Presentation by Surya Dharma, MD, PhD, FIHA, FAPSIC, FESC, FSCAI

1. Addressing
Radial Artery Spasm
Surya Dharma, MD, PhD
FIHA, FAPSIC, FESC, FSCAI

2. Disclosures
• Nothing to declare

3. Outline
• Epidemiology
• Pathophysiology
• Predictor of RAS
• Strategies to prevent RAS
• Role of vasodilators in transradial catheterization
• Summary

4. 25 Years of Transradial Intervention: Looking Back and Anticipating What Is Ahead
Sunil V Rao, Surya Dharma.
JACC Cardiovasc Interv
2017;10:2266-68.
Figure 1. Selected milestones in research, clinical and technical developments

5. 11.6%
7.8%
14.7%
2.7%
0.8%
0%
2%
4%
6%
8%
10%
12%
14%
16%
Coppola J
(2006)
Jia DA, et al
(2010)
Kristic I &
Lukenda J
(2011)
Goldsmit A, et
al (2014)
Dharma S, et al
(2015)
• Kristic I, Lukenda J. J Invasive Cardiol 2011; 23(12):527-531.
• Jia DA,et al. Chin Med J 2010; 123(7):843-847.
• Coppola J, et al. J Invasive Cardiol 2006; 18(4):155-158
• Goldsmit A, et al. Catheter Cardiovasc Interv 2014; 83:32-36
• Dharma S, et al. Catheter Cardiovasc Interv 2015; 85:818-825
N=379 N=1427
N=7197
N=1868
Incidence of radial artery spasm
N=1706

6. Diagnosis of RAS (Clinical Criteria)
- Sign and symptom: (RAS classification)
- No spasm (Grade 0): Absence of arm pain or discomfort during
immediately after the procedure.
- Mild spasm (Grade-1): Minimal local pain and discomfort during
catheter movement and/or immediate post procedure period.
- Moderate spasm (Grade-2): Significant local pain and discomfort during
catheter movement and/or immediate post procedure period. However,
movement was possible to complete the procedure.
- Severe spasm (Grade-3): Severe local pain and discomfort during
catheter movement compelling the operator to stop the procedure and
cross-over to the other route.
- Very severe spasm (Grade-4): Severe local pain and discomfort
associated with catheter trapping
Goldsmit A, Kiemeneij F, Gilchrist IC, Kantor P, Kedev S, Kwan T, Dharma S, Valdivieso L, Wenstemberg B, Patel T. Radial artery spasm associated with transradial cardiovascular procedures:
results from the RAS registry. Catheter Cardiovasc Interv. 2014; 83:32-36

7. Radial artery angiogram criteria
• severe constriction of the radial artery lumen
Astarcioglu MA et al. Herz 2015

8. Pathophysiology of RAS
• RAS occurs due to contraction of SMC in response to
activation of the predominant α-1-adrenoreceptors and, to a
lesser extent, α-2-adrenoreceptors  These receptors are
stimulated by circulating catecholamines and by mechanical
stimuli (catheter or wire manipulation), pain sensation due to
multiple punctures, or anxiety.
• The radial artery has been classified as a type III artery and has
a higher receptor-mediated contractility (to endothelin-1 and
angiotensin II), hence a higher risk of spasm compared to
other vessels.
• Larger than ulnar artery (median 2.8 mm vs. median 2.4 mm)
• Curtis E, Fernandez R, Lee A. The effect of vasodilatory medications on radial artery spasm in patients undergoing transradiol coronary artery
procedures: a systematic review. JBI Database System Rev Implement Rep. 2017;15(7):1952-1967.
• Dharma S, et al. Int J Cardiol 2017.

9. Predictor of RAS
Jia DA, Zhou YJ, Liu YY, Wang JL, Liu XL, Wang ZJ, Yang SW, Ge HL, Hu B, Yan ZX, Chen Y, Gao F. Incidence and predictors of radial artery spasm during transradial coronary angiography
and intervention. Chin Med J. 2010; 123(7):843-847.
Jia DA, et al (2010), N= 1427

10. Predictor of RAS
Predictors OR 95% CI P values
More than one puncture attempt 3.5 1.9 - 6.3 <0.001
The use of ≥ 7F sheath 9.1 1.06 – 78.6 <0.001
Goldsmit A, Kiemeneij F, Gilchrist IC, Kantor P, Kedev S, Kwan T, Dharma S, Valdivieso L, Wenstemberg B, Patel T. Radial artery spasm associated with transradial cardiovascular procedures:
results from the RAS registry. Catheter Cardiovasc Interv. 2014; 83:32-36
OR: Odds Ratio. 95% CI: 95% Confidence Interval
Goldsmit, et al, RAS registry (2014), N= 1868

11. Treatment of RAS
Goldsmit A, Kiemeneij F, Gilchrist IC, Kantor P, Kedev S, Kwan T, Dharma S, Valdivieso L, Wenstemberg B, Patel T. Radial artery spasm
associated with transradial cardiovascular procedures: results from the RAS registry.
Catheter Cardiovasc Interv 2014; 83:32-36
RAS registry (2014), N = 1868

12. Sheath/catheter entrapment
• Pharmacologic : Systemic vasodilation (NTG and/or Verapamil)
Sedation (IV midazolam and fentanyl)
• Non-pharmacologic: - Warm compresses
- Forearm heating
- Flow mediated vasodilatation technique
(clamp and release)
• Deep Conscious sedation/General anesthesia: IV Propofol, Intubation
• Invasive/Surgical: Regional Nerve Block, Endarterectomy

13. Strategies to prevent radial artery spasm
• Intra-arterial Vasodilator
• Topical Vasodilator
• Subcutaneous Vasodilator
• Sublingual Vasodilator
• Topical local anesthetic agent
• Sedation

14. Intra-arterial vasodilator
Hizoh I, et al. J Am Heart Assoc. 2014;3: e000588 doi: 10.1161/JAHA.113.000588
Hizoh I, et al (2014), N=591
RCT. 5 mg Verapamil vs Placebo. N = 591. VITROL TRIAL
P = 0,28
Difference in Conversion rate: 1%
95% CI: -1.1% – 3.3%
The preventive use of verapamil
may be unnecessary for
transradial procedures

15. Curtis E, Fernandez R, Lee A. The effect of vasodilatory medications on radial artery spasm in patients undergoing transradiol coronary artery
procedures: a systematic review. JBI Database System Rev Implement Rep. 2017;15(7):1952-1967.
Intra-arterial vasodilator
Meta-analysis (2017), N= 3614
Comparison between vasodilators and placebo
The evidence demonstrates a
benefit in the use of vasodilatory
medications for the reduction of
vasospasm in patients having
radial coronary procedures

16. 12.0% 12.0%
4.0%
16.0%
4.0%
2.0%
4.0%
3.0%
0%
2%
4%
6%
8%
10%
12%
14%
16%
18%
Placebo Verapamil
2.5mg
Verapamil
5mg
Nicorandil NTG 100
μg
NTG 200
μg
Isosorbide
Mononitrate
Nicardipine
Intra arterial vasodilator
Pooled analysis
Kwok CS, et al (2015),
N=8777
% of RAS
Intra-arterial vasodilators to prevent radial artery spasm
In this largest data on intra-arterial vasodilators and RAS, use of 5 mg verapamil and
nitroglycerin are the best combinations to reduce RAS.
Kwok CS, Rashid M, Fraser D, Nolan J, Mamas M. Intra-arterial vasodilators to prevent radial artery spasm: a systematic review and pooled analysis of clinical studies.
Cardiovascular Revascularization Medicine 2015;16:484-90.

17. 4.95
4.66
5.14
5.78
0
1
2
3
4
5
6
7
Baseline After Drug
Comparison radial artery cross-sectional area (mm2) before and after
the administration of topical placebo and nitroglycerin + Lidocaine
(N=86), RCT, PRE-DILATE study
Placebo Nitroglycerin + Lidocain
Beyer AT, Ng R, Singh A, Zimmet J, Shunk K, Yeghiazarians Y, Ports TA, Boyle AJ. Tpical nitroglycerin and lidocaine to dilate the radial artery prior to transradial cardiac catheterization: A
randomized, placebo-controlled, double-blind clinical trial. Int J Cardiol. 2013;168(3):2575-2578.
Topical
vasodilator
P < 0.0001
mm2
Pre-procedural administration of topical mixture of
nitroglycerin + lidocaine increases the size of the radial artery
in patients undergoing transradial cardiac catheterization

18. • RCT 2019: ongoing study: N= 300,
(40 mg Lidocaine + 30 mg NTG) Vs. (40 mg lidocaine +
placebo): June 2019
- Primary outcome : incidence of RAS
- Secondary outcome: change in radial artery diameter
Topical vasodilator
Gopalakrishnan P, et al. (NCT02832115)

19. Ezhumalai B, et al. Indian Heart J 2014;66(6):593-7
Subcutaneous vasodilator
Pre Injection Post Injection P values
(Nitroglycerin +
Lignocaine)
2.2 ± 0.3 mm 2.7 ± 0.4 < 0.0001
(Saline +
Lignocaine)
2.1 ± 0.4 2.3± 0.4 <0.0001
Nitro Saline P values
Pre-cannulation
spasm
1 % 8 % 0.03
Subcutaneously infiltrated nitroglycerin leads to significant increased of radial artery diameter. This avoids pre-
cannulation spasm of radial artery, enhances palpability of the radial pulse and thus makes the puncture of radial
artery easier
Effects of subcutaneously infiltrated nitroglycerin on diameter and pre-
cannulation spasm of radial artery during transradial coronary angiography
Ezhumalai B, et
al (2014), RCT,
N=200

20. Sublingual vasodilator
19.6%
24.0%
0%
5%
10%
15%
20%
25%
30%
Intra-arterial nitroglycerin Sublingual nitroglycerin
% of RAS
P = 0.81
SL nitroglycerin was not different from IA nitroglycerin in terms
of efficiency and safety in overall study population
RCT. Intra-arterial nitroglycerin vs Sublingual Nitroglycerin
Turan B, et al. Cardiovasc Revasc Med 2015;16:391–396
Turan B, et al
(2015), N = 101

21. Topical local anesthetic
EMLA: Eutectic Mixture of Local Anesthetic (Lidocaine and Prilocaine)
Curtis E, Fernandez R, Lee A.. JBI Database System Rev Implement Rep. 2018;16:738–751.
Meta-analysis: The effect of topical medications on RAS
Angiographic
criteria
Clinical
criteria

22. 2.60%
8.30%
0%
1%
2%
3%
4%
5%
6%
7%
8%
9%
10%
Fentanyl + Midazolam Control
Defteros S, et al. Moderate procedural sedation and opioid analgesia during transradial coronary interventions to prevent spasm.
JACC: Cardiovascilar Interventions. 2013;6(3):267-273.
% of RAS
Comparison of spasm rate between treatment group
(Fentanyl 0.5μg/kg + Midazolam 1 mg) and control group
Sedation for Radial Artery Spasm
P<0.001
OR: 0.29
95% CI: 0.18 – 0.47
Defteros S, et al,
RCT (2013),
N=2013
Routine administration of relatively low doses of an opioid/benzodiazepine combination during
transradial interventional procedures is associated with a substantial reduction in the rate of spasm

23. Which vasodilator is the best?

24. OR 95% CI P values
Verapamil 2.5 mg + Molsidomine 1 mg 0.16 0.08 – 0.33 <0.0001
ISDN 0.24 0.13 – 026 <0.0001
Verapamil 2.5 mg 0.25 0.16 – 0.40 <0.0001
Verapamil 5 mg 0.28 0.15 – 0.52 <0.001
Diltiazem 5mg 0.34 0.19 – 0.61 <0.0001
Molsidomine 1mg 0.51 0.30 – 0.87 0.013
Verapamil and ISDN are more effective than diltiazem to prevent RAS. These results suggest that
verapamil 2.5 mg could be considered as the first choice strategy to prevent RAS for TRA
RCT: Vasodilators agents in prevention of RAS
Adjedj J, et al (2016).
N=1950
Adjedj J et al. Eurointervention 2016.

25. Single vs. Combination of Vasodilator and RAS

26. 5%
7%
0%
1%
2%
3%
4%
5%
6%
7%
8%
9%
10%
Diltiazem + NTG NTG
Dharma S, Shah S, Radadiya R, Vyas C, Pancholy S, Patel T. J Invasive Cardiol. 2012;24:122-125
P= 1.0
RCT: Comparison of radial artery spasm between 5 mg Diltiazem + 200 μg NTG
and 200 μg NTG alone
% of RAS
Dharma S, et al (2012).
N=150
Diltiazem plus nitroglycerin showed no advantage compared to nitroglycerin alone in
prevention of RAS in transradial approach
Single vs. Combination of Vasodilator

27. 12.20%
13.40%
9.50%
1%
3%
5%
7%
9%
11%
13%
15%
Nitroglycerin Nitroprusside Nitroglycerin +
Nitroprusside
Coppola J, et al. J Invasive Cardiol. 2006; 18(4):155-158
In this prospective, randomized trial, the
addition of a direct nitric oxide donor to
nitroglycerin in an antispastic cocktail did not
reduce the risk of spasm, and the use of
nitroglycerin was found to be as effective as
nitroprusside
P=0.597
% of RAS
Coppola J, et al (2006), RCT, N=379

28. What do the guidelines tell?

29. Spasmolytic therapy
• Prophylactic use of pharmaceutical agents known to reduce vascular tone
• Calcium channel blockers (e.g., Verapamil 2.5 mg) and/or nitrates (e.g.,
Nitroglycerin 0.1–0.4 mg) are routinely utilized and are best given directly in the
radial artery immediately after vascular access, although the use of topical or
oral pretreatment may also be useful.
• In addition, diluting the spasmolytic cocktail with blood or saline can reduce
burning and artery irritation.
Caputo RP, Tremmel JA, Rao SV, Gilchrist IC, Pyne C, Pancholy S, Frasier D, Gulati R, Skelding K, Bertrand O, Patel T.
Transradial artery access for coronary and peripheral procedures: Executive summary by the transradial committee of the SCAI.
Catheterization and Cardiovascular Interventions 2011.

30. Real world experience on the use of
spasmolytic regimen

31. 36.5%
5.7%
5.0%
22.5%
International RAS Registry 2014
(N=1868 pts)
27.10%
17.10%
37.60%
14.10%
4.20%
International Survey 2010
(N=874 Interventionist)
45.70%
40.00%
14.40%
International Survey 2016-2017
(N=125 Interventionist)
Shroff AR, et al (2016)
Bertrand OF, et al (2010)
Goldsmit A, et al (2014)
Bertrand OF, et al. JACC: Cardiovascular Interventions. 2010;3(10):1022-1031.
Goldsmit A, et al. Catheter Cardiovasc Interv. 2014; 83:32-36.
Shroff AR, et al. Contemporary transradial access practices: Result of the second international survey. Catheter Cardiovasc Interv. 2018;1-12.
Verapamil
NTG
Verapamil + NTG

32. Mechanism of Action
• Verapamil: - inhibits Ca2+ ion influx into conductile and contractile
vascular smooth muscle cells.
- peak therapeutic effect: 3-5 min after bolus injection
• Nitroglycerin: - activation of cyclic GMP, directly relaxing SMC in artery
- immediate effect after injection
McNiff EF, et al. J Pharm Sci 1981;70:1054-1058.

33. Role of Vasodilators in Transradial Access
• Do experienced radial operators use routine vasodilators as
spasmolytic regimen to prevent RAS?
• Do Vasodilators prevent radial artery occlusion after trans-
radial procedure ?

34. • (RAS registry)
- Intra-arterial cocktail did not influence the occurrence of RAS.
- 21% cases (N=392) did not use spasmolytic regimen
• International Survey 2010: 14% interventional cardiologists did not use
routine spasmolytic regimen
(Goldsmit et al. Catheter Cardiovasc Interv 2014;83:32-36)
(Bertrand OF, et al. JACC Cardiovascular Interventions 2010;3:1022-1031)

35. Post procedural Intra-arterial 500 μg NTG
reduces the incidence of RAO
Dharma S, et al. Catheter Cardiovasc Interv 2015;85:818-825.

36. Dharma S, et al. J Invasive Cardiol 2018;30:461-464.
Spasmolytic regimen does not affect RAO
Post hoc analysis

37. Subcutaneous injection of
nitroglycerin at the radial artery
puncture site dilates the radial
artery and reduces the incidence
of early radial artery occlusion
post catheterization.
RCT: subcutaneous 500 μg NTG reduces the risk of early RAO (5.4% vs 14.4%, p= 0.04)
N= 188
Chen Y, et al. Circ Cardiovasc Interv. 2018;11:e006571. DOI: 10.1161/CIRCINTERVENTIONS.118.006571
Chen Y, et al (2018). N=188

38. How to increase the satisfaction of patients
undergoing trans-radial approach?
Multivariate predictors of post-procedural arm pain (VAS score >4 at a day after) in radial centers (N=1706)
Dharma S, et al. Cardiovasc Revasc Med 2018. https://doi.org/10.1016/j.carrev.2018.09.006

39. Concepts to enhance preservation of radial artery function in transradial catheterization
(cannulation, puncture, sheath and catheter selection, procedural characteristics, hemostasis protocol) .
Dharma S, Gilchris IC. Vasodilators and radial artery occlusion: A concept to reduce Radial Artery Occlusion.
Circ Cardiovasc Interv 2018;11:e007011. DOI: 10.1161/CIRCINTERVENTIONS.118.007011

40. Summary
• The incidence of moderate to severe RAS is low in radial
centers with experienced radial operators.
• The most common method for RAS prevention: Intra-arterial
Vasodilator after sheath insertion (Nitroglycerin, Verapamil).
• The use of mild sedation is associated with a reduced risk of
RAS.
• The use of a single vasodilator as a spasmolytic regimen is
effective.
• Benefit of intra-arterial vasodilator [after sheath insertion
(RAS) vs. before sheath removal (RAO)].