Clinical trial NCT03158532
Conditions: Injury of Radial Artery
Sponsor: Instituto de Cardiologia de Santa Catarina
Start date: 2017-07-06; Completion date: 2021-11-01
Enrollment: 2040 participants; Allocation: RANDOMIZED; Intervention model: FACTORIAL

Brief summary:
The radial approach for a coronary angiography has became popular in several centers because of its simplicity and fewer complications. The radial artery occlusion (RAO) is the main inconvenient and impose a limitation of future use of the radial artery as an access site for catheterization in the future. Several strategies have been used to decrease the incidence of RAO (heparin, patent hemostasis, etc). Nitrates in intra-arterial have been widely studied in prevention of this spasm. Current data show that nitroglycerin intra-arterial at the end of the procedure reduce the incidence of RAO. The hypothesis that use of nitroglycerin at the start of catheterization would have the same effect was not tested.

Detailed description:
Transradial access (TRA) has been increasingly adopted for diagnostic and interventional cardiovascular procedures in many centers worldwide. This is largely driven by the evidence supporting an unequivocal reduction in access site-related complications associated with TRA compared with transfemoral access, as well as reduction in cost and increased patient comfort. The radial artery occlusion (RAO) is the main inconvenient and impose a limitation of future use of the radial artery as an access site for catheterization in the future. RAO is the most commun complication of transradial access, and its incidence continues to reach up to 12%.

Nitrates in intra-arterial have been widely studied in prevention of this spasm. Nitroglycerin binds to the surface of endothelial cells and undergoes two chemical reductions to form nitric oxide (NO). The nitric oxide then moves out of the endothelial cell and into an adjacent smooth muscle cell, where it promotes the formation of cyclic guanosine monophosphate (cGMP), which then promotes muscle relaxation. Current data show that nitroglycerin intra-arterial at the end of the procedure reduce the incidence of radial artery occlusion.

A big sheath to artery size ratio could reduce the incidence of RAO, so the main objective of this study is to evaluate whether administration of nitroglycerin at the start of a transradial procedure may preserve the patency of the radial artery; as well, confirm if nitroglycerin administration just before sheet removal helps to keep the radial artery patency.

Arms: arm 1: 0,9% Saline 10 mL was given intra-arterially through the sheath at the start of a transradial procedure (right after sheath placement) and 0,9% Saline 10 mL was given intra-arterially through the sheath at the end of procedure (just before sheath removal). arm 2: 500 microgram of Nitroglycerin (in 10 mL saline) was given intra-arterially through the sheath at the start of a transradial procedure (right after sheath placement) and 0,9% Saline 10 mL was given intra-arterially through the sheath at the end of procedure (just before sheath removal). arm 3: 0,9% Saline 10 mL was given intra-arterially through the sheath at the start of a transradial procedure (right after sheath placement) and 500 microgram of Nitroglycerin (in 10 mL saline) was given intra-arterially through the sheath at the end of procedure (just before sheath removal). arm 4: 500 microgram of Nitroglycerin (in 10 mL saline) was given intra-arterially through the sheath at the start of a transradial procedure (right after sheath placement) and 500 microgram of Nitroglycerin (in 10 mL saline) was given intra-arterially through the sheath at the end of procedure (just before sheath removal).
Interventions: intervention 1: Nitroglycerin I intervention 2: Placebo I intervention 3: Nitroglycerin II intervention 4: Placebo II
Intervention descriptions: intervention 1: 500 microgram of Nitroglycerin intra-arterially administered through the radial sheath, right after sheath placement and before catheterization. intervention 2: Saline 0,9% intra-arterially administered through the radial sheath, right after sheath placement and before catheterization. intervention 3: 500 microgram of Nitroglycerin intra-arterially administered through the radial sheath, just before sheath removal and before hemostasis. intervention 4: Saline 0,9% intra-arterially administered through the radial sheath, just before sheath removal and before hemostasis.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
Design and rationale of the Prevention of radial Artery occlusion after Transradial accEss using 
NitroglyceriN (PATENS) 
 
 
NCT03158532 
 
 
 
 
 
 
 
 
Florianópolis, dec/04/2024 
 
 


 
Design and rationale of the Prevention of radial Artery occlusion after Transradial accEss using 
NitroglyceriN (PATENS) 
 
Abstract 
 
 
Background 
 
Radial artery occlusion (RAO) is an important access site complications after transradial 
catheterization (TRC). Acute loss of radial artery patency after TRC is thought be due to a thrombotic 
process, and a bigger sheath-to-radial-artery ratio could reduce the incidence of RAO. Nitroglycerin 
acts through the liberation of nitric oxide (NO), which promotes muscle relaxation and vasodilation. 
Leading to a bigger sheath-to-radial-artery ratio the nitroglycerin administration could help to keep 
the radial artery patency. The aim is to study if nitroglycerin is superior to placebo concerning 
incidence of radial artery occlusion, confirmed by vascular Doppler ultrasound, up to 24 hours after 
catheterization. 
 
Methods/Design 
 
 
PATENS is a national, multicenter, superiority, 2-by-2 factorial, randomized clinical trial. Two 
thousand one hundred twenty-eight patients submitted to TRC will be randomized to either 
nitroglycerin or placebo, administered intra-arterially through the sheath, in two different moments 
during TRC: after the arterial sheath insertion, at the beginning of procedure, and at the end of the 
radial procedure, before sheath removal. 
 
Results 
 
 
The primary efficacy objective is to test the hypothesis that nitroglycerin, dose of 500 mcg, is 
superior to placebo in decreasing rates of radial artery occlusion on ultrasound Doppler analysis up 


to 24 hours after procedures. As secondary objectives, the trial will evaluate the incidence of radial 
artery occlusion 30 days after catheterization. Enrollment was initiated in August 2017, and the 
inclusion phase is expected to last until the second half of 2019. 
 
Conclusions 
 
 
The PATENS trial will help define the role of prophylactic nitroglycerin as a RAO avoidance strategy 
in patients with submitted to TRC. 
 
Trial registration 
 
 
ClinicalTrials.gov identifier: NCT03158532 
 
 
 
 
 
 
 
 
Background 
 
The use of the transradial approach (TRA) for coronary catheterization has increased over the years, 
worldwide. Radial artery is nowadays utilized by default for percutaneous coronary procedures in 
many centers, thanks to the reduced rates of vascular and bleeding complications and easier post- 
procedural management. The use of TRA also improves patient comfort, saves costs and it has an 
equivalent procedural success when compared to the femoral approach. 
Although it is widely accepted by cardiologists and patients, some problems still exist. One of the 
major limitations is the development of radial artery spasm (RAS), which can reduce success rates, 
leading to femoral conversion, and cause significant pain to patients. The incidence of RAS varies 
between 2% and 34%. Aiming prevent RAS, the use of prophylactic intraarterial vasodilators is 


routinely recommended by experts, mainly verapamil or nitroglycerin. Most catheterization 
laboratories habitually use some medication to prevent RAS, however, it is not a consensus. 
Another important complication, often underestimated, is the post-procedural radial occlusion 
(RAO). Incidence of radial pulse loss has been reported to range from 1% to 12%. The benign nature 
of such an event has been constantly emphasized due to the dual blood supply to hand from the 
palmar arch. Mostly, the occurrence of radial occlusion is asymptomatic, symptomatic radial 
occlusion requiring medical attention occurred in only 0.2% of patients, but hand ischemia caused 
by RAO has been described. The most important aspect is that once artery is occluded, it can not be 
used neither as access site for future catheterization, nor be used as a conduit for bypass surgery nor 
fistula formation in hemodialysis patients. The use of small caliber catheters, adequate dose of 
heparin administration, immediate sheath removal after procedure, patent hemostasis technique 
and short time of compressive bandage are the key elements to reduce the risk of artery occlusion. 
Notably the presence of radial pulse does not exclude radial occlusion due to presence of collateral 
circulation; it can be more accurately evaluated by absence of antegrade flow in vascular doppler 
ultrasound. In fact, many operators do not assess radial artery patency before discharge. 
Acute loss of radial artery patency after cardiac catheterization is thought to be due to a thrombotic 
process. Sheath insertion leads to local endothelial injury and cessation of blood flow in the radial 
artery, creating an environment conducive to thrombosis. RAO tends to occur early after transradial 
catheterization, and roughly 50% of patients have spontaneous recanalization of the artery within 1 
month. Direct support for the thrombotic hypothesis has come from recent studies that have 
confirmed the presence of radial artery thrombus on vascular ultrasound, angiography, and 
pathology. Transradial catheterization can negatively affect radial artery structure as well. A study 
using optical coherence tomography found that 67% of radial arteries had intimal tears and 36% had 
medial dissections immediately after transradial PCI. A study of radial artery function after 
transradial catheterization found that flow-mediated dilatation was blunted up to 9 weeks. The 


radial artery response to nitroglycerin was also decreased, suggesting that the impairment in 
function was more than just temporary damage to the endothelium and involved long-term changes 
to the smooth muscle layer. 
Nitrates in intra-arterial have been widely studied in prevention of spasm. Nitroglycerin binds to the 
surface of endothelial cells and undergoes two chemical reductions to form nitric oxide (NO). The 
nitric oxide then moves out of the endothelial cell and into an adjacent smooth muscle cell, where it 
promotes the formation of cyclic guanosine monophosphate (cGMP), which promotes muscle 
relaxation. A bigger sheath-to-radial-artery ratio could reduce the incidence of RAO, indeed current 
data show that nitroglycerin intra-arterial at the end of the procedure reduce the incidence of radial 
artery occlusion, so the main objective of this study is to evaluate whether administration of 
nitroglycerin at the start of a transradial procedure may preserve the patency of the radial artery; as 
well, confirm if nitroglycerin administration just before sheet removal helps to keep the radial artery 
patency, probably mediated by vasodilation. 
 
 
Methods 
 
This is a randomized, multicenter, double-blind, placebo-controlled phase III study (Clinicaltrials.gov 
identifier NCT 03158532) with an all-comers design, comparing the use of nitroglycerin to decrease 
the rate of radial artery occlusion after transradial catheterization. Using a 2-by-2 factorial design, 
we will randomly assign 2128 patients with a clinical indication for coronary angiography (ad hoc 
angioplasty allowed) or percutaneous coronary intervention (PCI) to receive either 500 micrograms 
of nitroglycerin or placebo (0,9% sodium chloride), administered intra-arterially through the sheath, 
in two different moments during transradial catheterization: shortly after the arterial sheath 
insertion and at the end of the radial procedure, before sheath removal. Written, informed consent 
will be obtained from each subject. The study protocol has been presented to the institutional 
medical ethical committee of all participating hospitals to comply with local standards. 


Randomization and final acceptance into the study will take place after successful radial artery 
cannulation and guide wire advanced into the radial arterial lumen through the needle to allow 
exclusion of failed radial puncture. 
 
 
Patient population 
 
All eligible patients are aged 18 years or over with a clinical indication for coronary angiography (ad 
hoc angioplasty was allowed) or percutaneous coronary intervention (PCI) if the following pre- 
requisites are met: (i) choice of the operator to use the transradial access route and (ii) use of sheath 
size 5 or 6 French. Allen test was not obligatory performed. The exclusion criteria were: (I) primary 
angioplasty due to acute myocardial infarction; (ii) intubated patients; (iii) complications during 
procedure (cardiac arrest, pulmonary oedema, cardiogenic shock, and stroke); (iv) prior inclusion in 
this trial; (v) known allergy or intolerance to nitrates; (vi) patients medicated with continuous 
intravenous nitrates or whom received any nitrates on the last hour and (vii) use within 24 hours 
prior to randomization of phosphodiesterase inhibitors. 
 
Outcomes 
Primary outcome 
RAO: incidence of radial artery occlusion as confirmed by the absence of antegrade flow in vascular 
high resolution duplex ultrasound, up to 24 hours after catheterization. 
 
 
Secondary outcomes 
 
Late RAO: incidence of radial artery occlusion as confirmed by the absence of antegrade flow in 
vascular high resolution duplex ultrasound, 30 days after catheterization. 
Comfort assessment: pain felt by the patient in the forearm, assessed using numeric pain rating 
scale. The 11-point numeric scale ranges from '0' representing one pain extreme (e.g. “no pain”) to 


'10' representing the other pain extreme (e.g. “worst pain imaginable”). Only the numbers 
themselves are valuable answers, meaning that there are only 11 possible answers in the 0–10 
interval. 
Spasm (operator evaluation): catheter friction, as experienced by the operator (subjective 
measure), on a predetermined score: 0. No resistance during catheter manipulation or pain reported 
by the patient; 1. No resistance during catheter manipulation, but with pain reported; 2. Light 
resistance during catheter manipulation; 3. Moderate to strong resistance during catheter 
manipulation; 4. Catheter trapping. 
Procedure duration: total duration of the procedure, from sheath insertion to last catheter removal. 
 
Radiation exposure: total radiation used in the procedure (mGy). 
 
 
 
Study definitions 
 
RAO: the absence of an antegrade flow in radial artery was recorded by doppler ultrasound study. 
RAS: will be defined as spasm when: operator evaluation of spasm bigger than 2 by predefined scale; 
need of spasmolytic medication; access site convertion due to confirmed angiographic evidence of 
spasm. 
Access site convertion: impossibility of complete procedure without another arterial site access. It 
may be due to spasm or anatomical reason, and should be confirmed with angiography. 
Radial puncture attempt: defined as any skin puncture with positive blood draw through the 
needle. 
Local hematoma: will be classified according to the EASY scale: I, ≤5 cm diameter; II, ≤10 cm 
diameter; III, >10 cm but not above the elbow; IV, extending above the elbow; and V, anywhere with 
ischemic threat of the hand. 
Major bleeding: will be graded according to the Bleeding Academic Research Consortium definition: 
Type 3 ((3a) bleeding with hemoglobin drop ≥ 3 and < 5 g/dL, or packed red cells transfusion; (3b) 


bleeding with hemoglobin drop ≥ 5 g/dL, heart tamponade, bleeding requiring surgical intervention 
or bleeding requiring intravenous inotropic drugs; (3c) intracranial hemorrhage; subcategories 
confirmed by autopsy, imaging examinations or lumbar puncture; intraocular bleeding with vision 
impairment) or type 5 bleeding ((5a) possibly fatal bleeding, (5b) definitive fatal bleeding). 
 
 
Transradial procedure 
 
Local anesthesia will be administered with a subcutaneous injection of 1% lidocaine after skin 
preparation. Radial artery access will be obtained using either anterior or counter-puncture 
technique based on the operator’s preference, using a 21-gauge bare needle or 20/22 G sheath 
covered needle, following which a 5Fr or 6Fr hydrophilic sheath will be inserted over a guidewire. 
Then, the patient will receive the randomized solution (500 micrograms nitroglycerin or placebo), 
plus heparin 5,000 units through the radial sheath as an intra-arterial bolus. Additional heparin will 
be give in cases of PCI (total 100 UI/kg). Doses of heparin are used according to our study protocol. 
The use of additional medication, either vasodilators or analgesics, is left to operators’ discretion. 
No routine 
 
intravenous sedation was given. Transradial coronary angiography and/or PCI will be performed 
according to standard techniques, by the choice of operators. At the end of procedure, and before 
sheath removal, four to five ml of blood will be aspirated through the sheath to remove any residual 
thrombus and in a blinded fashion, either a 500 micrograms nitroglycerin or placebo will be 
administered through the radial sheath. Then, the arterial sheath will removed and hemostasis will 
be achieved. 
 
 
Arterial hemostasis 
 
A compression device designed to assist hemostasis of the radial artery after a transradial procedure 
will be applied according to a previously validated protocol. Immediately after procedure 


completion, the sheath is initially pulled by approximately 2 to 3 cm. The device is applied to the 
patient with the green marker (located in the center of the larger balloon) positioned exactly at the 
puncture hole to aid in the location, visualization and control of possible bleeding. The balloon is 
inflated with an adequate syringe injecting 15 ml of air with simultaneous and total sheath removal, 
resulting in the absence of active bleeding. If bleeding occurs, additional 3 ml of air is injected to 
obtain complete hemostasis. The device is then slowing deflated to the lowest allowable volume 
(minimum 7 ml) while maintaining hemostasis. If bleeding occurred, 1 ml of air was reintroduced 
from the bleeding point. Radial artery patency was evaluated utilizing plethysmographic and pulse 
oximetry evaluation, with sensor placed over the thumb or index finger, and occlusion (manual 
pressure) of the ulnar artery. Absence of plethysmographic waveform is indicative of interruption of 
radial artery flow. After 1 hour post diagnostic procedure or 2 hours post intervention, 3 ml of air is 
removed every 15 minutes. If bleeding occurs during any stage of device removal, the volume of air 
needed for hemostasis is again injected, restarting the deflation process 60 minutes later. When all 
the air is removed, and there is no bleeding, the device is removed and the access site is covered 
with a simple dressing. Dressing should not encircle the entire wrist. 
 
 
Statistical analysis 
 
The primary analysis of the study is a superiority comparison between the use of nitroglycerin to 
decrease RAO, in all randomized patients, based on the intention-to-treat principle. 
Using our primary end point to estimate the sample size, we suppose to have a 30% reduction in 
RAO for each trial intervention, considering potential interaction between them. Estimating RAO 
prespecified in the primary outcome of approximately 11.7% without use of nitroglycerin, with an 
alpha level of 0.05 and a beta level of 0.20, the minimum estimated sample size per group was 
established as 1064 individuals. As we do not expected any subsequent loss of follow-up due to the 
short primary evaluation, the enrolment of 2128 patients would provide sufficient power to the 


study. Continuous variables will be described as means and standard deviation and compared using 
Student’s t -test for normally distributed variables or assessed using Mann-Whitney test when not 
normally distributed. Categorical variables are expressed as frequencies and group percentage and 
will be compared with the chi-square or Fisher’s exact tests. To test the interaction between 
interventions, we used a multivariable logistic-regression model that included the two randomized 
treatments and their interaction as parameters. In the analysis of the primary and secondary end 
points, a two-tailed p value of less than 0.05 will be considered statistically significant. No 
prespecified interim analysis will be performed. All analyses will be performed using SPSS version 22 
(SPSS Inc., Chicago, Illinois). 
 
 
 
Discussion 
 
Cardiac catheterization is a common procedure and is need in many clinical scenarios and many 
times repeated procedures are need. The use of TRA is increasing aiming to improve patient 
comfort, save costs and reduce rates complications. This implies that the occurrence of RAO should 
be considered because, once it's occurred, it is impossible to use radial access for future 
catheterization. In most cases RAO occurs promptly after the procedure and up to 50% of patients 
have spontaneous recanalization of the artery within 1 month. A palpable pulse does not exclude the 
diagnosis of RAO: collateral blood flow may supply the periphery of the radial artery distally to the 
occlusion, giving a false impression of radial artery patency. Therefore, RAO can often be 
undiagnosed. Radial artery patency is better evaluated with clinical testing as the reverse Barbeau’s 
test and with Doppler ultrasonography. Many interventions are suggested to reduce the risk of RAO, 
mainly anticoagulation, patent hemostasis and a bigger sheath-to-radial-artery ratio. Although 
nitroglycerin promotes vasodilation and thus improves the sheath-to-radial-artery ratio, no 
recommendation is done to its routinely use. Handling confounding factors such as anticoagulation 
and hemostasis, this test has an ideal design to address the question of whether routine use of the 


nitroglycerin approach is superior to not use with respect to the occlusion occurrence, including 
possible predictors.