How to Prevent and to Manage Radial Artery Spasm during Coronary Interventions?
Olivier Varenne
Interventional CardiologyHôpital CochinRené Descartes University Paris France

Use of transradial approach.
Transradial approach for percutaneous coronary interventions (PCI) reduces vascular and bleeding complications at the puncture site, improves patient comfort and reduces the length and cost of hospitalization, when compared to femoral approach 1-4.
Transradial access has been shown to virtually eliminate local vascular complications compared to transfemoral access (0.3% vs. 2.8%, p<0.0001) 5. In addition in a recent meta analysis including 3224 patients from 12 randomized studies, transradial access virtually eliminate entry site complications (major haematoma, vascular surgery, or arteriovenous fistula) compared to femoral access (OR 0.20, 95% CI 0.09 to 0.42; p < 0.0001), but is associated with a higher rate of procedural failure (OR 3.30, 95% CI 1.63 to 6.71; p < 0.001) requiring an increased operator experience. Nowadays, feasibility and safety of transradial approach allows an early discharge after uncomplicated angioplasty.
Besides technical issues, radial artery spasm remains the major limitation of transradial approach, occurring in 12% to 22% of untreated patients 6-7. Higher reactivity of the radial artery may explain its propensity to spasm during catheterization and PCI 8. Increased occurrence of radial artery spasm has been reported in association with small radial artery size, female gender, long and difficult procedures with multiple catheter exchanges, bigger sheath size, operator inexperience 4.
What is known about spasm prevention in the literature?
In clinical daily practice, several combinations of vasodilators are used to reduce the rate of radial artery spasm, often based on physician experience and/or local practice.
Radial artery spasm could occur at anytime during the procedure. It is wise to select patients with large radial arteries at the beginning of the learning curve to allow an easy and smooth radial puncture. It is also important to control the advance of the catheter toward the aorta, and not advance the catheter without the 0.035” guidewire.
Molsidomine and verapamil are among the most widely used drugs to prevent radial artery spasm during PCI. Verapamil, a calcium channel blocker, is an arterial vasodilator that reduces radial artery spasm when administered in combination with nitroglycerin (22% versus to 8%; p=0.029) 7. Molsidomine is a nitric oxide (NO)-releasing prodrug converted to the active compound SIN-1 by liver esterases, and as only been evaluated in non randomized, non blinded trials, with some beneficial efficacy 4. However, data from large scale randomized trials in this setting are still missing.

Methods of the trial
To better evaluate vasodilators efficacy on radial artery spasm, we designed a large randomized, monocentric, double blind trial that evaluated the effects of molsidomine and verapamil and their combination in the prevention of radial artery spasm during PCI: the SPASM (Survenue Per Angioplastie d’un Spasme Majeur) study 9.
In our cathlab, all coronary interventions, expect those performed in patients presenting with cardiac arrest or cardiogenic shock, and in patients with an absent left radial pulse, are performed through the left radial approach. During the study period (May 2003-May 2005), 94% of PCIs were performed through the left radial artery, 2% through the right radial and 4% through the femoral arteries. The procedures were performed by interventional cardiologists with extensive experience in radial approach (total procedures over 1000, annual workload over 400).
All patients received one hour prior to the procedure a mild sedative (hydroxyzine dichlorhydrate 100 mg) and a topical anaesthesia (lidocaine and prilocaine, Emla® cream, Astra Zeneca, Sweden) was placed on the left wrist, except for patients admitted for acute myocardial infarction. Subcutaneous injection of lidocaine1% (0.5mL) was systematically administered before arterial puncture. A regular 20 Gauge needle was used for arterial puncture which was advanced through the radial artery (transradial puncture). A hydrophilic guidewire (Terumo, Japan) was gently advanced in the radial artery, and the arterial sheath (5 or 6 French, Radiofocus Introducer I, Terumo, Japan) was then advanced on the guidewire, after limited skin incision with a blade. If, indicated, coronary angioplasty was performed immediately after the coronary angiography (“ad hoc” angioplasty) in the vast majority of cases (82%) and as a separate procedure in 18% of cases (i.e. complex procedures, renal insufficiency requiring hydratation). All angioplasty procedures were performed using 6 French sheaths and catheters. For coronary angiography, a 5 French sheath was the first choice; a 6 French sheath was used with 5F diagnostic catheters when the probability of coronary angioplasty seemed high (i.e., acute coronary syndromes, restenosis). For diagnostic angiographies, left and right Judkins 4.0, and pigtail catheters were used as the first choice. For the left coronary artery, left Judkins 3.5 and 5.0 were occasionally used (3% of left artery catheterization). For the right coronary artery, Right Judkins 3.5 and Amplatz AL1 were also infrequently used (5% of right catheterization). The catheters were advanced and exchanged on a regular 0.035” guide (Boston Scientific). No general anaesthesia was used during

Correspondence:Dr Olivier Varenne Interventional Cardiology Hôpital CochinRené Descartes University Paris V27 rue du Faubourg Saint Jacques75014 Paris
E-mail: olivier.varenne@cch.aphp.fr

any procedures. Pain due to radial artery spasm was assessed using an analogical scale from 0 to 10 (0 no pain, to 10 intolerable) a threshold of 5 was used to define a severe pain. Morphine chlorydrate was administered at the investigator’s discretion.
A total of 1219 patients referred for PCI (including primary angioplasty for acute myocardial infarction) were randomized in a double-blinded fashion to receive verapamil 2.5mg (n=409), 5 mg (n=203) molsidomine (1mg, n=203), placebo (n=198) or a cocktail including verapamil 2.5mg and molsidomine 1 mg (n=206) in addition to 5,000U of unfractionated heparin in the radial artery.

The sample size was calculated to detect a 50% reduction in arterial spasm incidence with a a risk=0.05 and and ß risk=0.15, based on a reported radial spasm incidence of 22% in patients receiving placebo during PCI 7. The study solution was administered immediately after sheath insertion directly in the arterial lumen. All patients received aspirin 250 mg before the procedure. Anti thrombotic treatment was left to the physician’s discretion, but GpIIb/IIIa inhibitors were recommended in primary angioplasty for acute myocardial infarction and acute coronary syndromes, resulting in a 32% use during angioplasty procedures.
Clinical, angiographic and procedural data, including gender, sex, age and wrist size before the procedure were prospectively entered in the database. The primary end point of the study was the occurrence of an arterial spasm defined as a severe limitation of the catheters movements associated or not to angiographic confirmation (figure 1).
Patients were examined at discharge and local complications were assessed. Major local complications were defined by haematomas requiring blood transfusion or surgical repair.
Results
The SPASM study included a total of 1219 patients. The clinical and angiographic characteristics of the population were equally distributed between the groups (table 1). Most patients were male (72%) with a mean age ranging from 60.5 to 62.2 years according to treatment group. The wrist diameter before the procedure was identical among the groups: 17.5 cm, 17.5 cm, 17.5 cm, 17.5 cm, 17.4 cm (placebo, molsidomine, verapamil 2.5mg, verapamil 5mg and verapamil+molsidomine; respectively). 5F catheters were used more often than 6F catheters in all the groups. The average number of catheters used during the procedures was 3.3 +/- 1.1 and was the same among the different groups. A procedure with no detectable pain (pain scale=0) was significantly more frequent with verapamil 2.5 mg (24.7%) or 5mg (53.5%) and with the association verapamil and molsidomine (53.8%), than with placebo or with molsidomine alone (0%).

Figure1Severe radial spasm occurring after left coronary catheterization and before right Judkins catheterism (Varenne O. personal data).

Table 1. Demographic, Angiographic and Clinical Characterstics of  Population

Data are reported as mean (SD) and n (%) for continuous and categorical variables respectively; *ANOVA and Pearson chi-square test (Fisher exact test when expected count<5) for continuous and categorical variables respectively.

Rate of radial artery spasm in the different treatment groups
Radial spasm occurred during coronary intervention in 44 patients (22.2%) receiving placebo (Table 2). The rate of radial spasm was significantly reduced when molsidomine 1mg was administered in the radial artery at the beginning of the procedure (13.3%, p=0.02 vs. placebo). Radial spasm incidence was further reduced by intra arterial verapamil 2.5 mg (8.3%, p<0.0001 vs. placebo) and by the combination of verapamil and molsidomine 4.9%, p<0.0001). Radial spasm occurrence was not affected by the dose of verapamil (7.9% vs. 8.3%; verapamil 2.5 vs. 5mg; respectively).

Table 2. Occurrence of radial spasm in the different treatment groups.

Radial artery spasms risk factors
The occurrence of radial spasm was associated with several factors (table 3). Patients with radial spasm were younger (57.2 vs. 61.6 y, p<0.0001), more frequently female (55.4 vs. 25%, p<0.0001) and had a smaller wrist diameter (17.2 vs. 17.5 cm; p=0.01). In addition, the occurrence of radial spasm was related to severe pain (pain scale>5: 23.3 vs. 4.4%, p<0.0001) and to the use of major analgesics (6.9 vs. 3.1%; p=0.04). However, neither the procedure duration (35.2 vs. 33.9 min; p=0.48), nor the number of catheters used during the procedure nor arterial sheath size (4F-5F versus 6F) were associated with the occurrence of radial artery spasm.

Table 3. Characteristics of the population with radial spasm

Data are reported as mean (SD) and n (%) for continuous and categorical variables respectively;
*Student and Pearson chi-square test (Fisher exact test when expected count<5) for continuous and categorical variables respectively.

How to prevent radial spasm during PCI?
Bivariate analysis indicates that compared to placebo, vasodilators all reduced the odds of having a radial spasm during procedure, the relative risk reduction ranging from 46% for molsidomine to 87% for the association verapamil and molsidomine (table 4). After adjustment for confounders, the figures were minimally diminished.
Administration of vasodilators during the procedure was well tolerated, even in patients with depressed left ventricular function. Minor haematomas were noted in 70 patients (5.7%), and the absence of a left radial pulse with no ischemia in 12 (1%) No major local complication occurred during the study period.

Table 4. Univariate and multivariate odds ratio of radial spasm for the various treatment group.

OR were estimated by logistic regression and were systematically adjusted for the trial. *Analysis was additionally adjusted for age, sex, history of angioplasty, sheath and wrist diameters, number of catheters and pain scale.

In this study    that compares the efficacy of different vasodilatators and their combination against placebo in the prevention of radial artery spasm during unselected coronary angiographies and PCI, 22.2% of patients assigned to placebo had radial artery spasm, which is consistent with the study by Kiemeneij et al (2003)7
Compared to placebo, molsidomine 1 mg, verapamil 2.5 mg, verapamil 5 mg and the association of verapamil 2.5 mg and molsidomine 1mg all significantly reduced the occurrence of radial artery spasm. Therefore all these vasodilators strategies could be recommended to avoid radial artery spasm. Furthermore, the greatest magnitude in the reduction was observed with the association of verapamil and molsidomine (-87%), which could be recommended in patients with a high probability of radial artery spasm (young age, female, small wrist).
Among patients treated with verapamil, the higher dose (5mg) did not offer additional efficacy over the lower (2.5mg), but could theoretically increase the risk of side effects, especially when left ventricular dysfunction is present.
Of interest, radial spasm reduction was associated with less pain and less use of major analgesics. This could allow a more comfortable procedure and reduce the fear for the interventional cardiologist to switch from femoral to radial access.
 Patients with radial artery spasm were younger and were more often female, which is consistent with previous findings 4. Wrist diameter was inversely associated with the occurrence of radial spasm. Of interest, arterial sheath size, and the number of catheters used during the procedure (number of passages through the radial artery) were not associated with the occurrence of radial artery spasm. This could be explained by operator experience. Indeed, the relationship between limited operator experience and the occurrence of radial spasm has been previously reported 10. Careful patient selection therefore remains necessary, especially if the procedure is performed by low volume radial operators. Whether these low rates of radial spasm under vasodilator agents could be further reduced by using coated arterial sheaths remains to be investigated 11-12. In addition, because of the definition of radial artery spasm, asymptomatic spasms could not be excluded. However, the rate of such undiagnosed radial artery spasms is probably similar among all the groups, so that the effectiveness of each treatment is not affected.
Finally, other vasodilators such as phentolamine 13 or various vasodilator combinations such as nitroglycerin and verapamil or verapamil 5 mg and molsidomine 1 mg were not evaluated in the present study. Nevertheless, the drugs and the vasodilators association tested in the present study are extensively used in interventional cardiology teams prone to use radial artery approach and therefore, our results remain clinically relevant.

Management of radial spasm?
If a radial spasm occurs during the PCI, any catheter movement should be interrupted, to allow pain relief. While the patient is reassured about the benignity of the situation, analgesics should be injected (i.e. morphine 0.5cg IV). The catheter should remain in place while the guidewire is eventually removed. A rapid angiography will confirm the radial artery spasm and its severity. Vasodilators should be injected at the site of the spasm through the catheter lumen (verapamil 2.5mg, molsidomin 1mg). It is very important to let the drug act on the radial artery wall during 5 to 10 minutes. After this period, a gentle movement of the catheter is attempted, with or without angiographic control. If radial artery spasm is not alleviated, an exchange for a 4F catheter in case of diagnostic angiography could be attempted. When available, general anaesthesia is an efficient alternative to control radial artery spasm.
Conclusion
In our experience, radial artery spasm during transradial PCI is effectively prevented by the administration of different vasodilators like verapamil 2.5 and 5 mg, molsidomine 1 mg or the combination of verapamil 2.5 mg with molsidomine 1 mg. Female gender, young age and small wrist diameter are independent predictors of radial spasm. Molsidomine alone is the least efficacious treatment in the prevention of radial artery spasm. The combination of verapamil 2.5 mg and molsidomine 1 mg provided the strongest relative risk reduction (-87%) of artery spasm compared to placebo and should be recommended, at least in patients with a high risk of radial artery spasm (young, female, small wrist diameter).

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