Author + information
- Received June 16, 2014
- Revision received October 30, 2014
- Accepted November 6, 2014
- Published online April 20, 2015.
- Shaheen Pandie, MB ChB, MMed∗,
- Shamir R. Mehta, MD, MSc∗,
- Warren J. Cantor, MD†,
- Asim N. Cheema, MD, PhD‡,
- Peggy Gao, MSc∗,
- Mina Madan, MD§,
- Kari Niemela, MD, PhD‖,
- Sunil V. Rao, MD¶,
- Jon David Schwalm, MD∗,
- Vicent Valentin, MD#,
- James L. Velianou, MD∗ and
- Sanjit S. Jolly, MD, MSc∗∗ ()
- ∗McMaster University and Population Health Research Institute, Hamilton Health Science, Hamilton, Ontario, Canada
- †Southlake Regional Health Centre, University of Toronto, Newmarket, Ontario, Canada
- ‡St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada
- §Sunnybrook Health Science Centre, Toronto, Canada
- ‖Tampere University Hospital and Heart Centre, Tampere, Finland
- ¶Duke University Medical Centre, North Carolina
- #Hospital Universitari Dr. Peset, Valencia, Spain
- ↵∗Reprint requests and correspondence:
Dr. Sanjit S. Jolly, Room C3 118 CVSRI Building, Hamilton General Hospital, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada.
Objectives The purpose of this study was to determine the efficacy and safety of radial versus femoral access in women undergoing coronary angiography/intervention.
Background The risk of bleeding and vascular access site complications are higher in women than in men.
Methods In a pre-specified RIVAL (RadIal Vs femorAL access for coronary intervention) subgroup analysis, we compared outcomes in women (n = 1,861) and men (n = 5,160) randomized to radial versus femoral access.
Results Overall, women were at higher risk of major vascular complications compared with men (4.7% vs. 1.7%; p < 0.0001). Major vascular complications were significantly reduced with radial access in women (3.1% vs. 6.1%; hazard ratio [HR]: 0.5; 95% confidence interval [CI]: 0.32 to 0.78; p = 0.002) and in men (0.7% vs. 2.8%; HR: 0.27; 95% CI: 0.17 to 0.45; p < 0.0001; interaction p = 0.092). Crossover rates were higher with radial compared with femoral access in women (11.1% vs. 1.9%; HR: 5.88; p < 0.0001) and men (6.3% vs. 1.9%; HR: 3.32; p < 0.0001; interaction p = 0.054). Percutaneous coronary intervention (PCI) success rates were similar irrespective of access site (women: HR: 1.05; p = 0.471; men: HR: 1.00; p = 0.888; interaction p = 0.674), with no differences in PCI complications. In multivariable analyses, female sex was an independent predictor of major vascular complications (HR: 2.39; 95% CI: 1.76 to 3.25; p < 0.0001). There were consistent findings for women and men, with no difference for the primary composite endpoint of death, myocardial infarction, stroke, and non–coronary artery bypass grafting bleeding (women: 3.9% vs. 5.0%; HR: 0.77; 95% CI: 0.50 to 1.19; men: 3.54% vs. 3.5%; HR: 1.00; 95% CI: 0.75 to −1.34; interaction p = 0.325).
Conclusions Women undergoing coronary angiography and PCI have a higher risk of vascular access site complications compared with men, and radial access is an effective method to reduce these complications.
Over the past 5 years, there has been an increase in the uptake of radial access for percutaneous coronary intervention (PCI) for both elective and emergency cases in Europe and North America (1–3). The RIVAL (RadIal Vs femorAL access for coronary intervention) trial randomized 7,021 patients with acute coronary syndrome to either radial or femoral access for coronary angiography and PCI and showed that, overall, there was no difference in the primary composite outcome of death, myocardial infarction (MI), stroke, or non–coronary artery bypass graft (CABG) bleeding, with a significant reduction in major vascular complications (4).
Observational data suggest that female sex is an independent risk factor for major bleeding and that the use of radial access for PCI likely reduces this risk (5,6). However, there are concerns that radial access may be technically more challenging in women due to smaller radial arteries and increased rates of radial artery spasm, potentially leading to lower procedural success rates. Most randomized trials comparing radial with femoral access have enrolled more men than women, making data regarding radial access specific to women very pertinent (7).
We sought to determine the efficacy and safety of radial versus femoral access in women and men in this pre-specified subgroup analysis.
RIVAL was a randomized, parallel-group, multicenter trial. Patients with acute coronary syndromes, with or without ST-segment elevation, and planned for invasive therapy were included. Patients with cardiogenic shock, severe peripheral arterial disease precluding femoral approach, previous coronary bypass surgery with use of more than 1 internal mammary artery, and a negative Allen’s test (absence of dual circulation of hand) were ineligible for inclusion. The study was approved by all appropriate national regulatory authorities and ethics committees of participating centers, and participants provided written informed consent prior to enrollment. The trial was coordinated by the Population Health Research Institute at McMaster University and Hamilton Health Sciences in Hamilton, Ontario, Canada. Details of RIVAL’s study design are published elsewhere (4,8).
The primary efficacy outcome was a composite of death, MI, stroke, or non-CABG major bleeding at 30 days. Other outcomes included composite of death, MI, or stroke; components of primary outcome; major vascular complications; access site pain; crossover rates; PCI success and complication rates; procedure duration; contrast volumes used; and patient preference for next procedure.
Major vascular complications included retroperitoneal hematoma, pseudoaneurysm requiring ultrasound compression, thrombin injection or surgical repair, large hematomas requiring prolonged hospitalization, arteriovenous fistulae, limb ischemia or damage to adjacent nerve, and other surgical access site repair. RIVAL major bleeding was defined as bleeding that was fatal; resulted in transfusion of ≥2 U red blood cells; caused significant hypotension requiring inotropes; required surgical intervention; caused severe disabling sequelae; was intracranial or intraocular; or led to a drop in hemoglobin of at least 50 g/l. ACUITY (Acute Catheterization and Urgent Intervention strategy) non–CABG-related major bleeding was defined as RIVAL major bleeding, large hematomas, and pseudoaneurysms requiring intervention (4).
The final intention-to-treat analyses included all patients, irrespective of whether they crossed over to another access site or did not undergo PCI. A significance level of 0.05 with 2-sided test was used, and all analyses were performed using SAS version 9.2 (SAS Institute, Cary, North Carolina).
Women versus men was 1 of 6 pre-specified, pre-randomization subgroups. The efficacy and safety of radial versus femoral access for the primary and secondary outcomes in women versus men were assessed by comparison of survival curves (estimated with the Kaplan-Meier method) for the 2 approaches by log-rank statistic. The interaction p value was then calculated to estimate any significant differences between women and men. Centers were included as random effects in the COX model to account for any intercenter variability. Demographic, baseline therapy, clinical, investigatory, and procedural characteristics of the 2 comparison groups were compared using chi-square and Wilcoxon rank sum tests as appropriate.
A multivariable analysis using the Cox proportional hazard model was performed to determine whether women versus men was independently associated with increased risk of major vascular complications after adjusting for sex, age, body mass index, diabetes, arterial sheath size, use of a closure device, whether PCI was performed, glycoprotein (GP) IIb/IIIa inhibitor use, ST-segment elevation myocardial infarction (STEMI) versus non-STEMI, and peripheral arterial disease. A similar multivariable analysis was also performed to determine predictors of access site crossover after adjusting for sex, age, radial center volume, body mass index, height, diabetes, whether PCI was performed, STEMI versus non-STEMI, and previous CABG.
A total of 7,021 patients from 158 hospitals in 32 countries were originally enrolled in the RIVAL trial (June 6, 2006, to November 2, 2010). A total of 1,861 women (908 radial; 953 femoral) and 5,160 men (2,599 radial; 2,561 femoral) were included in the subgroup analyses. Table 1 shows baseline characteristics and procedural characteristics of the study population. It illustrates that both female and male subgroups allocated to radial versus femoral access were well matched in terms of demographics, background medical history, and type of acute coronary syndrome presentation. However, GP IIb/IIIa inhibitor usage was greater in the male subgroup. In terms of procedural differences, 5-F catheters were used more frequently with radial access (women 18.6%; men 12.9%) than femoral access (women 9.3%; men 5.7%), and catheters size ≥7-F were used more frequently with femoral access (women 3.9%; men 6.8%) than radial access (women 0.7%; men 1.0%). The rate of drug-eluting stent usage was similar for the 2 groups.
Findings for women and men were consistent, with no difference for the primary composite outcome of death, MI, stroke, or non-CABG bleeding at 30 days between radial and femoral access (women: radial 3.9% vs. femoral 5.0%; hazard ratio [HR]: 0.77; 95% confidence interval [CI]: 0.50 to 1.19; men: 3.5% vs. 3.5%; HR: 1.00; 95% CI: 0.75 to 1.34; p for interaction = 0.325) (Table 2). In the female subgroup, there was no significant difference between radial and femoral access and no difference, when compared with men, for the secondary outcomes of composite death, MI, stroke (p = 0.377; p for interaction = 0.298), and non-CABG major bleeding (p = 0.323; p for interaction = 0.748).
Major vascular complications were significantly reduced with the use of radial access in women (3.1% vs. 6.1%; HR: 0.50; 95% CI: 0.32 to 0.78; p = 0.002), and men (0.7% vs. 2.8%; HR: 0.27; 95% CI: 0.17 to 0.45; p < 0.0001; p for interaction = 0.092) (Table 2). In terms of absolute benefit for major vascular complications, among women, the absolute risk reduction for radial versus femoral was 3.0% (number needed to treat [NNT] = 33) and for men was 2.0% (NNT = 49; p for interaction = 0.07) (Figure 1).
There was a significant reduction in bleeding rate, as defined by ACUITY criteria, for both women (3.7% vs. 7.0%; HR: 0.50; 95% CI: 0.33 to 0.76; p = 0.001) and men (radial 1.2%; femoral 3.3%, HR: 0.36; 95% CI: 0.24 to 0.55; p < 0.0001) with no interaction between groups (p for interaction = 0.327).
Crossover rates from radial to femoral access were higher than femoral to radial in both groups (women: 11.1% vs. 1.9%; HR: 5.88; 95% CI: 3.60 to 9.61; p < 0.0001; men: 6.3% vs. 1.9%; HR: 3.32; 95% CI: 2.43 to 4.55; p < 0.001; p for interaction = 0.054). The reasons for access site crossover were collected in 3,190 of 7,021 patients enrolled in the RIVAL trial. In women, radial-to-femoral crossover occurred in 101 of 908 cases (11.1%). Of the cases that had documented reasons for crossover (3,190 of 7,021), the most common reasons were radial artery spasm (women: 9.5% vs. men: 3.3%; p < 0.001), radial artery loop (women: 2.5% vs. men: 0.78%; p = 0.006), and subclavian tortuosity (women: 2.5% vs. men: 1.7%; p = 0.33) (Figure 2).
PCI was completed successfully with equal efficacy in women and men irrespective of access site (women: 95.8% vs. 95.5%; HR: 1.05; 95% CI: 0.93 to 1.18; p = 0.471; men: 95.3% vs. 95.3%; HR: 1.00; 95% CI: 0.94 to 1.08; p = 0.888; p for interaction = 0.674), with no differences in procedural time, fluoroscopy time, or contrast volume used (Table 2). PCI complications (such as coronary dissection, abrupt closure, no reflow, coronary perforation, and catheter or stent thrombosis) were also unrelated to route of access in both female and male patients.
Compared with patients who had femoral access, major vascular complications were reduced among both women and men who had radial access, irrespective of whether PCI was performed (Table 3).
A significant portion (86.1%) of the female patients who had radial access noted that they would prefer repeat radial access. Only 50.1% of patients who had femoral access noted that they would prefer repeat femoral access (p < 0.001).
Overall, the rates of major vascular complications were higher in women than in men (4.7% vs. 1.7%; p < 0.0001). Multivariable analyses were performed to assess for possible predictors of major vascular complications and radial-to-femoral access site crossover. Significant predictors of major vascular complications included female sex (HR: 2.39; 95% CI: 1.76 to 3.25; p < 0.0001), increase in age per 10 years (HR: 1.41; 95% CI: 1.22 to 1.61; p < 0.0001), performance of PCI versus no PCI (HR: 2.07; 95% CI: 1.41 to 3.04; p = 0.0002), and use of GP IIb/IIIa inhibitors (HR: 1.48; 95% CI: 1.07 to 2.03; p = 0.0165) (Figure 3). Significant predictors for radial-to-femoral access site crossover (Figure 4) included female sex (HR: 1.39; 95% CI: 1.04 to 1.85; p = 0.023), increase in age per 10 years (HR: 1.14; 95% CI: 1.03 to 1.26; p = 0.0068), and previous CABG (HR: 2.95; 95% CI: 1.93 to 4.50; p < 0.0001).
RIVAL is the largest randomized trial to compare radial with femoral access for coronary angiography and intervention in patients with acute coronary syndromes (4). In addition, the subgroup of women is the largest cohort of women to undergo randomization to either radial or femoral access for PCI. The key findings of this analysis for women are: 1) improved safety with radial access, with a significant reduction in major vascular complications; 2) similar PCI success rates; and 3) women are at greater overall risk for major vascular complications.
Current observational data also suggest that women are at greater risk of post-PCI bleeding and that radial access may reduce this risk (5,6). However, operators may be reluctant to use radial access in women because of increased radial artery spasm, smaller arteries, and greater tortuosity.
Overall, in the RIVAL trial, the rate of major vascular complications in women was more than double that of men. Radial compared with femoral access reduced major vascular complications by one-half in women. Due to the higher baseline risk of women, the NNT to prevent 1 major vascular complication with radial instead of femoral access was 33 in women versus 49 for men.
Women randomized to radial access were more likely to cross over to femoral access than men. This is likely related to smaller radial arteries and higher rates of radial spasm. Technical skill and use of 5-F catheters help to extend the benefits of radial access to women. Despite these challenges, radial access still reduced major vascular complications compared with femoral access in women.
In terms of patient preference for subsequent procedures, both women and men would prefer radial access. This is important because despite smaller radial arteries and the potential for increased discomfort related to spasm, women chose radial access for subsequent procedures.
The only other trial to assess radial versus femoral access is the recent SAFE-PCI for Women (Study of Access site For Enhancement of PCI for Women) (7). This trial embedded randomization into the National Cardiovascular Research Infrastructure and randomized 1,787 women to radial or femoral access, with 691 undergoing PCI. Unfortunately, the trial was terminated early due to lower than expected event rates. In addition, there was no significant difference in the primary efficacy endpoint of Bleeding Academy Research Consortium bleeding (type 2, 3, and 5) or vascular complications requiring intervention in the PCI subgroup (radial 1.20%; femoral 2.90%; odds ratio: 0.4; 95% CI: 0.1 to 1.3; p = 0.21) (9). However, in the overall population (diagnostic and PCI), there was a significant reduction in primary outcome (radial 0.60%; femoral 1.70%; odds ratio: 0.3; 95% CI: 0.1 to 0.9; p = 0.03). A major difference between the cohorts of the SAFE-PCI for Women study and the RIVAL trial was that RIVAL focused on patients presenting with acute coronary syndromes (including STEMI, non-STEMI, and unstable angina), whereas SAFE-PCI focused on elective referrals for angiography and PCI (excluding STEMI). Even so, the findings of the RIVAL subgroup are consistent with SAFE-PCI, suggesting that radial versus femoral access is effective at reducing major vascular access site complications. Furthermore, the RIVAL trial suggested that the benefit of radial access in preventing vascular complications is present in both diagnostic and PCI cases.
The results of the RIVAL trial are not applicable to operators with little or no radial experience. It is possible that interventional cardiologists selected women with larger radial arteries to be randomized in the RIVAL trial.
Even though women versus men was a pre-defined subgroup, the RIVAL trial randomization was not powered to assess differences between sexes, and randomization was not stratified by sex.
Female sex is a subgroup analysis and so should be considered hypothesis generating. However, the results of our subgroup are consistent with an independent randomized trial performed in women.
Women undergoing coronary angiography and PCI are at higher risk of vascular complications compared with men. Radial access is an effective method to reduce these vascular complications.
Prior studies have suggested that women have higher rates of vascular access complications compared with men. However, radial access may be technically more challenging in women due to smaller radial arteries and radial spasm. In this analysis of the RIVAL trial, radial access reduced major vascular complications compared with femoral access in both women and men. Women were found to have a higher risk of vascular complications, and so they particularly benefit from radial access.
Dr. Jolly has received grant support from Medtronic; and has received speaker fees from AstraZeneca and St. Jude Medical. Dr. Rao has served as a consultant for and received an honorarium from Terumo Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- coronary artery bypass grafting
- confidence interval
- hazard ratio
- number needed to treat
- percutaneous coronary intervention
- ST-segment elevation myocardial infarction
- Received June 16, 2014.
- Revision received October 30, 2014.
- Accepted November 6, 2014.
- American College of Cardiology Foundation
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