,000)
5000 (5000-
15,000) 0.613
Spasmolytic cocktails, N (%)
200 μg nitroglycerin 513 (30%) 278 (32%) 235 (27%) 0.023
300 μg nitroglycerin 175 (10%) 87 (10%) 88 (10%) 0.936

10. Table 2. Procedural Characteristics.
Variables All patients
n = 1706
Nitroglycerin
group
n = 853
Placebo
group
n = 853
P
Value
5 mg diltiazem 1018 (60%) 488 (57%) 530 (62%) 0.038
Route of heparin administration, N (%)
Intravenous 1547 (91%) 777 (91%) 770 (90%) 0.560
Procedural Time, minute 20 (1-240) 20 (1-120) 20 (1-240) 0.095
Hemostasis device, N (%)
TR-Band 1309 (77%) 670 (78%) 639 (75%) 0.075
Duration of hemostasis, hours 6.31 ± 5.72 6.72 ± 6.28 5.89 ± 5.08 0.160
Duration of hemostasis, N (%)
≤ 4 h 1153 (68%) 568 (66%) 585 (68%)
0.379
> 4 h 553 (32%) 285 (33%) 268 (31%)
Severe RAS, N (%) 13 (0.8%) 5 (0.8%) 8 (0.9%) 0.404
Residual arm pain pre-discharge, N (%) 76 (4.5%) 40 (4.7%) 36 (4.2%) 0.639
Hematoma EASY score >3, N (%) 0 0 0 NS
Symptom of hand ischemia, N (%) 0 0 0 NS
Continous data are presented as median (min–max) or mean ± SD. RAS= radial artery spasm.

11. Table 3. Study outcome evaluated by doppler
ultrasound of the arteries at one day after the
trans-radial catheterization.
Variables All patients
n = 1706
Nitroglycerin
group
n = 853
Placebo
group
n = 853
P
Value
Presence of RAO, N (%) 170 (9.9%) 70 (8.3%) 100 (11.7%) 0.015
Radial artery diameter, mm 2.78 ± 0.55 2.8 ± 0.52 2.77 ± 0.58 0.217
Ulnar artery diameter, mm 2.40 ± 0.42 2.41 ± 0.40 2.40 ± 0.43 0.732
RAO= radial artery occlusion.

12. 11.7 %
110000//885533
12
9
6
3
0
8.3 %
p= 0.015
Incidence of RAO
70/853
Nitroglycerin group Placebo group
Figure 3. Primary Outcome of The Study.

13. Use of nitroglycerin
Age > 65 years
Male gender
Diabetes Mellitus
Body Mass Index > 25kg/m2
Multiple puncture attempt
Hemostatic compression >4h
Repeated radial access
Counter puncture technique
Use of > 6F sheath
Procedural time > 60 minutes
Several radial artery spasm
OR = 0.62; 95% CI 0.44 – 0.87, p = 0.006
OR = 1.15; 95% CI 0.79 – 1.70, p = 0.463
OR = 0.99; 95% CI 0.68 – 1.43, p = 0.958
OR = 1.12; 95% CI 0.78 – 1.62, p = 0.532
OR = 0.82; 95% CI 0.57 – 1.13, p = 0.208
OR = 0.90; 95% CI 0.52 – 1.55, p = 0.710
OR = 3.11; 95% CI 1.66 – 5.82, p < 0.001
OR = 1.22; 95% CI 0.81 – 1.85, p = 0.331
OR = 1.65; 95% CI 0.89 – 3.08, p = 0.109
OR = 1.07; 95% CI 0.69 – 1.64, p = 0.758
OR = 0.69; 95% CI 0.24 – 1.99, p = 0.495
OR = 2.38; 95% CI 0.69 – 8.24, p = 0.170
0 1 2 3 4 5 6 7 8
Figure 4. Multivariate predictors of RAO.
OR= odds ratio, CI= confidence interval.

14. Discussion
• A mechanism where by nitroglycerin (nitrous oxide donor)
may reduce the rate of RAO, is thought to be through its
vasodilatory effect of nitrous oxide.
• The dose of 500 μg nitroglycerin would have achieved a
maximal vasodilatory effect and expected to decrease the
intimal inflammation and intimal hyperplasia of the radial
artery.
• It is hypothesized that 500 μg of nitroglycerin would make a
vasodilation dominancy (through nitrous oxide) in the
endothelium of the radial artery that would pharmacologically
enhance flow, supporting a higher level of patency to preserve
the radial artery during a hemostasis compression.

15. • RAO as detected by ultrasound in this study was
9.9%. Other studies reported the incidence of
RAO varying from 1.1% to 38%. The present study
suggests that in the real world setting, the
incidence of RAO is higher than expected.
• The strong predictor for the development of RAO
showed from this study was the duration of
hemostasis (OR= 3.11).
• The consistent results with respect to the
duration of hemostasis compression give an
insight that earlier decompression has to be
implemented in our daily practice of TRA.

16. Study Limitation
• Due to the differences in hemostasis local
protocols and devices used, it was quite difficult
to apply a true patent hemostasis technique in all
patients.
• We did not perform a dose-ranging study nor
compare with other potentially more powerful
vasodilator agents.

17. Conclusion
• The administration of nitroglycerin through the
sheath at the end of a trans-radial catheterization
is associated with a reduced incidence of RAO,
one day after trans-radial procedures.
• This suggests that further evaluation of post-procedural
/ pre-hemostasis pharmacologic
regimens may be an important aspect of
minimizing the risks of RAO after radial
procedures.