Randomized Trial Comparing the Spasmolytic Effects of Nitroglycerin and Verapamil with Nitroglycerin Alone in Preventing Radial Artery Spasm during Cerebral Angiography

Abstract

Objective

To evaluate the effectiveness of nitroglycerin alone compared with a combination of nitroglycerin and verapamil in preventing radial artery spasm during transradial diagnostic cerebral angiography.

Methods

This double-blind randomized study involved 80 patients who were assigned to receive either 200 µg of nitroglycerin combined with 2.5 mg of verapamil or 200 µg of nitroglycerin alone. We compared hemodynamic changes, baseline and procedural parameters, as well as patient satisfaction between the two groups. The occurrence of radial artery occlusion was assessed using Doppler ultrasonography at 24 hours and 1 month following the procedure.

Results

Radial artery spasm occurred in three patients (7.5%) in the cocktail group and in four patients (10%) in the nitroglycerin-only group, with no statistically significant difference (p = 1.000). There were no significant differences in hemodynamic parameters, baseline characteristics, or procedural metrics. The majority of patients expressed satisfaction with the transradial approach. One case of radial artery occlusion was observed at the 1-month follow-up, with no differences noted between the groups.

Conclusion

Nitroglycerin alone is equally effective as the combination of verapamil and nitroglycerin in preventing radial artery spasm.

Keywords

cerebral angiography - DSA - radial access - vasospasm - radial cocktail - nitroglycerin

Introduction

Vascular access plays a vital role in the success of interventional procedures. Although the transfemoral approach has been the traditional choice among interventional neuroradiologists, the transradial approach is increasingly favored, with many patients expressing a preference for it after experiencing both methods.[1] [2]

Transradial access is relatively safe, with major vascular complications reported in only 0.2% of patients, according to a meta-analysis.[3] Nonetheless, it is not without complications, which may include radial artery spasm (RAS), radial artery occlusion (RAO), radial artery perforation, pseudoaneurysm, retained catheter, and arteriovenous fistulas. RAS is particularly common and can lead to discomfort, increased risk of complications, and, in some cases, procedural failure, necessitating a switch to an alternative access route. Additionally, RAS may heighten the likelihood of post-procedural RAO.[4] [5] [6] [7] [8] [9]

Various vasodilator medications, including calcium channel blockers, nitrates, and α receptor blockers, are used to prevent RAS during the transradial approach.[10] However, there is no established consensus on the optimal regimen. The American Heart Association recommends the intra-arterial administration of calcium channel blockers and nitroglycerin following sheath insertion.[11]

The incidence of RAS varies significantly; while some studies report rates as high as 52%, others suggest rates between 15 and 35%, depending on the vasodilatory regimen employed. Concerns have been raised regarding calcium channel blockers due to their negative chronotropic and inotropic effects, particularly in patients with severe aortic stenosis, hypotension, hemodynamic instability, cardiogenic shock, and hypertrophic cardiomyopathy.[12] [13] To investigate this further, we conducted a randomized controlled trial comparing the effects of a combination of nitroglycerin and verapamil against nitroglycerin alone in patients undergoing diagnostic cerebral angiography via the transradial approach.

Materials and Methods

This study was a single-center, prospective, double-blinded, randomized controlled trial conducted at our institute from January 2024 to October 2024. A total of 80 patients with indications for diagnostic cerebral angiography were initially included in the study. However, 16 patients were excluded due to various predefined exclusion criteria. The patient flow diagram is presented in [Fig. 1]. The inclusion criteria for participation in the study were age greater than 18 years and indications for diagnostic cerebral angiography. The exclusion criteria included age less than 18 years, radial artery diameter less than 1.8 mm, hypotension (systolic blood pressure below 90 mm Hg), significant bradycardia (heart rate below 50 beats per minute), severe left ventricular dysfunction (left ventricular ejection fraction less than 35%), history of Raynaud's phenomenon in the upper limb, severe atherosclerotic segmental stenotic disease in the upper limb arteries, only functional or injured limb, contraindications to diagnostic digital subtraction angiography (DSA), such as deranged renal function tests, and pregnancy.

Fig. 1 The patient flow diagram.

The primary objective of the study was to assess the incidence and severity of RAS in both groups of patients undergoing transradial diagnostic cerebral angiography. Secondary objectives were to evaluate occurrence of hemodynamic events in each group (includes decrease in the systolic blood pressure, decrease in the heart rate, fluid support requirement, need for any additional drug), to assess the influence of the baseline characteristics of patients in each group on the occurrence of RAS and evaluation of RAO, assessed by Doppler ultrasonography at 24 hours after the procedure and at 1-month follow-up after the procedure.

Randomization, Study Design, and Protocol

The study population was randomized into two study groups, each containing 40 patients, who received either a cocktail regimen consisting of nitroglycerin 200 µg plus verapamil 2.5 mg or nitroglycerin 200 µg alone. Randomization was performed by block randomization using computer-generated tables. A total of 40 blocks were permuted, with each block containing two patients. The study was approved by the Institutional Ethics Committee, and all participants provided written informed consent prior to participating in the study. The trial was registered, and the Declaration of Helsinki Ethical Guidelines were adhered to, CTRI/2024/04/066056 trial registration number.

Procedure

Before the procedure, the baseline characteristics of the patients were recorded. Diagnostic cerebral angiography was performed using the Philips Azurion biplane digital subtraction angiography machine, with a radial approach for access in all cases. A Doppler ultrasound of the radial artery was conducted to assess patency, waveform, and diameter.

The procedure was performed under local anesthesia and anxiolytics, with radial access achieved using ultrasound guidance and a micropuncture needle, followed by the insertion of a 5-F Glide Slender sheath (Terumo, Japan) via the Seldinger technique. A diagnostic angiogram of the radial artery was performed using a 5-F diagnostic catheter, Glidecath (Terumo, Japan).

Spasmolytic agents were prepared in blinded syringes, and after the initial diagnostic run, these agents were administered through the radial sheath. A second angiogram of the radial artery was performed to assess for spasms and identify any significant anatomical variations. Finally, a diagnostic cerebral angiogram was completed, with heparin given at a dosage of 50 IU/kg, adjusted according to the expected procedure duration. The occurrence of RAS was assessed through the following criteria:

1. Patient-reported pain: Pain was rated on a scale of 0 to 10, with 0 to 3 indicating mild spasm, 4 to 7 indicating moderate spasm, and 8 or higher indicating severe spasm.

2. Catheter and guidewire difficulty: The operator evaluated the difficulty in advancing or withdrawing catheters or guidewires, which was classified as mild, moderate, or completely stuck.

3. Angiographic evidence: Spasm severity was determined by radial artery angiographic runs before and after administering a spasmolytic agent. Stenosis was graded as mild (less than 25%), moderate (25–75%), or severe (greater than 75%).

Spasm was categorized as focal (length less than 2 cm) or diffuse (length greater than 2 cm).

Patients' blood pressure, heart rate, and pulse oximeter readings from the ipsilateral thumb were recorded before radial arterial puncture. After administering a spasmolytic agent, these parameters were monitored throughout the procedure for any significant changes.

Crossover instances between the right and left radial arteries, as well as transitions from transradial to transfemoral approaches, were noted. Hemostasis was achieved using a transradial compression band, and recovery, mobility, and neurological deficits were assessed post-procedure.

Patient satisfaction was evaluated through a questionnaire regarding pain (at the access site and in the forearm), back pain, ambulation, sensitivity and uneasiness of the access site (groin versus wrist), site preference, overall discomfort, and hospital experience, rated on a Likert scale from 1 (very unsatisfied) to 5 (very satisfied).

Follow-up Doppler ultrasonography of the radial artery was performed at 24 hours and 1 month to assess for RAO.

Statistical Analysis

Data analysis was effectively performed using SPSS v26 (IBM Corp.). Descriptive statistics were clearly presented as means and standard deviations for continuous variables, along with frequencies for categorical variables. For group comparisons involving continuous data, independent samples t-tests were confidently employed for two groups, and one-way ANOVA was utilized for comparisons involving more than two groups, with Tukey's HSD ensuring precise post-hoc analysis. In cases of non-normally distributed data, the robust Wilcoxon test or Kruskal-Wallis test was applied. The Chi-square test facilitated categorical comparisons, while Fisher's exact test was used whenever expected frequencies fell below 5 in over 25% of the cells. Linear correlations were thoroughly assessed using Pearson's correlation for normally distributed data and Spearman's correlation for non-normally distributed data. A clear threshold for statistical significance was established at p < 0.05.

Results

A total of 80 patients were effectively divided into two groups of 40, with one group receiving a cocktail regimen and the other nitroglycerin alone. [Table 1] clearly presents the baseline characteristics of both groups, while [Table 2] provides a comprehensive overview of their angiographic and procedural features. Notably, radial artery variations were identified in nine patients (11.25%), including brachioradial artery (four patients, 5%), a complete 360-degree arterial loop (two patients, 2.5%), and tortuosity (three patients, 3.75%).

Table 1 Summary of baseline characteristics of patients in both groups

Characteristics	Cocktail group (N = 40)	Nitroglycerin group (N = 40)	P-value
Age (years)	43.30 ± 11.57	41.95 ± 14.29	0.644
Age (years)
18–30	5 (12.5%)	9 (22.5%)	0.360
31–40	15 (37.5%)	10 (25%)
41–50	10 (25%)	10 (25%)
51–60	6 (15%)	9 (22.5%)
61–70	4 (10%)	1 (2.5%)
71–80	0 (0%)	1 (2.5%)
Gender
Male	25 (62.5%)	20 (50%)	0.260
Female	15 (37.5%)	20 (50%)
Height (cm)	164.98 ± 6.87	163.52 ± 6.62	0.137
Weight (kg)	66.90 ± 10.97	64.10 ± 12.11	0.282
BMI (kg/m2)	24.47 ± 3.15	23.83 ± 3.34	0.377
Smoking	9 (22.5)	6 (15%)	0.390
Diabetes	3 (7.5%)	4 (10%)	1.000
Hypertension	3 (7.5%)	7 (17.5%)	0.176

Table 2 Summary of angiographic and procedural characteristics between the two groups

Characteristics	Cocktail group (N = 40)	Nitroglycerin group (N = 40)	P-value
Access side
Right	36 (90%)	35 (87.5%)	1.000
Left	4 (10%)	5 (12.5%)
Number of puncture attempts
1	33 (82.5%)	32 (80%)	1.000
2	6 (15%)	7 (17.5%)
3	1 (2.5%)	1 (2.5%)
Radial artery diameter (mm)
Pre-spasmolytic	2.08 ± 0.33	2.06 ± 0.33	0.698
Post-spasmolytic	2.49 ± 0.40	2.48 ± 0.40	0.681
Brachial artery bifurcation
At elbow	37 (92.5%)	39 (97.5%)	0.615
High	3 (7.5%)	1 (2.5%)
Radial artery variation	4 (10%)	2 (5%)	0.675
Radial artery tortuosity	2 (5%)	1 (2.5%)	1.000
Brachial artery stenosis	0 (0%)	0 (0%)	1.000
Axillary artery stenosis	0 (0%)	0(0%)	1.000
Subclavian artery stenosis	0 (0%)	0(0%)	1.000
Hemostasis
< 15 minutes	0 (0%)	2 (5%)	0.451
15–30 minutes	16 (40%)	22 (55%)
> 30 minutes	24 (60%)	18 (45%)
Patient recovery
Immediate	40 (100%)	38 (95%)	0.241
Delayed	0 (0%)	2 (5%)
Mean fluoroscopy time (minutes)	11.56 ± 7.32	11.70 ± 7.99	0.814
Dose area product (Gy. cm2)	34.86 ± 17.78	31.80 ± 15.79	0.543
Total procedural time (minutes)	29.02 ± 8.50	30.52 ± 11.09	0.855

Comparison of Radial Vasodilatory Power between the Two Groups

Both groups of vasodilatory agents significantly increased the radial artery diameter after administration, with the cocktail group increasing from 2.08 ± 0.33 mm to 2.49 ± 0.40 mm (p < 0.001) and the nitroglycerin-only group increasing from 2.06 ± 0.33 mm to 2.48 ± 0.40 mm (p < 0.001). No significant difference was observed between the two groups in the mean change.

Ability to Prevent Radial Artery Spasm

RAS was observed in 7 out of 80 participants, representing 8.75% of the cohort. Among these cases, three patients (7.5%) were in the cocktail group, while four patients (10%) were in the nitroglycerin-only group, with no statistically significant difference between the two groups (p = 1.000) ([Table 3]). Notably, none of the cases necessitated crossover due to RAS, although one patient required a transition from transradial to transfemoral access due to significant subclavian artery tortuosity. An examination of baseline characteristics revealed no significant differences between patients with RAS and those without. Due to the limited sample size, regression analysis did not identify any independent predictors of RAS.

Table 3 Summary of radial artery spasm occurrence and severity

Radial artery spasm	Cocktail group (N = 40)	Nitroglycerin group (N = 40)	P-value
Incidence	3 (7.5%)	4 (10%)	1.000
Severity (angiographic)
Mild	2 (66.7%)	1 (25%)	0.657
Moderate	1 (33.3%)	1 (25%)
Severe	0 (0%)	2 (50%)
Patient pain perception (subjective)
Mild	1 (33.3%)	1 (25%)	1.000
Moderate	1 (33.3%)	1 (25%)
Severe	1 (33.3%)	2 (50%)
Catheter maneuverability
No difficulty	2 (66.7%)	1 (25%)	1.000
Mild difficulty	0 (0%)	1 (25%)
Moderate difficulty	1 (33.3%)	2 (50%)
Completely stuck Catheter	0 (0%)	0 (0%)
Length of spasm
Focal	0 (0%)	0 (0%)	1.000
Diffuse	3 (100%)	4 (100%)
Additional spasmolytic requirement	0 (0%)	2 (5%)	0.494

Complications at the puncture site were minimal, with the exception of a minor perforation of a small branch of the right radial artery, which was managed conservatively. Vital signs, including blood pressure, heart rate, and oxygen saturation, remained stable in both groups following the administration of spasmolytics.

Patient feedback was overwhelmingly positive, with 82.2% of the 79 respondents expressing satisfaction with the transradial approach, including 84.6% of those who had previously undergone transfemoral procedures.

At the follow-up, one patient in the nitroglycerin-only group experienced a reduction in radial artery diameter to 0.9 mm and developed an occlusion by the 1-month mark. Importantly, no additional cases of radial artery occlusion were identified, and there were no significant differences between the two treatment groups.

Discussion

This study is the first randomized controlled trial in neurointervention to evaluate the effectiveness of spasmolytic agents in preventing RAS during diagnostic cerebral angiography via the transradial approach. Although similar trials have been conducted in cardiology, none have specifically addressed neurointervention.[14] [15] [16] Our use of a double-blind design further enhances the significance of this research.

We randomized patients meeting the angiography criteria to receive either a cocktail of nitroglycerin (200 µg) and verapamil (2.5 mg) or nitroglycerin alone, with each group consisting of 40 well-balanced patients. The results confirm that the transradial approach is safe, with a low incidence of complications and RAS. These positive outcomes are likely due to the operators' expertise, a high success rate in first-attempt punctures, and the use of hydrophilic-coated sheaths and catheters to minimize mechanical stimulation.

The incidence of RAS was recorded at 8.75%, impacting seven patients: four in the nitroglycerin-only group and three in the cocktail group. There was no significant difference in RAS incidence between the two groups, and nitroglycerin alone proved to be as effective as the combination of verapamil and nitroglycerin. Both groups exhibited similar vasodilatory effects on the radial artery diameter, with no significant differences in hemodynamic changes or adverse events observed.

Furthermore, baseline characteristics such as age, gender, height, weight, BMI, smoking history, diabetes, and hypertension did not show significant differences between patients who experienced RAS and those who did not. Similarly, procedural characteristics—including the side of arterial puncture, number of attempts, duration of the procedure (both mean fluoroscopy time and total procedural time), and radiation dosage—revealed no significant differences.

In our study, we found that patients with radial artery spasm (RAS) were significantly younger, with a mean age of 36 years compared with 43 years in those without RAS. Furthermore, the RAS group demonstrated a markedly higher percentage of successful punctures on the second attempt (42.9%) versus only 12.3% in the no RAS group, although these differences did not reach statistical significance.

We performed regression analyses to identify predictors of RAS; however, the small sample size limited our ability to draw conclusive results. Existing research consistently points to factors such as female gender, younger age, and an increased number of puncture attempts as being associated with RAS. It is important to note that the strength of these associations has varied across different studies.[17] [18] [19] [20]

In our study, we noted three instances of significant spasm reported by patients, but none required conversion to a transfemoral approach. There was one crossover (1.25%) from the transradial to the transfemoral approach due to extreme right subclavian tortuosity in the nitroglycerin-only group.

Additionally, one case of radial artery occlusion (1.25%) was observed at the 1-month follow-up in the nitroglycerin-only group. The patient, who had experienced severe diffuse renal artery stenosis, was asymptomatic and showed no signs of hand ischemia. The ulnar artery was patent and of good caliber, and the patient was managed conservatively.

In our study, the incidence of variant radial arterial anatomy was 11.25%, with the brachioradial artery being the most common at 5%. This aligns with the literature, which reports the high origin of the brachioradial artery as a common variation, with incidences ranging from 8 to 24%.[21] [22] [23] [24] [25]

The majority of patients (83.75%) reported little to mild discomfort during the transradial procedure, with 12.5% experiencing moderate pain and only three patients (3.75%) indicating severe pain. Overall, 95% of patients expressed satisfaction or strong satisfaction with the transradial approach.

Among those who had previously undergone the transfemoral approach, all but one patient preferred the transradial method. The exception was a follow-up case involving coiling for an anterior communicating artery (ACOM) aneurysm. This patient experienced mild to moderate forearm pain despite normal Doppler ultrasound findings of the radial artery and was managed conservatively. No statistically significant differences were observed between the two approaches in terms of pain perception or patient satisfaction scores.

The results of our study reflect and mirror those in the neurointerventional and cardiology literature.[2] [8] [19] [26] [27] The access route in neurointervention, as well as cardiology and other fields, relies on the successful placement of a sheath or catheter through the radial arteries through which the rest of the hardware is introduced for the procedure. Although the procedures themselves may differ in these fields, the access methodology is generally similar. The risk of spasm and the need for a cocktail of drugs to mitigate spasm are common to all fields and are generally due to the sheath and catheters. The greater acceptance of radial access in neurointervention requires an understanding of the various cocktail regimes used in the cardiology literature. Our study provides insight into the comparison of these cocktail regimens in neurointervention procedures and found similar results.

Kwok et al found that the incidence of RAS was 9% with a combination of verapamil and nitroglycerin.[28] Curtis et al reported a 14.2% incidence in a study of 169 patients using the transradial approach.[20] In another study by Dharma et al with 150 patients, the incidence was 6%.[17] Malla et al observed a 14% incidence in their study of 207 patients randomized by spasmolytic regimen.[29] Lee et al also reported a 6% incidence in their comparison of spasmolytic agents.[10] Overall, these studies suggest that nitroglycerin is comparable to calcium channel blockers and cocktail agents in preventing the progression of RAS.

The radial artery is classified as a type III artery, according to He and Yang, making it more prone to spasms than somatic vessels, such as the internal mammary artery.[30] RAS results in a sudden narrowing of the arterial lumen, causing acute forearm pain that worsens with movement of the catheter.[18] This artery is particularly sensitive to catecholamines released during pain or anxiety, which can trigger RAS. Mechanical factors, such as cannulation and guide catheter manipulation, can also provoke spasms. Early RAS can complicate cannulation and hinder the establishment of successful vascular access.

During a procedure, RAS may compress the artery against the guide catheter, causing discomfort for the patient and presenting challenges for the operator. This can limit the procedure's success, necessitating a switch to the contralateral radial artery or a transfemoral approach, ultimately increasing procedural time, radiation exposure, and costs.[31] [32] [33]

Preventing spasms is more effective than treating them once they occur. Our study demonstrated that spasmolytic agents effectively prevent RAS.

Although concerns about calcium channel blockers exist—especially their negative effects on heart rate and contractility—caution is particularly important in patients with severe aortic stenosis, hypotension, hemodynamic instability, cardiogenic shock, and hypertrophic cardiomyopathy. The VITRIOL trial clearly indicated that preventive use of verapamil is unnecessary for transradial procedures.[15]

Nitroglycerin is a superior option with a better side effect profile and can be used safely. Our findings showed no significant differences in hemodynamic changes or adverse effects between the cocktail regimen and nitroglycerin alone. Notably, omitting verapamil during transradial diagnostic cerebral angiography effectively avoids its side effects without impacting the incidence or severity of RAS.

Our study has several limitations. The small sample size limited regression analysis for evaluating the relationship between baseline parameters and RAS and identifying independent predictors. Conducted at a single high-volume institution by experienced operators, our findings may not apply to low-volume centers or less experienced practitioners. We used hydrophilic-coated catheters and sheaths, which are known to reduce the incidence of spasm in the radial arteries as compared with non-coated sheaths and catheters. Use of other hardware may alter the incidence of spasm. Thus, multicenter studies are essential for validating our results. We also excluded patients with hypotension, significant bradycardia, and severe left ventricular dysfunction to focus on a relevant patient population.

Conclusion

Spasmolytics are essential in preventing RAS and enhancing the safety of the procedure. Employing nitroglycerin as a sole spasmolytic agent improves safety without diminishing the effectiveness of radial artery vasodilation. Our study has validated these findings.

Conflict of Interest

None declared.

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Publication History

Article published online:
28 January 2026