Author + information
- Received April 24, 2015
- Revision received July 8, 2015
- Accepted July 30, 2015
- Published online December 21, 2015.
- Mitul B. Kadakia, MD∗,
- Sunil V. Rao, MD†,
- Lisa McCoy, MS†,
- Paramita S. Choudhuri, PhD†,
- Matthew W. Sherwood, MD†,
- Scott Lilly, MD, PhD‡,
- Taisei Kobayashi, MD∗,
- Daniel M. Kolansky, MD∗,
- Robert L. Wilensky, MD∗,
- Robert W. Yeh, MD, MSc§ and
- Jay Giri, MD, MPH∗∗ ()
- ∗Cardiovascular Medicine Division, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
- †Duke Clinical Research Institute, Durham, North Carolina
- ‡Division of Cardiovascular Medicine, Ohio State University, Columbus, Ohio
- §Division of Cardiology, Massachusetts General Hospital, Boston, Massachusetts
- ↵∗Reprint requests and correspondence:
Dr. Jay Giri, Cardiovascular Medicine Division, Hospital of the University of Pennsylvania, Gates Pavilion, 9th Floor, 3400 Spruce Street, Philadelphia, Pennsylvania 19104.
Objectives The purpose of this study was to assess usage patterns of transradial access in rescue percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) and associations between vascular access site choice and outcomes.
Background Transradial access reduces bleeding and mortality in STEMI patients undergoing primary PCI. Little is known about access site choice and outcomes in patients undergoing rescue PCI after receiving full-dose fibrinolytic therapy for STEMI.
Methods Patients in the National Cardiovascular Data Registry’s CathPCI Registry undergoing rescue PCI for STEMI between 2009 and 2013 were studied. Patients were divided on the basis of access site. Patterns of access use and baseline demographics were noted. Unadjusted and propensity-matched analyses were performed comparing in-hospital bleeding, vascular complications, and mortality outcomes among transradial and transfemoral access patients. The falsification endpoint of gastrointestinal bleeding was specified to assess for persistent unmeasured confounding.
Results Transradial access was used in 14.2% of cases. In propensity-matched analyses, transradial rescue PCI was associated with significantly less bleeding than transfemoral access (odds ratio [OR]: 0.67; 95% confidence interval [CI]: 0.52 to 0.87; p = 0.003), but not mortality (OR: 0.81; 95% CI: 0.53 to 1.25; p = 0.35). Gastrointestinal bleeding was less frequent in the radial group (OR: 0.23; 95% CI: 0.05 to 0.98; p = 0.05).
Conclusions In a large, “real-world” registry, transradial access was used in a minority of cases and was associated with significantly less bleeding than transfemoral access in patients undergoing rescue PCI. However, given persistent differences in a falsification endpoint, the influence of treatment-selection bias on these results cannot be ruled out. Further studies are needed to determine predictors of bleeding and mortality in this understudied high-risk group.
Fibrinolytic therapy is a cornerstone of therapy in patients with ST-segment elevation myocardial infarction (STEMI) who present to facilities that do not offer prompt access to primary percutaneous coronary intervention (PCI). At least 12% to 17% of patients in the United States are treated with fibrinolytic therapy (1,2). Up to 40% to 50% of patients do not achieve restoration of Thrombolysis In Myocardial Infarction flow grade 3 in the infarct-related artery after administration of full-dose fibrinolytic therapy (3,4) and may undergo urgent cardiac catheterization with coronary intervention, so-called “rescue PCI.” In the setting of antithrombotic and antiplatelet agents used to treat acute coronary syndromes, bleeding complications in patients with STEMI are common and are associated with worse clinical outcomes and prognosis (5). These risks may be increased in those receiving fibrinolytic therapy for STEMI prior to cardiac catheterization (6). Many of these bleeding complications are related to the femoral artery access site used for cardiac catheterization (7).
Several analyses have demonstrated a reduction in bleeding outcomes in STEMI patients undergoing PCI via the transradial approach (8–14). However, little is known about differences in bleeding outcomes on the basis of access approach in patients undergoing rescue PCI. Given their high-risk clinical presentation and the concurrent use of antiplatelet, anticoagulant, and thrombolytic therapy, these patients may have the most to gain from “bleeding-avoidance strategies” like radial access. However, patients who fail to reperfuse with thrombolysis represent a high-risk subgroup whose procedural success rates may be worse, and the influence of transradial access upon procedural success and mortality in this group is unknown.
The National Cardiovascular Data Registry (NCDR) CathPCI Registry provides a unique opportunity to evaluate access site usage patterns and the differences in bleeding outcomes and mortality in patients undergoing transradial versus transfemoral access following fibrinolytic therapy in STEMI in clinical practice. We hypothesized that transradial access would be associated with improved outcomes in rescue PCI patients.
Data source and study sample
The NCDR CathPCI Registry is an initiative of the American College of Cardiology (ACC) Foundation and the Society for Cardiovascular Angiography and Interventions. Details of the CathPCI Registry have been previously described (15,16). The registry collects demographic, clinical, procedural, and institutional data elements from diagnostic catheterizations and PCI at 1,453 participating centers. Data is entered via a secure web-based platform or software provided by ACC-approved vendors. There is a comprehensive data quality program, including specifications for data capture and transmission, education and training for site data managers, and an auditing program. The data elements and definitions were created by a specially assigned ACC committee. The data collection form and a comprehensive description of the data elements are available online (17).
The study population included adult (age >18 years) patients presenting with STEMI initially treated with fibrinolytic therapy who subsequently underwent rescue PCI via either a transfemoral or transradial approach from July 1, 2009, to June 30, 2013. Rescue PCI was defined as PCI for STEMI after failed full-dose fibrinolytic therapy. The following patients were excluded: those who required femoral access for intra-aortic balloon pump or other mechanical ventricular support; those who underwent in-hospital coronary artery bypass surgery; those who underwent >1 PCI during the index hospitalization; those on hemodialysis; and patients who underwent catheterization >72 h after fibrinolytic administration. Following these exclusions, 9,494 patients from 603 sites were included in this analysis (Figure 1).
Endpoints and definitions
The primary endpoint for this analysis was bleeding complications. Bleeding was defined as the presence of 1 or more of the following within 72 h of PCI: overt access site bleeding, retroperitoneal hemorrhage, intracranial hemorrhage, gastrointestinal or genitourinary bleeding, cardiac tamponade, non–bypass surgery-related blood transfusion in patients with a pre-procedure hemoglobin ≤8 g/dl, or an absolute decrease in hemoglobin ≥3 g/dl from pre- to post-PCI in patients with a pre-procedure hemoglobin value of <16 g/dl. Secondary endpoints were in-hospital mortality and other vascular complications requiring treatment.
Patient and hospital characteristics were compared by vascular access site used for rescue PCI (radial vs. femoral). These included patient demographics, medical history, risk factors, intraprocedural and post-procedural events, lesions and devices, discharge, and hospital characteristics. Categorical variables are presented as frequencies (percentages), and differences were assessed using the chi-square test. Continuous variables are presented as medians with interquartile ranges and were compared using the Wilcoxon rank-sum test.
We accounted for potential selection bias in those who underwent transradial versus transfemoral procedures by constructing a propensity model for vascular access using logistic regression. Variables were selected a priori in a nonparsimonious fashion from the NCDR CathPCI version 4 pre-catheterization in-hospital mortality and bleeding models (8,18). Specifically, we adjusted for sex, age, race, body mass index (BMI), hypertension, hyperlipidemia, family history of premature coronary artery disease, prior myocardial infarction, heart failure history, cerebrovascular disease, peripheral vascular disease, prior PCI, prior coronary artery bypass graft, diabetes, tobacco use, history of dialysis, glomerular filtration rate, heart failure on presentation (New York Heart Association functional class), cardiac arrest, aspirin use, thienopyridine use, anticoagulant, glycoprotein (GP) IIb/IIIa use, pre-procedure hemoglobin (as a continuous linear spline with 1 knot at 13), time from symptom onset to presentation, and time from fibrinolytic therapy to procedure time. Pre– and post–inverse probability of treatment weighting (IPTW) balance of the covariates between radial and femoral patients was also checked.
To determine the association between radial versus femoral PCI and in-hospital outcomes, logistic regression with generalized estimating equations to account for within hospital clustering was used. The propensity to undergo radial or femoral access was included in the model by inverse probability of treatment weighting. Weights were stabilized using the marginal probability of radial access to maximize efficiency. For radial patients, the weights were calculated by dividing the marginal probability of radial access by the individual patient’s propensity score. Weights for femoral access patients were calculated as: (1 − marginal probability of radial access)/(1 − individual patient’s propensity score).
Pre- and post-IPTW balance of the covariates between treatment groups was assessed using Cramer’s phi for categorical variables and R2 for continuous variables. Values closer to 0 indicated better balance. After IPTW adjustment, the Cramer’s phi measure for each categorical variable except for history of prior coronary bypass surgery was <0.035 and the R2for each continuous variable was <0.003 (Figure 2). IPTW-adjusted subgroup analysis was performed in several key subgroups, including age >75 years, male sex, BMI ≥30 kg/m2, diabetic patients, creatinine clearance <45 ml/min, GP IIb/IIIa use, bivalirudin use, and cardiogenic shock. Given the known issue of residual confounding in observational analyses of radial versus femoral access (19), we tested a falsification endpoint of gastrointestinal bleeding on both groups. This endpoint served as a “negative control” in our analysis, as rates of gastrointestinal bleeding were unlikely to be influenced by the choice of access site. To further examine the role of baseline differences in bleeding risk between the 2 cohorts, we performed an analysis to ascertain the pre-procedure predicted bleeding risk of the 2 groups on the basis of a validated NCDR CathPCI bleeding risk model (20).
All analyses were performed by the Duke Clinical Research Institute using SAS version 9.3 (SAS Institute, Cary, North Carolina). This study was approved by the Duke University Medical Center institutional review board and was determined to meet the definition of research not requiring informed consent.
Baseline characteristics and treatment
Among 9,494 patients undergoing rescue PCI following fibrinolytic therapy for STEMI, 8,146 (85.8%) had femoral access and 1,348 (14.2%) had radial access. Those undergoing radial access were more often younger and male, and more often had higher BMI, family history of coronary artery disease, and history of congestive heart failure. They less often had a history of hypertension, dyslipidemia, previous coronary artery bypass graft surgery, cerebrovascular disease, or chronic lung disease (Table 1).
On presentation, patients undergoing radial access less often had heart failure within the 2 weeks prior to presentation, cardiogenic shock, and cardiac arrest. Mean glomerular filtration rate was higher in the radial access group. There was no statistically significant difference in baseline hemoglobin levels. The median time from fibrinolytic administration to cardiac catheterization was 189 min (interquartile range: 108 to 918 min). There were no differences in ejection fraction between the 2 groups. Radial access patients more often received aspirin and unfractionated heparin. There were no other statistically significant differences in medical therapies between the 2 groups, including usage of thienopyridines and GP IIb/IIIa inhibitors (Table 2).
Patients treated with transradial access had lower pre-procedure predicted bleeding risk scores (10.2 ± 8.2%) than those treated with transfemoral access (12.02 ± 8.5%) on the basis of a validated NCDR CathPCI bleeding risk model (p < 0.0001) (20).
Access approach and clinical outcomes
Fluoroscopy time was longer in the radial access group (14.4 ± 10.4 min vs. 12.1 ± 9.2 min; p < 0.0001). Contrast volume was greater in femoral access patients (197.1 ± 84.2 ml vs. 180.9 ± 78.4 ml; p < 0.0001). There was no statistically significant difference in successful dilatation of the culprit lesion (96.1% in radial access patients vs. 94.7% in femoral patients; p = 0.06) (Table 2).
Unadjusted analysis demonstrated a significantly lower incidence of the primary bleeding endpoint in the radial access group compared with the femoral access group (6.9% vs. 12.0%; p < 0.0001). The number needed to treat to prevent 1 bleeding complication with the radial approach was 20. There were fewer blood transfusions (1.1% vs. 2.8%; p = 0.0003), vascular complications (0% vs. 0.4%; p = 0.02), access site bleeding events (0.2% vs. 1.1%; p = 0.001), access site hematomas (0.22% vs. 1%; p = 0.004), and retroperitoneal bleeding events (0% vs. 0.4%; p = 0.02) in the radial access group. There was also a borderline associated mortality benefit in the radial group (1.7% vs. 2.6%; p = 0.05) (Table 3).
IPTW-adjusted analysis demonstrated that radial access was associated with significantly less bleeding than femoral access (odds ratio [OR]: 0.67; 95% confidence interval [CI]: 0.52 to 0.87; p = 0.003). In-hospital mortality was not significantly different between the groups (OR: 0.81; 95% CI: 0.53 to 1.25; p = 0.35) (Figure 3). IPTW-adjusted subgroup analyses in several key subgroups were consistent with the overall results (Figure 4).
The falsification endpoint of gastrointestinal bleeding demonstrated less gastrointestinal bleeding in the radial group after IPTW adjustment (OR: 0.23; 95% CI: 0.05 to 0.98; p = 0.05).
We found that the majority of patients in the United States undergoing rescue PCI following fibrinolytic therapy for STEMI have the procedure performed via the transfemoral approach. In patients undergoing radial catheterization in this setting, procedural success rates were high. Our primary analyses demonstrated lower associated bleeding risk in patients undergoing rescue PCI via the transradial approach, and this may be an underutilized bleeding avoidance strategy in this understudied patient population. We observed a “risk-treatment paradox” with the utilization of transradial access, as patients treated with this approach had significantly lower pre-procedure predicted bleeding risk scores. Despite the utilization of a nonparsimonious propensity-matched model, persistent differences in the falsification endpoint of gastrointestinal bleeding between the groups point to the presence of unmeasured confounders influencing our adjusted outcomes. Hence, our results must be interpreted as hypothesis-generating.
Several prior studies have examined bleeding outcomes with transradial access for STEMI, although nearly all of these studies have either excluded or not specifically analyzed rescue PCI patients. Two prior randomized trials and a large registry analysis have demonstrated improvements in outcomes with utilization of transradial access in primary PCI, but rescue PCI patients were excluded from these studies (11,12,14). The RIFLE-STEACS (Radial Versus Femoral Randomized Investigation in ST-Elevation Acute Coronary Syndrome) trial randomized 1,001 STEMI patients to radial or femoral access and found lower mortality, bleeding, and length of hospital stay in the radial access group. Similarly, a prior NCDR CathPCI registry–based analysis of 91,000 United States patients found lower adjusted risk of bleeding and in-hospital mortality in radial access patients compared with femoral access patients (8). Although rescue PCI patients were included in these 2 studies, outcomes specific to this important group were not examined.
Only 2 prior analyses have attempted to address differences in clinical outcomes between rescue PCI patients treated with varying access strategies. A 2004 study retrospectively examined transradial versus transfemoral access in 111 patients undergoing rescue PCI with adjuvant GP IIb/IIIa use (21). Additionally, a 2007 study examined 287 patients undergoing rescue PCI, 44 of whom underwent transradial access (22). Both studies suggested improvements in bleeding outcomes with use of transradial access. However, these studies were unadjusted analyses that were modest in size.
To our knowledge, there has been no large trial or observational analysis with statistical adjustment that has analyzed the association of access approach with bleeding complications and mortality specifically in STEMI patients treated with fibrinolytic therapy who have undergone rescue PCI. The current analysis also represents by far the largest population of rescue PCI patients ever studied. Moreover, many prior analyses of access approach are based on clinical trial populations, which exclude the elderly and patients with significant comorbidities who have increased risk of bleeding and in whom pharmacological reperfusion is less commonly employed (23–25). Our analysis avoids these pitfalls through examination of a contemporary patient population across a nationally representative group of hospitals.
Patients undergoing primary PCI for STEMI are at increased risk of bleeding (20), and this risk may be increased in those who receive fibrinolytic therapy prior to PCI (6). Bleeding has been associated with increased mortality in patients presenting with acute coronary syndromes (26). Thus, the reduction of bleeding in this group of patients is of particular interest. Despite possible reductions in bleeding via the transradial approach, our data indicates that 85% of patients undergoing rescue PCI are approached via the transfemoral access route. Additionally, patients chosen for treatment with transradial access were actually at lower predicted bleeding risk than those chosen for transfemoral access. This “risk-treatment paradox” in the use of transradial access for PCI has been noted in other studies (27). Our findings may be due to a lack of operator comfort with the transradial approach, lack of awareness of the benefits of transradial approach, and facility/catheterization laboratory staff unfamiliarity with radial setup leading to delays in time-sensitive situations such as acute myocardial infarction. Multiple societies aim to educate and increase U.S. operator utilization of the radial approach, particularly for higher-risk patient populations (28,29).
Of note, there were no associated improvements in in-hospital mortality observed in the current study. This is in contrast to prior findings from the NCDR that examined all patients presenting with STEMI treated with radial access (8), although it is consistent with the more recent STEMI-RADIAL (ST Elevation Myocardial Infarction treated by RADIAL or femoral approach) trial (30). It is likely that the currently examined rescue PCI population represents a group at intermediate risk of mortality as compared with the STEMI population as a whole. Our patient cohort had lower in-hospital mortality rates (1% to 2%) than all-comers with STEMI (5.5%) (1). In particular, patients requiring intra-aortic balloon pump or those requiring multiple PCIs were excluded from our analysis, because these procedures require additional access sites that could confound bleeding outcomes. As such, the current population may have more in common with non-STEMI and elective PCI populations that have lower PCI-related rates of mortality. In these groups, despite benefit in terms of bleeding and vascular complications, the mortality benefit of transradial access has been less clear (30). Another possibility is that the post-thrombolytic milieu may create a more favorable environment that leads to less distal embolization and no-reflow phenomenon, improving mortality to such a degree that it eliminates the propensity-matched mortality benefit in the radial group. Alternatively, given the low in-hospital mortality rates seen in the present analysis, it is possible that we did not have the power to accurately assess mortality in this patient group.
Our findings raise several interesting questions for future research and development in the understudied rescue PCI population. Other bleeding avoidance strategies, such as the use of bivalirudin, have been shown to reduce bleeding in STEMI, but have not been studied specifically in the rescue PCI population (31). Importantly, in our analysis, even in the subgroup of patients receiving bivalirudin, there was a sustained reduction in bleeding outcomes suggesting an added benefit of transradial access over bivalirudin alone. Additionally, we found increases in fluoroscopy time with radial access among rescue PCI patients, consistent with prior analyses of both PCI and diagnostic catheterization via the transradial approach (32,33). Although not associated with differences in overall procedural success, this consistent finding across studies does underscore the need for continuing technological development that facilitates transradial procedures as well as continuing education to increase operator experience and skill from the transradial approach.
We specified a falsification endpoint of gastrointestinal bleeding to formally assess for possible residual confounding in this observational analysis. Despite robust statistical adjustment and the use of a nonparsimonious propensity model, there may still be unmeasured residual confounders in the association among patient characteristics, access approach, and outcomes. This is reflected by the persistent difference in a bleeding outcome that is unlikely to be directly related to access approach (gastrointestinal bleeding) between the 2 groups after IPTW adjustment. This is an issue that may be particularly relevant to studies of radial versus femoral access that have been shown to experience possible residual confounding when assessed by falsification endpoints (19). It has proven difficult to obviate this residual confounding despite varying methods of statistical adjustment. The results of our falsification endpoint analysis demonstrate the necessity of employing more stringent methodologies to cardiovascular observational analyses to produce valid data that is unlikely to be contradicted by subsequent randomized studies.
In addition to possible residual confounding, our study has limitations inherent to registry analysis. The examined registry only contained data regarding in-hospital mortality. It is possible that radial access could confer a mortality benefit over the longer term (30 days or 2 years), as has been suggested by prior studies of radial access in STEMI (11,13,14). Additionally, it is possible that all bleeding outcomes were not captured, as the data is based on self-reporting by participating hospitals. Although the NCDR conducts a robust auditing program, all outcomes are not independently adjudicated as is the case in many randomized trials. Access site was recorded as the primary access site, and data on access-site crossover was not available. The dataset is limited to those that report to the CathPCI registry. Although this includes the largest contemporary group of institutions in the world performing PCI and does reflect a variety of hospitals by size, location, private/public, and academic/nonacademic, it does not reflect all hospitals in the United States. Finally, analyzed data are only from the United States, and global practice patterns likely vary.
In a large, “real-world” registry, transradial access was used in 15% of patients undergoing rescue PCI with high procedural success rates. Propensity-matched analyses suggested significantly less bleeding associated with a transradial approach in this population. Given persistent differences in a falsification endpoint, the influence of treatment-selection bias on these results cannot be ruled out. However, given the lack of research regarding bleeding avoidance in rescue PCI, the present study is likely to represent the best available data in this area for the foreseeable future.
WHAT IS KNOWN? Although radial access has been shown to reduce bleeding and mortality in STEMI, little is known about the role of radial access in rescue PCI.
WHAT IS NEW? Using the NCDR CathPCI Registry, we examined 9,494 STEMI patients undergoing rescue PCI and found that 14.3% of procedures were performed with radial access. IPTW-adjusted analysis demonstrated a significantly lower risk of bleeding in the radial access group (OR: 0.67; 95% CI: 0.52 to 0.87; p = 0.003), but no difference in in-hospital mortality (OR: 0.93; 95% CI: 0.61 to 1.44; p = 0.75). Gastrointestinal bleeding was also less frequent in the radial group (OR: 0.23; 95% CI: 0.05 to 0.98; p = 0.05) making it impossible to rule out the effect of unmeasured confounders on this analysis.
WHAT IS NEXT? Given the lack of research regarding bleeding avoidance in rescue PCI, the present study is likely to represent the best available data in this area for the foreseeable future.
Statistical support for this study was funded through a grant from the National Cardiovascular Data Registry. Dr. Rao is a consultant for Terumo Medical, Medtronic, and The Medicines Company (all modest); and has received an honorarium from Terumo Interventional Systems. Dr. Wilensky is a scientific advisory board member for Cardiostem, GenWay, Soteria, and Vascular Magnetics; and has equity interest in Johnson & Johnson. Dr. Yeh is an investigator for the Harvard Clinical Research Institute; has served on the advisory board of Abbott Vascular; and has served as a consultant for Gilead Sciences, Abbott Vascular, and Boston Scientific. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- confidence interval
- National Cardiovascular Data Registry
- odds ratio
- percutaneous coronary intervention
- ST-segment elevation myocardial infarction
- Received April 24, 2015.
- Revision received July 8, 2015.
- Accepted July 30, 2015.
- American College of Cardiology Foundation
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