1

Introduction

The radial artery is fast becoming the preferred access site for performing coronary angiography and percutaneous coronary intervention (PCI) . In UK, adoption of the transradial access site (TRA) for PCI has increased from 10% in 2006 to over 60% in 2012 . TRA is associated with reduced mortality and major adverse cardiac events (MACE) in selected cohorts at high risk of bleeding complications , thought to be related to a reduction in major access site related bleeding complications . Transradial access is also associated with improved patient comfort and has also shown to be the preferred access site amongst patients undergoing PCI and be more cost effective than transfemoral access .

However, TRA approach is not without limitations, it is associated with a longer learning curve and complex procedures requiring large French size guide catheters may not always be possible particularly in patients with small diameter radial arteries. Furthermore operators may encounter radial artery spasm (RAS) during TRA particularly at the beginning of the learning curve, or when encountering radial anomalies. A previous review of 19 papers with 7197 participants found that the incidence of RAS was 14.7% in patients in whom the radial artery was chosen as the access site for coronary angiography or PCI .

RAS leads to patient discomfort, increased risk of vascular complications and procedure failure rate. Various drugs such as nitroglycerin, verapamil, isosorbide mononitrate are used to reduced the risk of RAS. However, there is high variability in practice amongst operators for administration of these drugs. Furthermore, there are no guidelines or recommendations for using such drugs in day-to-day practice. Therefore, we conducted a systematic review of the available literature to evaluate the efficacy of agents used for prevention of RAS.

2

Methods

We searched MEDLINE and EMBASE on October 2014 using the broad search terms: “vasodilator” AND “radial artery occlusion” OR “radial artery spasm” OR “transradial.” The search results were reviewed by two independent judicators (CSK, MR) for studies that met the inclusion criteria and relevant reviews. The bibliographies of included studies and relevant reviewers were screened for additional studies.

We included studies that evaluated any intra-arterial drug administered in the setting of TRA. The inclusion criteria were

• 1.
  

  Studies had to compare more than one agent or include a control group. There was no restriction based on sample size.

  
  
• 2.
  

  The studies had to evaluate some form of measure related to RAS such as incidence of RAS, change in diameter of radial artery and any adverse events associate with intra-arterial drug administration.

We excluded studies that administered drugs that were not intra-arterial and in-vitro studies.

Data was extracted from each study into preformatted spreadsheets. The data collected was on the year, country, number of participants, age of participants, % of male participants, participant inclusion criteria, and type of treatments, efficacy outcomes and safety outcomes. These results were narratively synthesized and trials with similar treatment arms were pooled using methods previous described .

We also compared studies for secondary outcomes of procedure time, and procedure failure rate in setting of RAS prevention and radial artery occlusion.

2

Methods

We searched MEDLINE and EMBASE on October 2014 using the broad search terms: “vasodilator” AND “radial artery occlusion” OR “radial artery spasm” OR “transradial.” The search results were reviewed by two independent judicators (CSK, MR) for studies that met the inclusion criteria and relevant reviews. The bibliographies of included studies and relevant reviewers were screened for additional studies.

We included studies that evaluated any intra-arterial drug administered in the setting of TRA. The inclusion criteria were

• 1.
  

  Studies had to compare more than one agent or include a control group. There was no restriction based on sample size.

  
  
• 2.
  

  The studies had to evaluate some form of measure related to RAS such as incidence of RAS, change in diameter of radial artery and any adverse events associate with intra-arterial drug administration.

We excluded studies that administered drugs that were not intra-arterial and in-vitro studies.

Data was extracted from each study into preformatted spreadsheets. The data collected was on the year, country, number of participants, age of participants, % of male participants, participant inclusion criteria, and type of treatments, efficacy outcomes and safety outcomes. These results were narratively synthesized and trials with similar treatment arms were pooled using methods previous described .

We also compared studies for secondary outcomes of procedure time, and procedure failure rate in setting of RAS prevention and radial artery occlusion.

3

Results

Our search yielded 123 relevant articles and after screening and reviewing full manuscripts, 21 articles met the inclusion criteria with 22 clinical studies . The process of study selection is shown in Fig. 1 .

Flow diagram of study selection.

The study design and participant characteristics of the included trials is shown in Table 1 . Majority of studies (n = 14) used blinding and these studies took place between 1997 and 2007 in different centers around the world. There were a total of 8777 participants (range of participants in each study 30 to 1950) with an average age of 61 years and 70% were male participants. All studies took place in the setting of transradial access (TRA).

Table 2 shows the different treatments that have been used as intra-arterial vasodilators and results from the studies. Many agents were evaluated including verapamil, magnesium sulphate, nitroglycerin, nicorandil, diltiazem, isorobide mononitrate, petolamine, isosorbide dinitrate, molsidomine, nicardipine, placebo and combinations of these drugs as well as other drugs such as nitroprusside. A variety of outcomes evaluated included any measure of changes in radial diameter, RAS rates, procedural success, blood pressure changes and radial occlusions and semi-occlusions.

Table 2

Intra-arterial vasodilator treatments, results and interpretation.

Study ID	Treatments	Results	Interpretation
Abe 2000	Saline, ISDN 1 mg, 3 mg, 5 mg, verapamil 1 mg, 3 mg, 5 mg, lidocaine 10 mg, 30 mg, 50 mg, n = 10 in each group.	Change ratio: (diameter after drug injection − diameter before drug injection) × 100/(diameter before drug injection) for proximal and distal: saline 3.1%/6.1%, ISDN 1 mg 19.1%/20.3%, 3 mg 17.4%/18.6%, 5 mg 31.0%/28.8%, verapamil 1 mg 6.4%/14.6%, 3 mg 4.3%/7.6%, 5 mg 9%/10.8%, lignocaine 10 mg − 15.6%/− 12.1%, 30 mg − 12.7%/− 17.3%, 50 mg − 7.3%/− 1.6%.	ISDN was most potent vasodilator compared to verapamil, lignocaine and placebo.
Boyer 2013	Verapamil 200 μg/nitroglycerin 200 μg (n = 43), placebo (n = 78)	Radial artery origin: no vasodilator 2.09 ± 0.41 mm, vasodilator 2.29 ± 0.47 mm, p = 0.022. Radial artery narrowest segment: no vasodilator 1.39 ± 0.43 mm, vasodilator 1.83 ± 0.56, p < 0.001 mm.	Nitroglycerin and verapamil was associated with greater vasodilation compared to placebo.
Byrne 2008	Verapamil 1 mg, magnesium sulphate 150 mg.	Increase in radial artery: magnesium 0.36 ± 0.03 mm, verapamil 0.27 ± 0.03 mm, p < 0.05. Decrease in MAP with verapamil − 6.6 ± 1.4 mmHg, p < 0.01, magnesium − 0.25 ± 1.4 mmHg, p = NS. Vagal reaction requiring IV atropine: verapamil 3, magnesium 1.	Magnesium is a more potent vasodilator than verapamil.
Carrilo 2011	Nitroglycerin 200 μg/verapamil 2.5 mg (n = 15), verapamil 2.5 mg (n = 15).	Relative diameter increase: nitroglycerin/verapamil 6.6 ± 6.7, verapamil 8.6 ± 14.5, p = 0.69.	Similar vasodilation can be achieved with verapamil with and without nitroglycerin.
Chen 2006	Nitroglycerin 100 μg/verapamil 1.25 mg (n = 133), nitroglycerin 100 μg (n = 135), placebo (n = 93).	RAS rate: nitroglycerin/verapamil 5/133, nitroglycerin 6/135, placebo 19/93.	Similar rates of RAS with nitroglycerin with and without verapamil which were lower than placebo.
Cho 2008	Nicorandil 12 mg (n = 72), nitroglycerin 200 μg/verapamil 100 μg (n = 72).	Change in radial artery diameter at proximal segment: nicorandil 1.58 to 1.92 mm, nitroglycerin/verapamil 1.67 to 1.93 mm. Change of minimal luminal diameter: nicorandil 0.63 vs nitroglycerin/verpamil 0.48. RAS rate (proximal and middle segment): nicorandil 37/72, nitroglycerin/verapamil 51/72, proximal only nicorandil 22/72, nitroglycerin/verapamil 24/72, middle segment nicorandil 15/72, nitroglycerin/verapamil 27/72.	Nicorandil is not superior to nitroglycerin and verapamil as a vasodilator.
Coppola 2006	Nitroglycerin 100 μg/diltiazem 5 mg (n = 123), nitroprusside 100 μg/diltiazem 5 mg (n = 119), nitroglycerin 100 μg/nitroprusside 100 μg/diltiazem 5 mg (n = 137).	Radial artery diameter: nitroglycerin/diltiazem 2.37 mm, nitroprusside/diltiazem 2.36 mm, nitroglycerin/nitroprusside/diltiazem 2.33 mm. RAS rate: nitroglycerin/diltiazem 15/123, nitroprusside/diltiazem 16/119, nitroglycerin/nitroprusside/diltiazem 13/137.	No improvement in RAS with nitroglycerin/diltiazem, nitroprusside/diltiazem and nitroglycerin/nitroprusside/diltiazem.
Dalal 2011	Nitroglycerin 200 μg/diltiazem 5 mg (n = 100), nicorandil 4 mg (n = 100).	Decrease in radial artery diameter in proximal segment: nitroglycerin/diltiazem 80 ± 48%, nicorandil 80 ± 37%. Decrease in systolic blood pressure: nitroglycerin/diltiazem 13 ± 9, nicorandil 6 ± 5.	Similar decreases in radial artery diameter with nicorandil compared to nitroglycerin/diltizem but there is less blood pressure drop with nicorandil.
Dharma 2012	Nitroglycerin 200 μg/diltiazem 2.5 mg (n = 75), nitroglycerin 200 μg (n = 75).	Procedural success 100% in both groups. Systolic BP nitroglycerin/diltiazem 162.68 ± 27.68 to 125.56 ± 21.30 mmHg, nitroglycerin 161.12 ± 27.54 to 141.24 ± 26.15 mmHg. Diastolic BP nitroglycerin/diltiazem 80.11 ± 11.03 to 71.60 ± 11.21 mmHg, nitroglycerin 78.31 ± 13.61 to 75.88 ± 11.45 mmHg. Heart rate nitroglycerin/diltiazem 81.69 ± 18.37 to 86.61 ± 18.05, nitroglycerine 81.61 ± 17.27 to 84.69 ± 18.08.	Similar rates of procedural success with nitroglycerin with and without diltiazem.
Hizoh 2014	Verapamil 5 mg (n = 294), placebo (n = 297).	RAS rate: verapamil 5/294 (1.0%), placebo 3/297 (1.7%).	Lower rates of RAS with verapamil compared to placebo.
Kiemeneij 2003	Verapamil 5 mg/nitroglycerin 200 μg (n = 50), placebo (n = 50).	Maximum pullback force: verapamil/nitroglycerine 0.53 ± 0.52, placebo 0.76 ± 0.45. RAS rate: verapamil/nitroglycerin 4/50, placebo 11/50.	RAS lower with verapamil/nitroglycerin compared to placebo.
Kim 2007	Nicorandil 4 mg (n = 75), verapmil 200 μg (n = 75).	Blood pressure change: nicorandil reduced by 15.4 ± 11.5 mmHg, verapamil reduced by 16.3 ± 13.4 mmHg. Change in diameter: proximal nicorandil 2.59 ± 0.49 mm to 2.91 ± 0.48 mm, verapamil 2.62 ± 0.57 mm to 2.89 ± 0.56 mm. Mid-segment increase nicorandil was 0.34 ± 0.23 mm, verapamil 0.24 ± 0.15 mm. RAS rate: nicorandil 39/75 (50.7%) vs verapamil 39/75 (52%).	Similar RAS rates with nicorandil and verapamil.
Manickam 2011	Verapamil/nitroglycerin (likely n = 300), nicorandil 2 mg (likely n = 300).	RAS rate: nicorandil 3% (likely 9/300), verapamil/nitroglycerin 12% (likely 36/300).	RAS lower with nicorandil compared to verapamil/nitroglycerin.
Mont’AlverneFino 2003	ISMN (n = 23), diltiazem/ISMN (n = 27).	Radial artery diameter: ISMN before 2.39 ± 0.45 mm after 2.35 ± 0.47 mm, diltiazem/ISMN before 2.15 ± 0.32 mm after 2.46 ± 0.39 mm. Radial artery output ISMN before 7.07 ± 5.37 ml/min after 5.89 ± 3.33 ml/min, diltiazem/ISMN before 5.74 ± 2.79 ml/min after 9.06 ± 7.78 ml/min. RAS rate: ISMN 1/23, diltiazem/ISMN 0/27. Radial spasm, occlusion, partial occlusion: ISMN 4/23, diltiazem/ISMN 0/27.	RAS rates similarly low in ISMN and diltiazem ISMN but study is underpowered.
Rosencher 2012	Diltiazem 5 mg (n = 117), verapamil 2.5 mg (n = 109), ISDN 1 mg (n = 106).	RAS rate (severe and minor): ISDN 22/106 (21%), verapamil 23/109 (21%), diltiazem 42/117 (26%).	Higher rates of RAS with diltiazem compared to ISDN and verapamil.
Rosencher 2013 SPASM 3	Diltiazem (n = 252), verapamil (n = 235), ISDN (n = 244).	RAS rate: diltiazem 67/252 (26.6%), verapamil 38/235 (16.2%), ISDN 42/244 (17.2%).	Higher rates of RAS with diltiazem compared to ISDN and verapamil.
Ruiz-Salmeron 2005	Petolamine 2.5 mg (n = 250), verapamil 2.5 mg (n = 250).	Change in diameter petolamine 12.6 ± 12.9%, verapamil 13.6 ± 14.5%. RAS rate: verapamil 33/250 (13.2%), pentolamine 58/250 (23.2%). Radial semiocclusion and occlusion: verapamil 19/250 (7.7%), pentolamine 16/250 (6.4%).	Radial semi-occlusion and occlusion with verapamil and pentolamine.
Sakai 1999	ISDN 1 m g, nitroglycerin 1 mg, verapamil 5 mg.	Enlargement greatest with nitroglycerine 12.7% vs ISDN and verapamil.	Greater vasodilation with nitroglycerine compared to ISDN and verapamil.
Varenne 2006 SPASM 1 and 2	Verapamil 2.5 mg (n = 409), verapamil 5 mg (n = 203), molsidomine 1 mg (n = 203), verapamil 2.5 mg/molsidomine 1 mg (n = 206), placebo (n = 198).	RAS rate: placebo 44/198 (22.2%), verapamil 2.5 mg 34/409 (8.3%), verapamil 5 mg 16/203 (7.9%), mosidomine 1 mg 27/203 (13.3%), verapamil/mosidomine 10/206 (4.9%). No difference in symptomatic hypotension.	RAS is lowest with verapamil/mosidomine combination.
Varenne 2014	Diltiazem, verapamil, mosidomine, isosorbidedinitrate or placebo.	RAS rate: placebo 44/198 (22.2%), molsidomine 27/203 (13%), verpamil 88/847 (10.4%), similar for placebo ISDN and diltiazem. Significant blood pressure fall occurred more with diltiazem and ISDN.	RAS lowest with verapamil and/or molsidomine and ISDN and diltiazem should be not be used.
Xiaolong 2012	Nitroglycerine 200 μg (n = 60), nicardipine 200 μg (n = 60), nicardipine 200 μg/nitroglycerine 100 μg (n = 60).	RAS rate: baseline nitroglycerin 9/60 (15%), nicardipine 5/60 (8.3%), combination 5/60 (8.3%), 2 min nitroglycerin 1/60 (1.7%), nicardipine 2/60 (3.3%) and combination 0/60 (0%).	Nitroglycerin and nicardipine are effective at lowering RAS but combination is best.

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