RAO and UAO occur with similar frequency and in the order of 7% to 8% when evaluated early by vascular ultrasonography following coronary procedures. More‐intensive anticoagulation is protective. Late recanalization occurs in a substantial minority of patients.

Meta‐analysis of 112 studies assessing RAO and/or UAO (N=46 631) were included. Overall, there was no difference between crude RAO and UAO rates (5.2%; 95% confidence interval [CI], 4.4–6.0 versus 4.0%; 95% CI, 2.8–5.8; P =0.171). The early occlusion rate (in‐hospital or within 7 days after procedure) was higher than the late occlusion rate. The detection rate of occlusion was higher with vascular ultrasonography compared with clinical evaluation only. Low‐dose heparin was associated with a significantly higher RAO rate compared with high‐dose heparin (7.2%; 95% CI, 5.5–9.4 versus 4.3%; 95% CI, 3.5–5.3; Q=8.81; P =0.003). Early occlusions in low‐dose heparin cohorts mounted at 8.0% (95% CI, 6.1–10.6). The RAO rate was higher after diagnostic angiographies compared with coronary interventions, presumably attributed to the higher intensity of anticoagulation in the latter group. Hemostatic techniques (patent versus nonpatent hemostasis), geography (US versus non‐US cohorts) and sheath size did not impact on vessel patency.

Incidence of radial artery occclusions (RAO) and ulnar artery occclusions (UAO) in coronary procedures, factors predisposing to forearm arteries occlusion, and the benefit of anticoaggulation vary significantly in existing literature. We sought to determine the incidence of RAO/UAO and the impact of anticoagulation intensity.

Clinical Perspective What Is New? Incident radial artery occlusion following coronary procedures range from single‐ to 2‐digit numbers, occurs within a broad spectrum of prophylactic anticoagulation, and prohibits the subsequent use of the artery as an access site for future catheterization or as a potential graft.

In this meta‐analysis of 112 studies, we found that the rate of forearm artery occlusion following a cardiac catheterization (diagnostic coronary angiography or intervention) ranges between 6% and 8% on average when evaluated early after catheterization using vascular ultrasonography, whereas the occlusion rate is higher when anticoagulation intensity is low, when the patency status is assessed early, and when coronary angiography, rather than intervention, is performed. What Are the Clinical Implications Postcatheterization unavailability of the radial artery raises several teleological, nephrological, and long‐term natural history issues beyond its loss as a potential graft for bypass surgery.

Therefore, reduction of forearm artery occlusion rates should become a priority target in interventional cardiology.

This meta‐analysis indicates that coronary angiography is not just a “simple” procedure, given that every tenth of these patients may be at risk for early vessel occlusion when on low‐anticoagulation regimen.

Adequate anticoagulation during coronary angiography, that is, ≥50 IU/kg of heparin and ultrasonographic patency assessment before discharge appear therefore mandatory.

Introduction

Radial artery occlusion (RAO) remains the silent protagonist in transradial coronary procedures. Its percentage rate ranges from single‐ to 2‐digit numbers and occurs within a broad spectrum of prophylactic anticoagulation.1 When RAO happens, it prohibits the reuse of this artery for future transradial coronary procedures as well as the use of this artery as a graft for coronary artery bypass surgery. On the other hand, although RAO is almost always clinically silent in the acute setting, the long‐term natural history of this condition is not very well characterized. Notably, although there is plenty of evidence regarding the incidence of forearm artery occlusion following cardiac catheterization, the populations studied and the sizes of the populations have been highly diverse and thus have provided highly variable estimates of RAO incidence. Furthermore, several studies have shown that anticoagulation prevents forearm artery occlusion, but the ideal intensity of prophylactic anticoagulation is rather ill‐defined in the existing literature.1, 2, 3 We therefore conducted this meta‐analysis to systematically evaluate the incidence of RAO and ulnar artery occlusion (UAO) as well as the role of anticoagulation intensity on forearm artery occlusions following diagnostic and interventional coronary procedures, and to define potential clinical and procedural factors that may impact on this incidence.

Methods

We sought for relevant studies through electronic searches of MEDLINE, EMBASE database, and the Cochrane Central Register of Controlled Trials from 1989 through August 15, 2016, and we also searched the www.tctmd.com, www.clinicaltrials.gov, www.clinicaltrialresults.org, and www.cardiosource.com websites for preliminary reports within the past year. We matched the results derived after having used the following key words: for radial artery occlusion: “radial artery” OR “radial catheterization” OR “radial access” OR “radial spasm” OR “transradial” AND “radial occlusion” OR “radial thrombosis” (Table 1); for ulnar artery occlusion: “ulnar artery” OR “ulnar catheterization” OR “ulnar access” OR “ulnar spasm” OR “transulnar” AND “ulnar occlusion” OR “ulnar thrombosis” (Table 2). Reference lists of relevant studies was additionally scanned.

Table 1. Search Strategy for Radial Artery Occlusion Search Terms 1. (“radial artery” OR “radial catheterization” OR “radial access” OR “radial spasm” OR “transradial”) 2. (“radial occlusion” OR “radial thrombosis”) 3. 1 AND 2

Table 2. Search Strategy for Ulnar Artery Occlusion Search Terms 1. (“ulnar artery” OR “ulnar catheterization” OR “ulnar access” OR “ulnar spasm” OR “transulnar”) 2. (“ulnar occlusion” OR “ulnar thrombosis”) 3. 1 AND 2

Study Selection

We included full‐length publications in English, German, or French language reporting RAO or UAO rates after a coronary angiogram (CAG) or percutaneous coronary intervention (PCI). No restrictions regarding the detection methods of arterial (radial or ulnar) patency were applied. Therefore, studies reporting RAO or UAO based on clinical grounds (ie, palpation, clinical examination, and/or Allen's test as well as reverse Allen's test), Barbeau's test, or Doppler ultrasonography (duplex, color, or nonimaging) alone or in combination were included. We prioritized the first screening method for RAO/UAO detection (eg, clinical evaluation only when palpation was used to screen RAO/UAO), rather than selecting further downstream techiques utilized after the first abnormal test (eg, typically vascular ultrasonography if pulsation was absent). No restrictions regarding the mode and dose of anticoagulation were applied. Exclusion criteria were: (1) irretrievable data; (2) ongoing studies; (3) trials not reporting RAO or UAO rates; (4) data in abstract form; and (5) duplicate reports.

Data Extraction

The search of literature, selection of studies, extraction of data, and quality assessment were initiated independently by 2 investigators (G.H. and K.A.) by using a standardized approach. Disagreements were resolved by consensus. For each study, we recorded the arterial occlusion rates after transradial or transulnar procedure, as well as all variables which are reported in the section “Outcomes.” Numerical aggregate data and categorical data as appearing in the publications were used for analysis.

Outcomes

The primary end points of this meta‐analysis were the (1) general crude rate of RAO and UAO and (2) rate of RAO and UAO according to anticoagulation intensity. Frequency of forearm artery occlusions was estimated in studies reporting early (ie, in‐hospital or within 7 days after CAG and PCI), late (ie, >7 days after the coronary procedure), and total occlusions (referring to all occlusions whether reported as early only or late only). The impact of anticoagulation intensity was assessed depending on whether patients received a low (ie, ≤5000 IU or up to 50 IU/kg body weight) versus a high (ie, >5000 IU or ≥70 IU/kg or activated clotting time >200 seconds) dose of unfractionated heparin (UFH). A patient group was allocated in the high‐anticoagulation‐dose group if a low dose of UFH was given but activated clotting time exceeded 200 seconds. Patients undergoing PCI had invariably received either ≥70 IU/kg of UFH or bivalirudin or both and were categorized into the high‐anticoagulation group. We adopted the occlusion rates as mentioned in the original articles or according to the intention‐to‐treat principle when figures were additionally given in a per protocol analysis.

Subgroup analysis was performed to assess the potential effect of the following parameters on the primary outcome: (1) study design, that is, randomized versus nonrandomized studies regardless of whether RAO/UAO was the study primary end point; also studies reporting RAO/UAO as a primary end point versus studies reporting arterial occlusion as a nonprimary end point; (2) duplex or color Doppler ultrasonography as a mode of detection of RAO and UAO versus other detection methods; (3) studies performed in the United States versus outside the United States; (4) CAG versus PCI; (5) coronary procedures with ≤5‐ versus >5‐Fr catheters; and (6) patent hemostasis versus all other hemostatic techniques after sheath removal. Coronary procedures performed with sheathless catheters were categorized according to their actual size relative to conventional sheath size (eg, a 6.5‐Fr sheathless catheter was considered a ≤5‐Fr catheter and a 7.5‐Fr sheathless catheter a >5‐Fr catheter).

Statistical Analysis

The rate of RAO and UAO of each study is reported as a percentage. We performed meta‐analyses of studies estimating the rate of RAO to obtain the pooled estimate for the whole cohort of studies. Similar separate analysis was performed for UAO. The proportion of inconsistency across studies not explained by chance was quantified with the I2 statistic. Heterogeneity between subgroups was calculated with Cochran's Q test.4 Because of significant heterogeneity among studies, the random‐effects model was used to obtain the pooled estimate. Finally, we performed stratified analysis to evaluate whether the pooled rates of RAO or UAO differ between subgroups (early versus late occlusion, high‐ versus low‐dose heparin, use of Doppler to evaluate occlusion versus non‐Doppler studies, CAG versus PCI studies, patent hemostasis versus all other hemostatic techniques after sheath removal, US versus non‐US studies, use of ≤5‐ versus >5‐Fr catheters, randomized versus nonrandomized studies, and studies assessing artery occlusion as a primary end point versus rest of studies). Univariable random‐effects metaregression analysis was used to examine whether effect sizes were affected by these factors. Estimates of occlusion rates between subgroups were compared with a test of interaction.5 In addition, age and duration of procedure at study level were included in univariable metaregression. All tests used in our analysis were 2‐sided. Results were considered statistically significant at P<0.05. Rates of arterial occlusion and confidence intervals (CIs) were illustrated with forest plots.

Presence of publication bias was investigated graphically by funnel plots of precision, and its implications for our results were assessed by Duval and Tweedie's trim‐and‐fill method.6 All analyses were performed with Comprehensive Meta Analysis software (Version 2; Biostat, Englewood, NJ).7

Results

Qualitative Summary

Our search identified 9949 potential eligible publications reporting RAO and 2041 publications reporting UAO, which were narrowed by preliminary review to 145 potentially relevant original articles. Of those, 28 articles were excluded because either no RAO/UAO rates were reported or they were reviews/editorials or meta‐analyses not reporting original data on RAO/UAO rates, whereas 5 studies were excluded because they were duplicate reports (Figure 1). Finally, 112 original articles assessing RAO and/or UAO8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119 were deemed eligible for our meta‐analysis, of which 99 cohorts from 92 studies publishing RAO8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 and 25 cohorts reporting UAO were analyzed28, 40, 73, 75, 85, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119 (Tables S2 and 3).

Figure 1. Electronic literature search. Summary of the literature search results.

Table 3. Overview of Studies Assessing UAO Sorted by Date of Publication Author, Year (Country) Sample Size (N) Age (y) Women (%) Study Design Sheath Size Anticoagulation Intensity Hemostasis UAO Rate (%) (Early/Late RA Patency Assessment) Assessment of Arterial Occlusion Comments and Authors’ Conclusions Terashima,100 2001 (Japan) 9 71 55.6 Observational L LD Non‐Patent 0.0/NA Clinical First report on TU catheterization; complications such as bleeding, loss of a UA pulse, ulnar nerve injury, and the formation of an aneurysm or fistula were not observed in any patient Dashkoff,101 2002 (United States) 5 68 40 Observational NA NA Non‐Patent 0.0/0.0 Clinical UA strongly palpable at 1‐week and at 3‐month F‐U in all patients; authors’ conclusion: “the TU approach to coronary procedures is feasible and may be preferable in selected cases” Limbruno,102 2004 (Italy) 13 NA NA Observational H HD Non‐Patent NA/0.0 Ultrasonography TU primary PCI; authors’ conclusion: “TU access may represent an additional option in patients undergoing primary angioplasty when the RA access site is not available” Gourassas,103 2004 (Greece 3 61 33.3 Observational H HD Non‐Patent 0.0/NA Clinical TU PCI in 3 patients; authors’ conclusion: “TU coronary angioplasty is feasible and may turn out to be the favorable method in certain cases where the radial artery may serve as a free graft for surgical revascularization” Lanspa,104 2004 (United States) 1 52 100 Observational L LD Non‐Patent 0.0/NA Clinical TU CAG in the presence of RAO and normal inverse Allen's test in a patient with limited vascular access Lanspa,105 2005 (United States) 12 12 68 NA Observational NA LD Non‐Patent 0.0/NA Clinical TU CAG in 4 patients with pre‐existing RAO (1 chronic and 4 acute RAOs) Rath,106 2005 (India) 100 NA NA Observational NA NA NA 0.0/NA Clinical This study was conducted to assess the safety and feasibility of a transulnar approach in performing coronary procedures Mangin,107 2005 (Canada) 117 62 31.6 Observational NA HD Non‐Patent 0.0/NA Clinical, ultrasonography No ulnar pulse loss was noted Aptecar,108 2005 (France) 17 60 24.9 Observational L NA Non‐Patent NA/0.8 Ultrasonography 158 patients catheterized by the UA; 173 procedures performed, including 122 CAG and 51 PCI Aptecar‐UA,28 2005 (France) 216 63 24.5 RCT H HD Non‐Patent NA/5.88 Ultrasonography After sheath removal and local hemostasis, heparin infusion was continued at the discretion of the operators in those patients with ACSs (=55% of the TU group of patients); PCI patients n=103 (of the 216 patients in the UA group); access site artery occlusion more frequently after a second PCI; authors’ conclusion: “the transulnar approach has the potential to spare injury to the RA in anticipation of its use as a coronary bypass conduit” Knebel,109 2008 (United States) 28 60 32.1 Observational NA HD Non‐Patent 3.57/7.14 Clinical A bolus of heparin (100 IU/kg) was given IV and additional doses (60 IU/kg) were repeated if the procedure lasted longer than 1 h; 5‐ and 6‐Fr catheters were used for CAG or PCI; Andrade,110 2008 (Brazil) 1 63 0 Observational H HD Non‐Patent 0.0/NA Clinical Primary TU PCI without ischemic hand complications despite past RAO; authors’ conclusion: “the transulnar approach represents an alternative to the transradial approach in selected cases when performed by radial‐trained operators, sharing a high success rate and extremely low incidence of access site complications” Vassilev,111 2008 (Bulgaria) 131 69.1 36.6 Observational H NA Non‐Patent 0.0/NA NA PCI in 10 of 59 patients; spasm frequency: 13.6%; authors’ conclusion: “the TU approach has higher access site failure rates in an unselected patient population” Li‐UA,40 2010 (China) 118 60 32.3 RCT H HD Non‐Patent 5.1/1.7 Ultrasonography Asymptomatic UA stenosis 1 and 30 days after procedures: 11.0% and 12.3% Hussein,112 2010 (Egypt) 1 71 0 Observational H HD Non‐Patent NA/0.0 Ultrasonography Recanalization of a CTO Agostoni,113 2011 (Italy) 1 67 0 Observational H HD Non‐Patent 0.0/NA Clinical, oximetry TU PCI in ipsilateral RAO James,114 2012 (United States) 1 78 100 Observational H HD Non‐Patent 0.0/0.0 Barbeau's Sheathless TU PCI de Adrade,60 2012 (Brazil) 387 61.2 54.3 Observational NA NA Non‐Patent 0.73/NA Clinical, Barbeau's Allen's test not routinely performed Kwan,115 2013 (United States) 17 77 23.5 Observational L HD PH‐modified 0.0/NA Barbeau's TU PCI with a 5‐Fr Glide sheath in the presence of RAO In patients with RAO; authors’ conclusion: “ipsilateral TU catheterization may not be an absolute contraindication. Our results suggest that extensive collaterals from the anterior interosseous artery may be the reason for protection against hand ischemia…” Agostoni,116 2013 (Italy) 42 63 31 Observational NA NA Non‐Patent 11.9/NA Clinical Multicenter SWITCH registry: ipsilateral TU catheterization after TR failure; no hand ischemia after UAO; authors’ conclusion: “in case of failed radial sheath insertion, switching directly to the homolateral UA for PCI is feasible and it appears to be safe, without cases of symptomatic hand ischemia” Hahalis‐UA,117 2013 (Greece) 462 64.3 21.6 RCT NA NA PH‐modified NA/8.9 Ultrasonography The AURA of ARTEMIS study the largest to‐date comparison of a \default TU relative to TR comparison for coronary procedures in terms of feasibility and safety; need for crossover in the TU group inferior to TR access site with a difference of 26.3% (95% CI, 11.96–40.69; P=0.004); authors’ conclusion: “as a result of higher crossover rates, a first‐line TU strategy was proven inferior to the TR\ approach for coronary procedures. At present, the TU route should not be regarded as an acceptable alternative to the transradial access site” Kedev,118 2014 (FYROM) 476 60 34.9 Observational NA NA Non‐Patent NA/3.15 Ultrasonography TU approach for CAG, PCI and carotid stenting; subgroup of 240 patients with ipsilateral RA unavailability Geng‐UA,73 2014 (China) 271 64.2 31 RCT NA NA Non‐Patent 1.1/1.1 Ultrasonography RA vs UA comparison for CAG and/or PCI; PCI in 58.7% of the patients; Allen's test and inverse Allen's test were not routinely performed; a motor abnormality of the hand was observed in 1 patient Liu‐UA,75 2014 (China) 317 58.6 30.9 RCT H HD Non‐Patent NA/6.3 Clinical, oximetry, Ultrasonography Prospective, randomized study of TU vs TR PCI in ACS patients; authors’ conclusion: “the TU approach has results and access complications similar to the TR approach and is a safe and feasible alternative for ACS patients” Gokhroo‐UA,99 2015 (India) 410 58.6 ? Observational NA NA Non‐Patent 0.7/NA Clinical AJULAR study; comparison of the TU group with a retrospective cohort of patients undergoing TRA angiography; ad‐hoc PCI in only 22 of 410 patients (ie, 5.2%) in the TU group Roghani‐Dehkordi,119 2015 (Iran) 97 57 44.3 Observational NA NA Non‐Patent 0.0/NA Clinical NA Gokhroo‐UA,85 2016 (India) 1270 67.12 36.4 RCT NA HD Non‐Patent 1.3/NA Clinical AJULAR trial; a RCT of the TR vs the TU approach for coronary procedures (Table S1)

In total, the included studies analyzed 46 631 subjects. All studies were published since 1989. Sample sizes ranged from 3102, 108, 110, 111, 112 to 9609 individuals.60 The quality of the included studies reporting RAO was assessed by using the Newcastle–Ottawa scale (Table S1). Overall, the majority of studies had a score of 6, whereas 5 studies had a score of 8.

Meta‐Analysis

Overall arterial occlusion.

The overall rate of RAO was 5.2% (95% CI, 4.4–6.0%; Q=812.5; I2=87.9; 99 cohorts). The overall rate of UAO was 4.0% (95% CI, 2.8–5.8%; Q=50.2; I2=62.2; 20 cohorts). There was no significant difference between the overall RAO and UAO rates (P=0.171; Figure 2). For these calculations, a mean of early and late occlusion was introduced in analysis when both were reported in a study.

Figure 2. Overall rates of radial and ulnar occlusions. The diamonds and their width represent the pooled rates and the 95% CI (confidence interval), respectively.

Early and late arterial occlusion.

When only early occlusion was considered, the rate of early RAO was nonsignificantly higher than the early UAO (5.6%; 95% CI, 4.7–6.5; 82 cohorts versus 3.4%; 95% CI, 2.0–5.7%, 15 cohorts; Q=3.08, P=0.079 between groups). There was no difference between late RAO and late UAO rates (5.1%; 95% CI, 4.2–6.2, 42 cohorts versus 4.8%; 95% CI, 2.9–7.8; 7 cohorts; Q=0.049; P=0.83). In the 27 studies reporting both early and late occlusion, the early combined occlusion rate (RAO or UAO) was significantly higher than the late combined occlusion rate (7.7%; 95% CI, 6.6–8.9 versus 4.8%; 95% CI, 3.9–5.8; P<0.001 for comparison between early and late occlusion; Figure 3). This difference was confirmed when the 24 studies reporting early and late RAO were analyzed, after the 2 studies reporting UAO were excluded.40, 109

Figure 3. Rates of early vs late arterial occlusions (combined radial and ulnar occlusions) in studies reporting both early and late occlusions. Diamonds and their width as in Figure 1. CI indicates confidence interval.

Effect of anticoagulation intensity.

The overall rate of RAO (early, late, or combined) was significantly higher in the 24 studies using low‐dose UFH compared with the 57 studies using high‐dose UFH (7.2%; 95% CI, 5.5–9.4 versus 4.3%; 95% CI, 3.5–5.3; Q=8.81; P=0.003 between groups), with a mean of early and late RAO being introduced in analysis when both reported (Figure 4). Similarly, when only early RAO was considered, the rate of early RAO was significantly higher in the 21 cohorts using low‐dose UFH (8.0%; 95% CI, 6.1–10.6) compared with the 45 cohorts using high‐dose UFH (4.4%; 95% CI, 3.5–5.5; Q=10.69; P=0.001 between groups). In contrast, when late RAO was analyzed, the rate of late RAO was similar between the 12 cohorts of low‐dose UFH (5.4%; 95% CI, 3.7–7.8) and the 21 cohorts of high‐dose UFH (5.0%; 95% CI, 3.6–6.8; Q=0.11; P=0.745 between groups; Figure 4).

Figure 4. Effect of intensity of anticoaggulation on radial occlusion rate in unselected (randomized and observational) studies. Diamonds and their width as in Figure 1. CI indicates confidence interval.

Analysis of the 5 randomized studies specifically designed to address the impact of high versus low UFH dose on RAO showed that high UFH was accompanied by a significantly lower rate of RAO (3.7%; 95% CI, 1.8–7.7) compared with low UFH (9.6%; 95% CI, 4.9–17.9; Q=3.57; P=0.05 between subgroups with random‐effects model; Figure 5).

Figure 5. Effect of intensity of anticoaggulation on radial occlusion rate in randomized studies. Squares indicate the occlusion rate and lines indicate the respective 95% confidence interval (CI). The size of the squares corresponds to the number of subjects in each study. Diamonds and their width as in Figure 1.

Stratified Analysis According to Procedural Characteristics

The rate of combined RAO was significantly higher in the 50 cohorts that used Doppler for RAO diagnosis compared with the 31 cohorts using palpation of the radial artery (6.4%; 95% CI, 5.3–7.7 versus 3.8%; 95% CI, 2.9–4.9; Q=10.35; P=0.001; Figure 6). When only early RAO was considered, the rate of RAO was higher in the 38 cohorts that used Doppler compared with the 30 cohorts that used palpation only (6.7%; 95% CI, 5.4–8.3 versus 4.3%; 95% CI, 3.3–5.5; Q=6.77; P=0.009). On the other hand, there was no difference in late RAO between the 25 cohorts using Doppler and the 10 cohorts using palpation (5.8%; 95% CI, 4.5–7.4 versus 4.3%; 95 CI, 2.9–6.3, Q=1.67; P=0.196). Use of Barbeau's test was not associated with a difference in detection of the combined (early and late) RAO (5.7%; 95% CI, 4.0–8.1 in the 16 cohorts that used Barbeau's test versus 4.9%; 95% CI, 4.1–6.0 in the 64 cohorts that did not use Barbeau's test; Q=0.46; P=0.49). There was no significant difference in the overall rate of arterial occlusion between the 16 studies (14 RAO studies and 2 UAO study) using patent hemostasis compared with the 78 studies using occlusive hemostasis (5.3%; 95 CI, 3.7–7.5 versus 5.3%; 95% CI, 4.5–6.3, Q=0.0; P=0.99; Figure 6). The overall rate of RAO (early and late) was higher in the 27 studies done in patents undergoing CAG compared with the 40 PCI studies in which more‐intense anticoagulation was used (5.9%; 95% CI, 4.5–7.7 versus 4.0; 95% CI, 3.0–5.2; Q=3.87; P=0.049; Figure 6). This difference was driven by the early RAO (6.8%; 95% CI, 5.1–9.1 in the 23 CAG studies versus 4.3%; 95% CI, 3.1–5.8 in the 32 PCI studies; Q=4.68; P=0.031). The size of sheath had no impact on the combined RAO and UAO occlusion frequency (5.8%; 95% CI, 4.6–7.3 in the 33 studies using sheaths ≤5 Fr versus 5.5%; 95% CI, 4.5–6.8 in the 43 studies using >5 Fr; Q=0.088; P=0.77; Figure 6).

Figure 6. Effect of procedural characteristics on radial occlusion rates. Diamonds and their width as in Figure 1. CAG indicates coronary angiography; CI, confidence interval; PCI, percutaneous coronary intervention.

Subgroup Analysis According to Study Design

In the 37 studies reporting RAO as a primary end point, the rate of combined RAO was significantly higher (7.1%; 95% CI, 5.8–8.8) compared with the 62 studies reporting RAO as a secondary end‐point (4.2%; 95% CI, 3.5–5.1; Q=13.58; P<0.001; Figure 7). The rate of RAO was numerically higher, but statistically nonsignificant, in the 55 observational studies compared with the 43 randomized studies reporting rates of RAO (5.7%; 95% CI, 4.6–7.1 versus 4.5%; 95% CI, 3.6–5.7; Q=2.16; P=0.142; Figure 7). There was no significant difference in the overall rate of RAO between the 13 studies done in the United States (4.5%; 95% CI, 2.8–7.0) and the 86 non‐US studies (5.3%; 95% CI, 4.5–6.2; Q=0.468; P=0.494; Figure 7).

Figure 7. Effect of study design characteristics on radial occlusion rates. Diamonds and their width as in Figure 1. CI indicates confidence interval.

Analysis of Continuous Variables

Univariable metaregression analysis showed that mean age at study level was not a predictor of arterial occlusion when both RAO/UAO and early/late occlusions were analyzed (Z=1.37; P=0.17 by meta‐regression of 122 cohorts). In contrast, there was a weak positive relationship between early RAO and age (Z=2.55; P=0.011 in 79 cohorts). There was not an association between duration of procedure and early RAO (Z=−1.09; P=0.27).

Publication Bias

The funnel plots for the overall (early and late) RAO rate was slightly asymmetric to the left, indicating minor bias and possible unpublished or undiscovered studies with a high arterial occlusion rate (Figure 8). The trim‐and fill method imputed 26 theoretically missing studies and recalculated our pooled risk estimate. The imputed RAO rate (6.9%; 95% CI, 5.8–8.1) was not substantially different from the initial estimate, suggesting the absence of significant publication bias.

Figure 8. Publication bias and its potential impact. The funnel plots of precision plot a study's effect size against its precision, which is the inverse of standard error. The white circles represent individual original studies and the white diamond is the pooled mean difference and 95% CI for the meta‐analysis. Large studies tend to appear toward the top and cluster near the mean effect. Small studies tend to appear toward the bottom and are dispersed across a range of values. A symmetric funnel plot (white circles symmetrically around the mean effect) indicates absence of publication bias. To check for publication bias, the trim‐and‐fill method imputes the—theoretically—missing studies (shown in black circles) and then recomputes the pooled effect (black diamond). Although the plots were slightly asymmetric, there was no significant difference between the recomputed effect and the respective effects derived from the original studies, suggesting absence of significant publication bias. CI indicates confidence interval; RAO, radial artery occlusion.

Discussion

Main Findings

This meta‐analysis in 46 631 patients found that the crude unadjusted rates of RAO and UAO rates were similar, relatively low and in the order of 4% to 6%. Incident arterial occlusion was variable, being highest in the order of 7% to 8% in studies with patients on less‐intense anticoagulation; in early as compared with delayed assessment of vessel patency; in patients undergoing diagnostic angiography compared to angioplasty; in studies having the frequency of arterial occlusion as a primary end point; and in reports utilizing vascular ultrasonography to detect this kind of complication. Notably, the upper 95% CI for early RAO on low‐heparin dose was 10.6% in the current meta‐analysis, revealing that every tenth patient may be at risk for forearm artery occlusion if not appropriately anticoaggulated during and after a transradial coronary procedure. Recent publications confirm the difficult challenge encountered by the transradial interventionalists to maintain postprocedural forearm artery patency with ranging frequencies between 9.24% of ultrasonography‐detected late RAOs using the patent hemostasis technique (56 of 606 patients)89 and 25% of clinically detected RAOs with low‐dose heparin.92 Analysis of observational studies showed a benefit of higher heparin dose in terms of forearm artery patency, which was also confirmed after analyzing 5 small randomized, controlled trials49, 80, 81, 84, 92 specifically designed to address this issue. We found no geographical disparity of RAO/UAO frequency. Catheter size and procedural duration had similarly no impact on arterial occlusion rates.

Anticoagulation

In observational studies, several independent risk factors for RAO have been identified; yet anticoagulation appeared only inconsistently to predict RAO.47, 51, 81, 91, 92, 117 In 1 report, a 1% reduction of RAO per 1‐IU/kg heparin dose increase has been suggested.117 Randomized, control trials and pooled 1‐center data have indicated some benefit of “standard” (ie, 5000 IU) over low (ie, usually 2000–2500 IU) heparin dose, but have been inconclusive because of inadequate statistical power.49, 80, 81, 84, 92 By considering both observational reports and randomized studies, this meta‐analysis elucidates the advantage of higher anticoagulation intensity. The fact that larger versus smaller sheath sizes were not associated with higher forearm artery occlusions and that the longer‐lasting PCI was associated with lower occlusion rates versus CAG may demonstrate a possible protective effect of a more‐intensive anticoagulation regimen used in PCI over CAG. Whether antiplatelet therapy in PCI decreases further the risk of arterial occlusion remains hypothetical. In 1 study, no such favorable antiplatelet effect was evident.80 Data from the study of Uhlemann et al59 confirmed a higher than 2‐fold RAO incidence with 6‐Fr as opposed to 5‐Fr catheters in CAG patients having received 2500 heparin units. An ongoing study (ClinicalTrials.gov Identifier: NCT02570243) comparing standard dose with high heparin dose may clarify the uncertainty with regard to heparin requirements in transradial CAG.

Early and Late Occlusion Rates

This meta‐analysis confirms the prevailing belief of significantly lower late over early RAO and UAO rates. This finding may suggest late recanalization in a minority of patients as a result of the disease natural history. Additionally, short‐term anticoagulation with low‐molecular‐weight heparins may facilitate the delayed patency of the artery in some patients with early RAO.27, 46, 52, 59 This observational data provide further indirect evidence regarding the beneficial effect of anticoagulation on forearm vessel patency, but this has not been formally tested in a randomized, control trial. Interestingly, late RAOs not detected in the early phase have also been reported.54, 87

Methods to Detect Arterial Patency

Ultrasonography demonstrated clear superiority over clinical evaluation with respect to RAO and UAO detection rates. Absence of flow on Doppler ultrasonography along with the simultaneously obtained anatomic information (eg, thrombus delineation)18, 19, 21, 46, 89, 91, 96, 98 appears as a straightforward detection technique of RAOs and UAOs. In this regard, the predictive accuracy of solely anatomic stenosis20 or partial flow46, 92 remains to be established. Clinical methods (ie, arterial palpation) have been associated with both false‐negative and false‐positive findings attributed to low blood pressure, local edema and hematoma, subocclusive wall thrombus and trauma, remaining postprocedural tissue compression, as well as retrograde perfusion from the contralateral forearm artery. For example, although palpation appears to overestimate RAOs,66, 94, 95 one fifth to one third of patients with ultrasonographically documented RAOs may demonstrate palpable radial artery.59, 94 Notably, the ulnar artery poses additional difficulties in determining patency status with palpation as a result of its deeper course compared with the radial artery.117 Whether strategies for the accurate detection of RAOs and UAOs (such as the utilization of the Barbeau's test or ultrasonography once clinical evaluation indicates RAO/UAO) are sufficient remains hypothetical. Such strategies were reported in many of the studies in the current meta‐analysis.1 In this context, and while future systematic investigations on this topic are awaited, our meta‐analysis reinforces the role of ultrasonography as a reliable and probably indispensable detection method.

Patent Hemostasis

Similar occlusion rates between patent hemostasis and all other applied hemostatic techniques, including simple compression bandage, should not be interpreted as a failure of patent hemostasis. Whether meticulously carried out or not, patent or patent‐like hemostasis was reported in only 16 studies,2 most of which comprised predominantly older studies with diverse designs and end points. Although patent hemostasis has shown clear superiority in the pioneer work of Pancholy et al,30 additional studies elucidating feasibility and other practical issues of this technique are needed. In a very recent work an impressive reduction of RAO has been documented after meticulous patent hemostasis protocol and additional compression of the contralateral UA,120 thereby confirming a smaller study with similar design.95

Clinical Implications

Even the short‐lasting CAG appears not to be just a “simple” procedure in terms of forearm artery occlusion. Interestingly, our analysis showed an average occlusion rate of ≈6% (with higher 95% CI at ≈8) after diagnostic angiography, which may result from less‐intense‐than‐required periprocedural heparin administration, arterial spasm, longer procedures, multiple attempts for arterial access, etc.80, 94, 117 Maintenance of radial artery and ulnar artery patency should become a target of highest priority in interventional cardiology. Ideally, interventionalists should have adequate experience on forearm procedures with low crossover rates, avoid and timely treat spasm,104 administer at least 5000 heparin units for CAG,3 apply hemostasis after sheath removal according to the “patent artery principle,”1, 30 and evaluate patients with ultrasonography in the short term with late re‐evaluation when RAO or UAO was initially present.1

Limitations

The main limitation of the current meta‐analysis is the lack of individual patients’ data that would allow identifying independent predictors of forearm artery occlusions. An additional limitation is the inclusion of studies with substantial diversity of protocols and designs as well as the lack of rigorous, large‐scale, randomized, control trial, thereby increasing the impact of the observed heterogeneity on the results. Finally, very few studies have reported time to achieve hemostasis depending on anticoagulation level; thus, we were unable to reach conclusive evidence on the trade‐off of possible very long hemostasis time in patients on higher heparin dosage.

Conclusions

Incident RAO and UAO following coronary procedures is similar and relatively low, ranging between 5% and 8%, with occlusion rates being higher when the forearm arteries are evaluated early with ultrasonography. Higher anticoagulation levels are protective and probably neutralize the aggravating effects of larger sheath size and long‐lasting coronary interventions. Ultrasonography appears as a first‐line tool, but the simpler Barbeau's test may be equally useful in evaluating arterial patency. Studies elucidating the possible beneficial effect of angioplasty‐equivalent heparin dosage for CAG and exploring the potential impact of procedural factors on arterial occlusion are currently warranted.

Notes 1 References 8, 17, 24, 30, 33, 34, 43, 44, 47, 52, 58, 67, 90, 92, 95. 2 References 30, 51, 57, 58, 68, 71, 76, 79, 81, 84, 89, 95, 96, 97, 113, 115.

Disclosures

None.

Supplementary Information

Table S1. Quality Score of Studies Using the Newcastle—Ottawa Scale (NOS)

Footnotes