Randomised clinical trial comparing transradial catheterisation with or without prophylactic nitroglycerin

Br J Cardiol 2017;24:100–4doi:http://doi.org/10.5837/bjc.2017.020 Leave a comment
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First published online July 18th 2017

Spasm after transradial approach for catheterisation decreases procedural success and offers discomfort to the patient. Nitroglycerin is one of the drugs applied prophylactically to prevent spasm. The aim of this study was to assess the effect of preventive nitroglycerin on the comfort of patients during cardiac catheterisation.

A total of 328 patients were randomly assigned to receive either 200 µg nitroglycerin (n=164) or placebo (n=164). The main outcome was the evaluation of spasm using a visual analogue scale to measure the pain of the patient, and procedural time and radiation used to measure the operator difficulty during the examination. 

The pain evaluation was equal in both groups (nitroglycerin 24.74 vs. placebo 24.75, p=0.72). Using the operator’s impression, there was a higher incidence of spasm in the placebo group (9.1% grade 3 or 4 vs. 2.4% in the nitroglycerin group, p=0.004), while procedural time (21.36 minutes vs. 22.24 minutes, p=0.23) and radiation exposure (655.61 mGy vs. 660.92 mGy, p=0.63) were comparable in both arms.

In conclusion, the prophylactic use of nitroglycerin offers no advantage in terms of comfort to the patient during cardiac catheterisation by a transradial approach. Although there was difference in operators’ perception of spasm, omission of vasodilator does not cause any objective difficulty to operators.

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The use of the transradial approach (TRA) for coronary catheterisation has increased over the years, worldwide, and it has been shown to be safe and comfortable for patients.1 Transradial interventions have been found to be feasible in many situations of clinical practice, reducing vascular and bleeding complications, improving patient comfort, saving costs and with equivalent procedural success compared with the femoral approach.2,3 Some studies have shown that in acute coronary syndromes, the use of TRA is associated with better outcomes and lower mortality.4,5

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 and reduce the comfort of patients, causing significant pain. The incidence of RAS varies between 2% and 34%, and may lead to femoral conversion.6,7 This wide variation in RAS incidence may be attributed to a lack of consensus on the definition of RAS. In consequence, inter-trial comparisons and meta-analyses are of limited value. Therefore, several preventive measures are being used to prevent RAS.8-10 Of them, the use of prophylactic intra-arterial vasodilators is routinely recommended by experts. Most catheterisation laboratories habitually use some medication to prevent RAS, however, in Japan, 72% of procedures are made without the use of any prophylactic medication.11

The common spasmolytic cocktail uses verapamil and nitroglycerin, alone or associated.11-13 Both medications have haemodynamic effects; verapamil has a strong negative inotropic and chronotropic effect on the heart and is contraindicated in some clinical settings; nitroglycerin has a potent vasodilator effect, has a safer profile than verapamil, but it is still contraindicated in some situations, such as severe hypotension.

With the advance in technology and the increased expertise from operators, we supposed that the prophylactic use of vasodilators is less important than it used to be, maybe not even needed at all. The aim of this study was to assess the effect of preventive nitroglycerin on the incidence of RAS during cardiac catheterisation.


This study was designed as a single-centre, prospective, randomised, placebo-controlled, double-blind trial with an all-comers design. All subjects provided informed consent, and the institutional ethics committee approved the study. The study is registered at ClinicalTrials.gov, number NCT02343276. Our centre performs more than 1,500 procedures per year, of which, more than 70% are undertaken transradially. All operators, but one, have high TRA experience. All eligible patients were aged 18 years or over with a clinical indication for coronary angiography (ad hoc angioplasty was allowed) or percutaneous coronary intervention (PCI). Allen test was not performed routinely in our institution. The exclusion criteria were: primary angioplasty due to acute myocardial infarction; intubated patients; complications during procedure (cardiac arrest, pulmonary oedema, cardiogenic shock, and stroke); and prior inclusion in this trial. We only excluded these patients because they could not give reliable information about the forearm pain.

Study protocol and randomisation

All randomised patients were assigned to receive, after the arterial sheath insertion, either 200 µg nitroglycerin diluted with 0.9% saline to 10 ml (group A) or placebo (10 ml 0.9% saline alone) (group B). Treatment and control groups were blinded. The randomisation scheme was generated using specific software by an independent researcher. The randomisation was performed in blocks of four to keep an equal number of patients in different groups throughout the study period. Each patient was allocated into one group, which was informed to the operator prior to the procedure. Medication or placebo was prepared in equal syringes by a nurse that was not involved in the treatment of the patient and did not take part in the procedure, the syringes were labelled as Group A or Group B. The same nurse prepared all the solutions during the study period.

Transradial procedure

Local anaesthesia was administered with a subcutaneous injection of 1% lidocaine after skin preparation. Puncture was performed using a 21-gauge bare needle or 20 G sheath-covered needle, following which a 5Fr or 6Fr hydrophilic sheath (Radifocus® Introducer II, Terumo, Japan) was inserted over a guidewire. Then, the patient received the randomised solution (nitroglycerin or placebo), plus heparin 5,000 units through the radial sheath as an intra-arterial bolus. Additional heparin was given in cases of PCI (total 100 UI/kg). Doses of heparin were used according to our institutional protocol. The use of additional medication, either vasodilators or analgesics, was left to operators’ discretion. No routine intravenous sedation was given. Transradial coronary angiography and/or PCI were then performed according to standard techniques, by the choice of operators. The arterial sheath was removed immediately after procedure completion and haemostasis was achieved with conventional pressure application using simple gauze compression dressing.

Figure 1. Visual analogue scale
Figure 1. Visual analogue scale

RAS assessment

RAS was detected by the patients’ feeling of pain in the forearm, and it was measured using a visual analogue scale (VAS) (figure 1), applied at the end of the procedure, up to five minutes after the sheath removal, by an interventional nurse. The VAS consists of a single line measuring 100 mm, anchored by verbal descriptors, saying ‘no pain’ and ‘worst possible pain’. The patient was instructed to mark on the line the point that represented their pain during the catheterisation. The distance between the ‘no pain’ point and the marked point scored the intensity of pain.14,15 Operators reported the presence of spasm on the following scores:

  1. No resistance during catheter manipulation or pain reported by the patient
  2. No resistance during catheter manipulation, but with pain reported
  3. Light resistance during catheter manipulation
  4. Moderate resistance during catheter manipulation
  5. Strong resistance during catheter manipulation or catheter trapping

In order to avoid subjective operators’ impressions, we marked the time and the total radiation required to complete the catheterisation, both are objective measures of difficulty during the procedure.

Outcome measures

The primary end point was the discomfort experienced by the patient during the whole procedure, using the VAS. Secondary end points were time to complete the catheterisation, and total radiation required.


Puncture attempt was defined as any skin puncture with positive blood draw. The examination time was marked from the application of study medication until removal of the sheath.

Statistical analysis

Using our primary end point to estimate the sample size, we were supposed to have a 30% reduction in pain measured on VAS with the use of nitroglycerin. A previous study, conducted to evaluate pain during TRA using VAS, showed a mean pain of 25.54 mm.16 We estimated the sample size using a two-sided alpha error of 0.05 and a beta error of 0.15. The enrolment of 328 patients (164 in each group) would provide sufficient power to the study. Continuous variables are described as mean ± standard deviation and compared using student t-test or assessed using Mann-Whitney test when not normally distributed. Categorical variables are expressed as frequencies and compared with the chi-square test. A two-tailed p value <0.05 was considered statistically significant. All analyses were performed using SPSS version 22 (SPSS Inc., Chicago, Illinois).


Table 1. Baseline characteristics and procedure data
Table 1. Baseline characteristics and procedure data

A total of 328 patients were randomised between January and August 2015 and were included in the analysis. Baseline characteristics and procedure data are detailed in table 1. The two study arms were well balanced, without statistical differences between them. The mean age of the patients was 60.4 years; most patients were male (64.6%); and the mean body mass index was 28.1 kg/m2. Catheterisation was performed via the right radial artery in all cases. Procedural success was high in both groups, one (0.6%) case in each group could not be completed via the TRA due to RAS and one (0.6%) case in the placebo group had to crossover to femoral because of unfavourable vascular anatomy. Neither group presented any haemodynamic effect, with no severe hypotension nor tachycardia. There was no significant difference in the crossover rate between the groups (p=0.562). Primary and secondary end points are shown in table 2. Mean pain scores were similar between both groups (24.74 vs. 24.75 in nitroglycerin and placebo groups, respectively). Using the operator’s impression, there was a higher incidence of spasm in the placebo group (9.1% grade 3 or 4 vs. 2.4% in the nitroglycerin group, p=0.004); the complete classification is shown in table 3; however, there was no difference in objective measures of difficulty during the procedures, with equal procedure duration and radiation exposure, as shown in table 2. There was a statistically significant difference in the use of additional nitrate, as radial vasodilator, favouring the nitroglycerin group (3.0% vs. 9.8% in nitroglycerin and placebo groups, respectively, p=0.013), but there was no difference in the use of opioid analgesics (3.0% vs. 4.9% in nitroglycerin and placebo groups, respectively, p=0.418).

Table 2. Primary and secondary end points
Table 2. Primary and secondary end points

Table 3. Radial artery spasm (RAS) classification according to operators’ impression
Table 3. Radial artery spasm (RAS) classification according to operators’ impression


The TRA for percutaneous cardiovascular diagnostic and therapeutic interventions is recognised as being associated with lower vascular and bleeding complication rates, early mobilisation and shorter hospitalisation, and less patient discomfort. The safety and efficiency of TRA in patients with ST-segment elevation myocardial infarction (STEMI) was evaluated in the RIVAL (Radial Versus Femoral Access for Coronary Intervention) primary PCI sub-analysis,17 RIFLE-STEACS (Radial Versus Femoral Randomized Investigation in ST-Elevation Acute Coronary Syndrome) trial4 and meta-analysis by Karrowni et al.18 showing favourable outcomes at 30 days compared with femoral access, including decreased bleeding and improved survival. The MATRIX (Minimizing Adverse Haemorrhagic Events by TRansradial Access Site and Systemic Implementation of angioX) trial19 concluded that unselected acute coronary syndrome (ACS) patients, irrespective of the type of ACS, undergoing invasive management should receive TRA. In STEMI, more than in non-ST-segment elevation ACS, adequate transradial operators’ experience is key to maximise transradial versus transfemoral benefits.

However, RAS is still a major limitation, occurring in up to 24% of cases. The lack of a uniform definition of RAS contributes to the great variability in the incidence of RAS found in the literature. Clinically relevant RAS can result in an increase in access site crossover rates, and is characterised by subjective pain for the patient and increased difficulty of catheter manipulation. The only objective method to quantify RAS, an automatic pullback device to evaluate the maximal pullback force during the sheath removal, has a close correlation with clinical symptoms (severity of patient’s pain).6 Therefore, in our study, in order to estimate the impact of using prophylactic medication on RAS, we applied a VAS to measure patient’s discomfort, showing no difference from placebo.

Previous studies have shown differences in the operators’ impression of difficulty in catheter manipulation.8,12,20 This was not used as the principal end point of spasm classification in our study because it lacks objectivity. Instead, we used the total time to complete the procedure and the total radiation as objective measures of any difficulties that could be experienced throughout catheterisation. Interestingly, there was a difference in the subjective operator’s impression, favouring the use of a vasodilator, but not in the objective ones; that difference could explain the greater use of additional vasodilator in the placebo arm. The fact that no differences in objective measurements of difficulty were found corroborates the decision to avoid the use of operators’ subjective impressions in RAS assessment.

As we aimed to evaluate the clinical effect of a prophylactic vasodilator in the transradial catheterisation setting, we chose nitroglycerin in the habitual dose (200 µg) compared with placebo. Use of a vasodilator cocktail is not a common practice in many centres, and there is no standard medication of choice.20,21 Nitroglycerin is the second most used medication to avoid radial spasm during catheterisation.11 The most used drug, verapamil, was recently tested against placebo in a randomised controlled trial by Hizoh et al. This study showed that RAS is a rare event in experienced operators after a learning curve (1.7%). The authors found no clinically relevant differences between the placebo and the preventive verapamil (5 mg) groups in terms of the investigated end points, including rates of access site conversion, the most important aspect related to RAS; RAS itself and subjective pain of the patients using an arbitrary semi-quantitative scale (1=no pain to 6=unbearable pain).22 This was a similar finding in the present study. The subjective operators’ impression was not evaluated by Hizoh et al., but procedural and fluoroscopic times were similar between groups.

Since recent advances in technique and materials could have mitigated the risk of access failure, we expected a low rate of crossover; so we designed our study to show difference in the pain referred by the patient using a quantitative scale (VAS). In fact, we observed a low and equal rate of crossover due to spasm in both groups.

The lack of difference between groups could be partly explained by the high experience of operators on TRA, because spasm becomes less of an issue as experience increases, but in our study one of the operators was on the learning curve, and he accounted for 20% of cases. Usually the procedures in other studies were made only by experienced operators,12,20,22 so our study is the first that included operators with less experience, and even so, the use of prophylactic nitroglycerin showed no advantage over placebo.


The main limitation of our trial is that it was conducted in a single, high-volume institution, in which TRA is the main technique for catheterisations. As only one operator was still on the learning curve, caution should be used to apply the results in centres with low-volume. Second, a qualitative evaluation of RAS was used, which could increase the potential bias; nevertheless, a close association has been shown between quantitative measurement of RAS and the pain reported by the patients.6

We did not evaluate the impact of nitroglycerin on radial artery occlusion, which has been shown to have a benefit with post-procedural use, but that study did not administer a standardised intra-arterial cocktail.23 Prevention of occlusion is at least as important as spasm, however, our study was assessing the impact of prophylactic use of nitroglycerin on the incidence of clinical RAS. The influence of pre-procedural medication on occlusion has not yet been shown, and it should be evaluated in future trials.


Our data indicate that prophylactic use of nitroglycerin offers no advantage in terms of comfort to patients during cardiac catheterisation by TRA. Furthermore, while there was difference in operators’ perception of spasm, omission of a vasodilator does not cause any objective difficulty during catheterisation. Therefore, the prophylactic use of nitroglycerin may not necessarily be required in TRA.

Key messages

  • The transradial approach for coronary catheterisation is an elegant and valuable method for diagnostic and therapeutic procedures
  • The incidence of radial artery spasm varies between 2% and 34%, and may lead to femoral conversion
  • Prophylactic use of nitroglycerin offers no objective advantage in this scenario



Ethical approval

“All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.”

Conflict of interest

None declared.


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