• A comparison of standard versus low dose heparin on access-related complications after coronary angiography through radial access: A meta-analysis of randomized controlled trials

    Abstract

    Background

    Transradial access (TRA) is preferred for coronary angiography (CA) or percutaneous coronary intervention due to reduced access-related complications, and mortality especially for patients with ST elevation myocardial infarction. Radial artery occlusion (RAO) is a known complication of TRA, and precludes its use as a future access site, conduit for coronary artery bypass grafting or for hemodialysis fistula placement. Although a standard dose (SD) heparin of 5000 Units is used during TRA, the risks of RAO and hematoma compared to lower dose (LD) remain unclear. To compare the risks of RAO and hematoma using SD vs. LD heparin after CA through TRA, we performed a meta-analysis of randomized controlled trials (RCT).

    Methods

    We searched PubMed, EMBASE, CINAHL and CENTRAL for RCTs since inception through 06/30/2017 and used random effects model for analysis. The outcomes analyzed were RAO, hematoma formation and radial artery compression time (RACT).

    Results

    We identified a total of 6 RCTs with a total of 2239 patients. SD heparin resulted in a trend toward a lower risk of RAO [4.2% vs. 10.7%; risk ratio (RR): 0.40, 95% confidence interval (CI): 0.16–1.0; P = 0.05], a trend toward increased risk of hematoma [2.2% vs. 1.1%; 1.83 (0.91–3.66); P = 0.09], and a longer duration of RACT [mean difference: 9.64 min (4.01–15.28); P = 0.0008] compared to LD.

    Conclusions

    The current meta-analysis showed a trend towards reduction in the risk of RAO with the use of standard dose heparin. Larger randomized trials should explore the appropriate dosing of heparin to prevent radial artery occlusion.

    Highlights

     

    •  

      Radial artery occlusion (RAO) is a known complication of transradial access (TRA)

    •  

      The risks of RAO and hematoma remain unclear when Standard dose heparin (SD), 5000U, is compared to Low dose heparin (LD).

    •  

      We compared the risks of RAO and hematoma using SD vs. LD heparin after coronary angiography through TRA using meta-analysis

    •  

      SD heparin resulted in a trend toward lower risk of RAO, and higher risk of hematoma compared to LD

     

    Introduction

    Transradial access (TRA) is gaining popularity over femoral artery access for performance of coronary angiography (CA) or percutaneous coronary interventions (PCI) due to reduced rate of access-related complications, and mortality for patients with ST elevation myocardial infarction  . The most common complication of TRA is radial artery occlusion (RAO) with incidence ranging from < 1% to 33% depending on the timing of follow-up  . Development of RAO precludes its use as a future access site, conduit for coronary artery bypass grafting or for hemodialysis fistula or arterial-line placement  . There are reported cases of hand ischemia and regional pain syndrome after TRA  . Additionally, hematoma formation after TRA is uncommon yet reported complication, the incidence of which is < 1%  .

    An international survey of interventional cardiologists showed that most of them used heparin in the dose of 2000–5000 Units to prevent the occurrence of RAO during the performance of CA or PCI  . The Society of Cardiovascular Angiography and Interventions consensus statement on best practices for transradial angiography and interventions recommend at least 50 Units/Kg or 5000 Units of heparin for the performance of such procedures through radial access.  Standard dose heparin has been compared with a lower dose (≤ 2500 Units) or weight-based approach in several randomized trials with varying results  . To ascertain the appropriate dose of heparin during coronary angiography in reduction of RAO or hematoma formation, we performed a meta-analysis of randomized controlled trials comparing standard versus lower dose of heparin.

    Methods and materials

    Data sources and search strategy

    The meta-analysis has been performed and reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines  . We searched MEDLINE, EMBASE, CINAHL and Cochrane CENTRAL Register of Clinical Trials for publications without language restriction from inception through October 13, 2016. An updated MEDLINE search was performed on 06/30/2017 that resulted in no additional citations. The search terms were “heparin” or “heparin dose” and “radial artery access” and “coronary angiography”. Database search was independently performed by two researchers (K.D. and S.S.) and disagreement was resolved by consensus. In addition, a manual search was performed for all relevant references.

    Study inclusion and exclusion criteria

    Randomized controlled trials that compared standard dose of heparin versus other doses (2000 Units, 2500 Units or weight based approach) in adults, who were at least 18 years of age or older undergoing coronary angiography through transradial access were included in the analysis. The studies reporting on at least one outcome of interest were included in the final analysis whereas non-randomized or single-arm studies and meeting abstracts without full-text publication were excluded.

    Data extraction and major outcomes

    Data were extracted by two authors (K.D. and A.Y.) in duplicate using standardized data extraction tables and double-checked for accuracy. Baseline study and patient characteristics and outcome data (radial sheath size, dose of heparin, use of radial cocktail, duration of follow-up, access-related complications and ultrasound use) were extracted.

    The outcomes assessed were radial artery occlusion (RAO), hematoma formation and radial artery compression time (RACT), defined as the time duration since sheath removal to TR band removal.

    Statistical analysis

    RACT, which was a continuous variable was pooled as mean difference (MD) with 95% confidence interval (CI). RAO and hematoma formation, which were categorical variables were pooled as risk ratio (RR) with 95% CI using crude events provided by each study. The analyses were performed using DerSimonian-Laird random-effects model to compute the effect size. The P < 0.05 (two-tailed) was considered statistically significant. Cochrane Collaboration's Bias Assessment Tools were used to assess the quality of studies based on random sequence generation, allocation concealment, binding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other relevant sources of bias. Study heterogeneity was evaluated with Cochran's Q and I statistics and I > 60% with P < 0.10 were considered significant. Review Manager (RevMan 5.3, Cochrane Collaboration, Nordic Cochrane Center, Copenhagen, Denmark) was used for meta-analysis.

    Results

    Fig. 1 shows the PRISMA flow diagram for study selection. Electronic database search and manual search resulted in a total of 68 citations including 44 duplicates leaving 24 eligible studies for review. A total of 7 records were extracted for full-text review as 17 did not meet inclusion criteria for different reasons leaving 6 studies for meta-analysis  . 

    Fig. 1
    Flow diagram for study selection.

     

    Description of included studies

    The description of individual studies and patient characteristics is presented in Tables 1 and 2 . There was a total of 2939 patients (SD: 1141 and VHD: 1098) in six studies. The studies enrolled patients who underwent coronary angiography only. The sheath size was 5–6 Fr and methods used to diagnose RAO were ultrasound for five out of six studies and Barbeau's test for one study. The dose of heparin was 5000 Units in the standard dose whereas lower dose consisted of 2000 Units, 2500 Units or weight based approach not exceeding 5000 Units. Majority of the patients were males (52.9–80.6%) with average age 58.8–65.4 years. Five studies used transradial band (TR Band) for hemostasis and in one study the type of hemostasis device was not clear. Hematoma size was not reported by two studies while three studies reported large hematomas (> 15 cm) only ( Figs. 2 and 3 ). 

    Table 1
    Characteristics of individual studies.
    Study name (First author, year)Aykan et al, 2015Bernat et al, 2011Degirmencioglu et al, 2015Hahalis et al, 2015Roghani et al, 2016Schiano et al, 2010
    Country of origin Turkey Czech Republic Turkey Greece Iran France
    Design Randomized Randomized Randomized Randomized Randomized Randomized
    Total patients 459 465 404 308 441 162
    SD 242 243 202 154 221 79
    LD 217 222 202 154 220 83
    Follow-up 1 month 3–4 h 7 days Within 60 days 24 h Within 24 h
    Doppler use Yes Yes Barbeau's test Yes Yes Yes
    Procedure CA CA CA CA CA CA
    Route of heparin Intraarterial Intraarterial Intraarterial Intraarterial Intraarterial Intraarterial
    SD dose 5000 Units 5000 Units 5000 Units 5000 Units 5000 Units 5000 Units
    LD dose 2500 Units 2000 Units 2500 Units 2500 Units 2500 Units Wt based 50 Units/Kg
    Radial cocktail Yes Yes Yes Yes Yes Yes
    Sheath 6 Fr 5 Fr 6 Fr 5 Fr 5 Fr 5 Fr
    Hemostasis device Inflatable device TR Band TR Band TR Band TR Band TR Band
    CA: coronary angiography; LD: low dose; SD: standard dose, wt: weight.
    Table 2
    Patient characteristics in the included studies.
    Study name (First author, year)Aykan et al, 2015Bernat et al, 2011Degirmencioglu et al, 2015Hahalis et al, 2015Roghani et al, 2016Schiano et al, 2010
    Age (in years), SD 60.72 ± 10.63 62 ± 10 59.7 ± 9.6 65.1 ± 10.0 62.48 ± 9.40 62.5 ± 12.9
    Age (in years), LD 58.85 ± 9.82 62 ± 10 60.2 ± 10 63.2 ± 11.4 62.87 ± 9.10 65.4 ± 12.3
    Male (%), SD 80.6% 68% 66.8% 75.3% 52.9% 82.2%
    Male (%), LD 73.7% 64% 60.4% 70.1% 55.9% 77.1%
    HTN (N, %), SD 126 (52.1%) 181 (74%) 131 (64.9%) 111 (72.1%) 43 (19.5%) 35 (44.3%)
    HTN (N, %), LD 119 (54.8%) 154 (69%) 129 (63.9%) 103 (66.9%) 48 (21.8%) 31 (37.3%)
    HLD (N, %), SD 156 (64.5%) 160 (66%) NR 105 (68.2%)   34 (43%)
    HLD (N, %), LD 121 (55.8%) 146 (65%) NR 101 (65.6%)   32 (38.5%)
    Smoker (N, %), SD 104 (43%) 105 (43%) 55 (27.2%) 64 (41.6%) 35 (15.8%) 27 (34.1%)
    Smoker (N, %), LD 84 (38.7%) 84 (38%) 45 (22.3%) 69 (44.8%) 39 (17.9%) 34 (40.9%)
    BMI (mean ± std. dev.), SD 27.35 ± 4.24 NR 28.7 ± 4.4 29.4 ± 4.8 25.59 ± 3.1 26.9 ± 4.8
    BMI (mean ± std. dev.), LD 27.65 ± 4.19 NR 29.1 ± 4.6 28.6 ± 4.2 26.09 ± 3.6 25.9 ± 3.8
    BMI: body mass index; HLD: hyperlipidemia; HTN: hypertension; LD: low dose; N: number; NR: not reported; SD: standard dose; std. dev.: standard deviation.
    Fig. 2
    Forrest plot for radial artery occlusion and hematoma.
    Fig. 3
    Forrest plot for radial artery compression time.

     

    Outcomes

    SD heparin, compared to a LD resulted in a trend toward a lower risk of RAO [4.2% vs. 10.7%; risk ratio (RR): 0.40, 95% confidence interval (CI): 0.16–1.0; P = 0.05; I = 84], trend toward higher risk of hematoma [2.2% vs. 1.1%; 1.83 (0.91–3.66); P = 0.09; I = 0], and longer duration of RACT [mean difference: 9.64 min (4.01–15.28); P = 0.0008; I = 96] ( Fig. 3 ).

    We performed subgroup analyses based on the sheath size (5 Fr vs. 6 Fr.) and heparin dosing in LD category (2000 Units and 2500 Units). Analyses restricted to 5 Fr radial sheath use showed that SD, compared to LD resulted in similar risks of RAO [0.35 (0.08–1.45); P = 0.15; I = 90] and hematoma [1.14 (0.28–4.62); P = 0.85; I = 0], and similar duration of RACT [19.03 (− 2.44, 40.51); P = 0.08; I = 91]. Analyses restricted to 6 Fr radial sheath use showed that SD and LD had similar risks of RAO [0.49 (0.12–1.97); P = 0.32; I = 72] and hematoma [2.44 (0.72–8.28); P = 0.15; I = 19]. The patients who received 2500 Units of heparin compared to SD had similar risks of RAO [0.37 (0.11–1.21); P = 0.10; I = 88] and hematoma [1.73 (0.64–4.72); P = 0.28; I 2= 23]. There was not enough data to perform analysis on 2000 Units of heparin and outcome of RACT in different dosing groups.

    Additionally, we performed analysis after removing the study that compared weight based approach vs. SD. There was a trend toward reduction in the risk of RAO [0.40 (0.16–1.0); P = 0.05; I = 84], and longer RACT [6.32 (0.94–11.7); P = 0.02; I = 96] with the use of SD vs. LD. Further analysis was performed after removing the study that used Barbeau's test to assess RAO. SD vs. LD showed a trend in reduction of the risk of RAO [0.32 (0.10–1.0); P = 0.05; I = 86] and similar risk of hematoma [1.94 (0.42–8.96); P = 0.40; I = 29].

    Study quality and publication bias

    Study quality was assessed with the Cochrane collaboration's bias assessment tools and five out of six were deemed to be moderate quality studies mainly due to non-blinding of the outcomes and participants. One study was of low quality due to quasi-randomized design  . The publication bias was not assessed per the recommendations of Cochrane Collaboration as the total number of trials were fewer than 10.

    Discussion

    The data from randomized trials were inconsistent on the appropriate dosing of heparin in patients undergoing diagnostic procedures through radial artery access. Our meta-analysis of available randomized trials showed that the 5000 Units of heparin, compared to lower doses resulted in a trend toward a lower risk of radial artery occlusion, a trend toward higher risk of hematoma and increased radial artery compression time.

    To our knowledge, this is the first and largest systematic review and meta-analysis of randomized controlled trials comparing various doses of heparin in transradial access. A previous study with a total of 4 studies (with both randomized and non-randomized trials) showed superiority of 5000 Units compared to lower dose in reduction of radial artery occlusion. Our meta-analysis is strengthened by larger of number randomized trials, exploration of other outcomes of interest and performance of subgroup analyses for different sheath size and different doses of heparin.

    As the interventionalists are increasingly using radial access instead of femoral access for coronary procedures due to significant reduction in access-related complications and mortality especially in patients with ST segment elevation myocardial infarction (STEMI), the incidence of RAO may rise further, which calls for the approaches to reduce radial artery occlusion in these patients. Among various approaches to reduce RAO, heparin use is commonly practiced approach to maintain RA patency post-procedure; therefore, our study is an effort to study the appropriate dosing of heparin.

    The potential mechanism of radial artery occlusion consists of occlusive and non-occlusive injury  . Endothelial dysfunction, intimal tear and hyperplasia, medial calcification and adventitial inflammation are patterns of non-occlusive injury whereas thrombus formation is occlusive injury. The prevention of radial artery occlusion entails different interventions and techniques, heparin administration being one of them.

    Study limitations

    The current meta-analysis is limited by small number of randomized trials and lack of patient level data. Significant heterogeneity was observed in some of the outcomes, which could not be lowered despite subgroup analyses. One study reported significantly higher rates of RAO. Meta-regression could not be performed due to small number of studies (< 10). Nevertheless, the current study is strengthened by inclusion of all available randomized trials comparing various doses of heparin in patients undergoing coronary angiography.

    Conclusions

    The current meta-analysis showed a trend towards reduction in the risk of RAO with the use of standard dose heparin (5000 Units) in patients undergoing transradial coronary angiography. Larger randomized trials with adequate power should explore the appropriate dose of heparin in this setting.

    Author contribution

    Study concept and design : Dahal, Modi and Tandon.

    Acquisition analysis or interpretation of data : Dahal, Yousuf, Sharma, Azrin, Lee, Jimenez, Modi and Tandon.

    Drafting of the manuscript : Dahal and Yousuf.

    Critical revision of the manuscript for important intellectual content : Sharma, Azrin, Lee, Jimenez, Modi and Tandon.

    Statistical analysis : Dahal.

    Study supervision : Sharma, Yousuf, Azrin, Lee, Jimenez, Modi and Tandon.

    Conflict of interest disclosures: All authors have nothing to disclose.

    Funding/support: There was no external funding for this study.

    Author bio

    Cardiovascular Revascularization Medicine, 2018-07-01, Volume 19, Issue 5, Pages 575-579, Copyright © 2018

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