Topical Nitroglycerine Treatment for Radial Artery Spasm Prevention

Background:

Vascular access site complications (VASC) during cardiac catheterizations are significantly
higher in transfemoral access compared to transradial access. Main disadvantage in radial
access is the restriction in size of catheters as well as incidence of radial artery spasm.
Radial spasm is identified by pain in the forearm aggravated by movement of the
catheter/sheath; difficulty in manipulating the catheter; loss of radial pulse or damping of
radial arterial pressure. Tortuosity and loops in upper extremity arterial tree could mimic
some findings of radial artery spasm. Incidence of radial spasm has been reported to range
between 4% and 20%. Risk factors include smaller radial artery diameter, atherosclerotic
lesions, entrance of guidewires into side branches, vessel tortuosity, larger arterial sheath
diameters, procedure duration, female sex, younger age, lower BMI, DM, number of catheters
used, volume of contrast, unsuccessful access at first attempt, fear and anxiety. Mean size
of radial artery is reported at 2.44 mm. Women and persons of south Asian descent tend to
have smaller radial arteries with means of 1.91mm and 2.00 mm respectively. Outer diameters
of commonly used 5F and 6F sheaths are 2.16 mm and 2.62 mm respectively. Ratio of radial
artery to sheath size affects post-procedural radial artery flow.

Intraarterial vasodilators reduce radial artery spasm. Transdermal vasodilators prior to
vascular access would increase chance for successful arterial access in first attempt and
increase radial artery to sheath size ratio both of which should have additive benefit to
intraarterial vasodilators in reducing spasm. Transdermal lidocaine would reduce pain during
s.c. lidocaine, which can further ameliorate the risk of radial artery spasm. Use of
transdermal nitroglycerine has been shown to safely increase radial artery size without
significant hypotension.

Aim:

To study the role of transdermal vasodilators as an adjunct to parenteral vasodilators, in
reducing radial artery spasm and improving patient comfort and post procedure radial artery
patency during transradial coronary angiograms and interventions.

Hypothesis:

Transdermal vasodilators will increase radial artery size and reduce radial artery spasm as
well as improve patient comfort and post procedure radial artery patency.

Study Design:

Single center, double blinded, randomized placebo-controlled study comparing effect of
transdermal preparations of lidocaine + Nitroglycerine and lidocaine + placebo on radial
artery spasm and procedural success in patients undergoing transradial coronary angiograms
and interventions. All patients will receive standard parenteral cocktail including
intraarterial or intravenous heparin and intraarterial nitroglycerine and / or verapamil.
Exact doses and combinations would be at the discretion of individual provider based on
patient's hemodynamic status and comorbid conditions.

End Points:

Primary:

1. Radial artery spasm: Incidence of radial artery spasm indicated by a Radial artery spasm
score of 1 or more. Radial artery spasm score is sum of:

1. Verbal or nonverbal expression of discomfort in the forearm during catheter/sheath
manipulation - Absent :0; Present:1

2. Difficulty in manipulating the catheter- Absence :0; Present:1

3. Difficulty with sheath removal: Absent: 0; Present:1

4. Additional use of intraarterial nitroglycerine or verapamil after the initial
vasodilator cocktail for suspected radial artery spasm- No:0; Yes:1.

Secondary:

1. Change in ipsilateral radial artery dimension (mm) before application of topical
nitroglycerine / placebo (pre-dilation) vs. prior to arterial puncture after application
of topical nitroglycerine / placebo (Post-dilation).

2. Procedural failure: Need to abort procedure or convert to transfemoral approach.

3. Patient forearm discomfort or pain during procedure measured using Visual analog scale
0-10.

4. Ipsilateral radial pulse at end of procedure 0-4+.

Safety endpoints:

1. Asymptomatic Hypotension: SBP < 90 mm Hg

2. Symptomatic Hypotension: Dizziness or lightheadedness and SBP < 100 mm Hg

3. Intractable headache unrelieved by 1gm of acetaminophen

Adverse Effects of investigational product:

1. Hypotension: SBP < 90 mm Hg requiring intervention any time after application of
investigational product (IP) in Ambulatory Cardiac Unit (Same Day) until removal of IP
in cathlab

2. Dizziness or lightheadedness requiring intervention any time after application of IP in
Ambulatory Cardiac Unit (Same Day) until removal of IP in cathlab

3. Headache requiring intervention anytime after application of IP in Ambulatory Cardiac
Unit (Same Day) until removal of IP in cathlab

Complications of Radial artery catheterization:

1. Forearm hematoma > 5cm 2. Absent ipsilateral radial pulse (0) after procedure

Methods:

1. Patient enrollment:

1. Outpatient:

i. Whenever feasible, information about the study would be provided to the patient prior
to arrival in Ambulatory Cardiac Unit (Same Day) (preferably at the time of scheduling).
When not feasible, patients will be contacted via phone prior to the day of procedure or
approached in the Ambulatory Cardiac Unit (Same Day) unit on the day of the procedure by
one of the investigators to assess interest in participation.

ii. Patients who are interested and meet all inclusion criteria and none of the
exclusion criteria will be enrolled in the trial in the Ambulatory Cardiac Unit (Same
Day) on the day of their scheduled procedure. One of the participating investigators
will obtain informed consent after the patient has had time to review the consent and
all questions have been answered.

b. Inpatient: i. Hospitalized patients who are interested and meet all inclusion
criteria and none of the exclusion criteria may be enrolled in the trial on or before
the day of their scheduled procedure, but always prior to transfer to the
Catheterization Lab. One of the participating investigators will obtain informed consent
after the patient has had time to review the consent and all questions have been
answered.

2. After reviewing the most current vital signs, patients without any exclusion criteria
will be randomized 1:1 to control arm (40 mg Lidocaine + placebo) or study arm (40 mg
lidocaine + 30 mg nitroglycerine)

3. Study drug assignment will be randomized and distributed by a delegated member of the
study staff, with oversight by the PI or Sub-Is, for patients consented and enrolled in
the trial at least 60 minutes prior to the procedure start time.

4. Pre-medication cross sectional image of ipsilateral radial artery (approximately 1 inch
proximal to radial styloid process) will be recorded using bedside sonogram with no more
than gentle pressure and site marked with a skin marker.

5. Ipsilateral wrist circumference (1 inch proximal to radial styloid process) will be
documented.

6. Pre-procedure ipsilateral radial pulse strength (0-4+) will be documented. (4+ Bounding,
3+ Increased, 2+ Normal, 1+ Weak, 0+ Absent or nonpalpable)

7. Transdermal preparation will be applied to ipsilateral wrist overlying radial pulse
(centered approximately 1 inch proximal to radial styloid process) at least 60 minutes
before procedure start time at a dose of 40mg (6 ribbons of 2 inches each) of 5%
Lidocaine and 30mg (8 ribbons of 2 inches each) of 2% Nitroglycerine/Placebo.

8. Patients will complete the Amsterdam Preoperative Anxiety and Information Scale (APAIS).

9. Vitals signs to be checked every 30 minutes (±10 minutes) after application of the
topical preparation for 60 minutes (±10 minutes) then every 60 minutes (±10 minutes)
until procedure.

10. If SBP < 100 mm Hg and patient complains of dizziness or light-headedness or if SBP < 90
mm Hg, the topical preparation will be removed promptly, 250 ml of 0.9% Normal Saline
(NS) IV bolus will be given over 15 minutes, and provider will be notified immediately.

11. If patient complains of headache, one or two tablets of 500 mg acetaminophen will be
given by mouth every 4 hours as needed. One tablet will be given if the patient reports
a value of 0-3 on the pain scale, and two tablets will be given if the patient reports a
value of 4 or greater on the pain scale. The maximum dose of acetaminophen is 4g in 24
hours.

12. If 30 minutes after acetaminophen administration, headache intensity ≥ 5/10 or patient
unable to tolerate intensity of headache, the topical preparation will be removed
promptly and provider will be notified immediately.

13. If any of the safety endpoints occur, an investigator will be notified immediately and
further decision to proceed with cardiac catheterization or additional workup or
treatment would be at the discretion of the investigator.

14. Immediately prior to sterile preparation of access site, transdermal preparation will be
removed in Cath Lab and post-dilation cross sectional image of ipsilateral radial artery
(approximately 1 inch proximal to radial styloid process) will be captured using bedside
sonogram applying no more than gentle pressure.

15. Conscious sedation with intravenous fentanyl and midazolam given with exact dosing at
operator's discretion (based on patient's hemodynamic status and comorbid conditions).

16. After sterile preparation 0.5 - 1.0 ml of subcutaneous lidocaine is administered and
radial artery cannulated using modified seldinger technique with 5F or 6F hydrophilic
sheath.

17. Parenteral radial cocktail (IV/IA heparin +/- IA nitroglycerine +/- IA verapamil) is
given with exact combination and dose at discretion of operator based on patient's
hemodynamic status.

18. Coronary angiogram and or intervention performed adopting best practices with care to
minimize procedure time, contrast volume and catheter exchanges and avoiding side
branches.

19. Following parameters are documented:

1. Patient demographics (Age, Sex, BMI, Race)

2. Conscious sedation drugs and doses used

3. Sheath size

4. Number of arterial sticks before arterial access: One or more (Blood in arteriotomy
needle equates arterial stick)

5. Wire passage in one or more attempts

6. Sheath insertion in one or more attempts

7. Radial parenteral cocktail used

8. Radial artery spasm score:

9. Verbal or nonverbal expression of discomfort in the forearm during catheter/sheath
manipulation - Absent:0; Present:1 ii. Difficulty in manipulating the catheter -
Absent:0; Present:1 iii. Difficulty in sheath removal - Absent:0; Present:1 iv.
Additional use of intraarterial nitroglycerine or verapamil after the initial
vasodilator cocktail for suspected radial artery spasm - No:0; Yes:1

i. Use of long sheath j. Use of hydrophilic wires or catheters k. Tortuosity of UE
vessels / anatomic variants l. Catheters used m. Contrast volume n. Difficulty in
removing catheters and sheath o. Use of IA/IV NTG and/or verapamil at end of procedure
for sheath removal: provisional use when radial artery spasm present or suspected vs.
routine pre-emptive use to avoid radial artery spasm per operator standard practice.

p. Length of procedure q. Change to femoral arterial access and reason r. Procedures
performed

20. Patient's perceived peri-procedure forearm discomfort documented using VAS (1-10) at the
completion of the procedure

21. Post procedure strength of ipsilateral radial pulse (0-4+) after radial band removal
documented and presence and size of hematoma at access site at time of radial band
removal documented

22. For patients who have the sheath left in place for percutaneous coronary intervention
(PCI) as a separate procedure at a later time, data will be collected for the initial
diagnostic catheterization only. The procedure will be considered completed with removal
of last diagnostic catheter. Post procedure pulse will be the radial pulse after the
PCI.

23. Patients are monitored for adverse events for the following duration:

a. For patients discharged home from the ambulatory cardiac unit (same day unit) after
procedure completion: i. Until discharged home b. For hospitalized patients: i. Until
120 minutes after Radial band, or comparable product, removal

Inclusion Criteria:

1. Age: 18 years or older

2. Radial artery catheterization

Exclusion Criteria:

1. Hypersensitivity or contraindication to lidocaine

2. Hypersensitivity or contraindication to nitroglycerine

3. Recent use of PDE5 inhibitors (<24 hours after sildenafil or vardenafil; <48 hours
after tadalafil)

4. Baseline weak radial pulse (0 or 1+)

5. Baseline hypotension SBP < 100mmHg at the time of enrollment

6. Dizziness or light-headedness at the time of enrollment

7. Severe Aortic Stenosis or HOCM

8. Previous unknown bypass grafts or known LIMA graft

9. Chest pain within 6 hours of IP administration

10. More than 2 episodes of chest pain within 24 hours prior to IP administration

11. Use of sublingual, transdermal, or intravenous nitroglycerine within 6 hours prior to
IP administration

12. Likely need for use of nitroglycerine for non-study indication

13. Narcotic or sedative within 4 hours of enrollment

14. Women who are suspected or known to be pregnant or breastfeeding