Trends and Outcomes of Radial Approach in Left-Main Bifurcation Percutaneous Coronary Intervention in the Drug-Eluting Stent Era: A Two-Center Registry

Abstract: Objective. To analyze the immediate and long-term outcomes of transradial (TR) percutaneous coronary intervention (PCI) to unprotected left main stem (ULMS) bifurcation and to assess the main aspects affecting access-site choice in this specific PCI setting. Background. TR-PCI to the ULMS is feasible, but data specifically comparing TR and transfemoral (TF) approaches in ULMS-bifurcation PCI are limited. Methods. We set up a two-center (Rome, Italy and Oxford, United Kingdom) retrospective registry aimed at comparing the immediate and 1-year outcomes of consecutive patients who underwent ULMS-bifurcation PCI with drug-eluting stent implantation from 2005 to 2013 using the TF or TR approach. Clinical endpoints were: total mortality; major adverse cardiac and cerebrovascular event (MACCE) rate; and net adverse clinical event (NACE) rate. Results. A total of 467 patients undergoing ULMS-bifurcation PCI were enrolled (221 TF and 244 TR). TR approach was increasingly adopted over time for both simple and complex procedures. No significant differences were observed between the TR and TF groups in terms of 1-year mortality (10.7% vs 9.8%; P=.79) and MACCE (18.2% vs 15.2%; P=.44). TR patients, as compared with TF, had significantly fewer access-site complications (2.0% vs 6.3% in TF; P=.02), resulting in a significant reduction of NACE rate (6.9% vs 15.7;%; P=.01). Conclusion. In patients undergoing ULMS-bifurcation PCI, the selection of TR instead of TF approach is associated with similar early and long-term ischemic complications and with a significant reduction of access-site complications, resulting in lower NACE rate. 

J INVASIVE CARDIOL 2015;27(7):E125-E136

Key words: unprotected left main stem, bifurcation, percutaneous coronary intervention

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Coronary artery bypass graft (CABG) surgery remains the treatment of choice for unprotected left main stem (ULMS) disease,¹ in elective patients with a class Ia and Ib indication in the European² and American guidelines,³ respectively. However, the widespread availability of drug-eluting stents (DES) implantation^4-6 and significant technical advances have progressively changed attitudes toward percutaneous coronary intervention (PCI), especially in emergency patients. Subgroup analysis of the SYNTAX trial has already suggested a broadly similar outcome in patients with ULMS disease in the low-intermediate SYNTAX score tertiles and results of the EXCEL trial designed to compare the two revascularization modalities are forthcoming.^7-9 

PCI to ULMS remains a challenging procedure, especially when the bifurcation is involved,¹⁰ so that various technical aspects (like stenting technique and invasive imaging) are advocated.¹¹ As a consequence of such an anticipated technical complexity, operators often select large guiding catheters inserted through the “standard” transfemoral (TF) approach. Yet, transradial (TR) approach has been shown to reduce vascular complications (compared with TF) in some PCI settings, so that high-volume radial centers have successfully adopted it for the routine clinical practice.¹² Some studies have shown the feasibility of TR approach in ULMS-PCI.^13-16 However, no data are available regarding the effectiveness of the radial approach in the specific, complex, subset of ULMS-bifurcation PCI.

The aim of the present study is to assess the clinical impact of TR approach selection for PCI to ULMS bifurcations in the contemporary DES era.

Methods

Study population. The LABOR (Left Main Bifurcation Oxford-Rome) is a non-sponsored, collaborative registry from two tertiary large-volume PCI centers (John Radcliffe Hospital, Oxford, United Kingdom and Policlinico A. Gemelli, Rome, Italy). All patients admitted to the two centers who underwent PCI to an ULMS bifurcation from January 2005 to November 2013 were included in the registry. ULMS-bifurcation disease was defined as a visually estimated stenosis ≥50% involving at least one of the three branches of the ULMS bifurcation. Plaque pattern distribution was denoted according to Medina classification; true bifurcation disease was defined as atherosclerotic involvement of side branch plus at least one between proximal and distal main branch (Medina 1,1,1; 1,0,1; or 0,1,1).¹⁷ The SYNTAX score⁷ was calculated prior to the procedure for all patients after 2009 and was calculated retrospectively for those enrolled before 2009. 

Patients with ostial or shaft ULMS disease in which stenting was possible without involvement of the bifurcation were excluded. Similarly, bail-out stenting of the ULMS bifurcation due to PCI-related complications affecting the ULMS during PCI to left anterior descending (LAD) or left circumflex (LCX) arteries represented a further exclusion criterion for the present analysis. In cases of prior CABG, patients with patent conduits to LAD or LCX arteries were excluded. All patients treated with bare-metal stents were also excluded.

Elective, urgent, and emergent PCI to ULMS bifurcation were all considered in the analysis, including patients admitted with ongoing cardiogenic shock, which was defined by the presence of systemic hypotension, pulmonary congestion, and signs of impaired organ perfusion. 

All patients undergoing elective intervention to the ULMS bifurcation had an agreed mode of revascularization at a heart team discussion prior to the procedure.²

PCI procedure and clinical management. Decision about access site was left to operator discretion. In both centers, provisional single-stent strategy was recommended when the side branch was not diseased. In case of bail-out second stent or intentional double-stenting strategy, choice of double-stenting technique was at operator preference. In addition, the decision of proximal optimization technique (POT), final kissing-balloon inflation, intravascular imaging guidance, rotational atherectomy in case of heavily calcified disease, and preventive left ventricular (LV) support were at operator discretion.

Furthermore, stent type selection was left to operator discretion, and given that this analysis spanned a time interval of 9 years, both first-generation and second-generation DESs were included in the analysis. 

Procedural success was defined as successful stent deployment with final Thrombolysis in Myocardial Infarction (TIMI) flow grade 3 and a residual stenosis <30% of the luminal diameter at visual angiographic assessment. 

The use and type of closure device for postprocedural hemostasis of the access site was also left to operator discretion.

Procedural complexity of ULMS-bifurcation PCI was defined by patient-related and procedure-related factors and included the occurrence of at least one of the following variables: true bifurcation disease; adoption of a double-stent technique; use of rotational atherectomy; use of preventive LV support; and cardiogenic shock at presentation.

All patients were on a dual-antiplatelet regimen at the time of PCI. Unfractionated heparin (100 UI/kg to maintain an activated clotting time between 250-300 seconds) or bivalirudin (0.75 mg/kg bolus followed by an infusion of 1.75 mg/kg/minute for up to 4 hours after the procedure as clinically warranted) were used as procedural antithrombotic therapy. Glycoprotein IIb/IIIa adoption was at operator discretion. 

All patients were prescribed maintenance doses of dual-antiplatelet therapy following the procedure. According to the standard clinical practice of the enrolling centers, patients were evaluated at 6 months and 1 year by clinic visit or phone contact. 

All patients gave informed consent and all procedures were performed in accordance with ethical standards and the Helsinki Declaration.

Study endpoints. All-cause mortality, cardiac events, and cerebrovascular accidents (CVAs) were recorded. Myocardial infarction (MI) was defined as a new onset of typical ischemic symptoms and/or ischemic eletrocardiographic changes associated with a rise and fall of troponin or creatine-kinase MB levels. Target lesion revascularization (TLR) was defined as any repeated PCI to treat in-stent restenosis or a new stenosis within 5 mm from the stent edges. The rate of patients undergoing CABG due to target lesion failure was also recorded. Cases of definite stent thrombosis were recorded and defined as early, late, and very late according to Academic Research Consortium classification.¹⁸

Occurrence of procedure-related vascular complications was recorded. Access-site related complications included minor and major bleeding, pseudoaneurysm, arteriovenous fistula, and compartment syndrome. Bleeding was classified as minor or major according to the presence of hemodynamic compromise and/or necessity for blood transfusion.

Major adverse cardiac and cerebrovascular event (MACCE) rate was defined as the combination of all-cause mortality, MI, TLR, CABG, stent thrombosis, and CVA. Net adverse clinical event (NACE) rate as defined as the combination of MACCE and access-related complications.¹⁹

Statistical analysis. All continuous variables are expressed as mean ± standard deviation (SD) or as median and interquartile range (IQR), as appropriate. Comparisons of normally distributed variables were performed by using T-test for independent samples, while non-normally distributed variables were analyzed using Mann-Whitney test. Categorical variables are presented as count and percentage of valid cases and frequency comparisons were made using the Chi-square test or Fischer test, as appropriate. 

A multivariable binary logistic regression model was used to estimate the independent predictors of radial access adoption in ULMS-bifurcation PCI. Sequential univariate models were performed for biologically and clinically relevant covariates (age, sex, year of the procedure, cardiovascular risk factors, renal dysfunction, history of previous MI, PCI, or CABG, LV dysfunction, SYNTAX score, presence of true bifurcation disease, stenting strategy, stent type, multivessel PCI, intravascular imaging adoption, rotational-atherectomy supported PCI, cardiogenic shock at presentation, and preventive LV support). Covariates with a P-value <.05 at univariate analysis were entered into a final model using a forward stepwise method. Association between the dependent variable and each covariate was expressed by odds ratio (OR) and respective 95% confidence interval (95% CI). 

Survival analysis at 365 days was performed by applying the Kaplan-Meier method and group differences were assessed with the log-rank test. Since allocation to TR or TF approach could have been biased due to the retrospective non-randomized nature of the study, a 1:1 matched propensity score analysis was performed. Binary logistic regression model was first performed to calculate the propensity score for each patient, using access site as the dependent variable and age, sex, coronary syndrome, year of the procedure, true bifurcation disease, admission with cardiogenic shock, preventive use of LV support, intravascular imaging, and rotational atherectomy as covariates. Patients treated via TR approach were ordered and each TR patient was matched according to the estimated propensity score to the nearest unmatched TF patient. Each pair was considered suitable for the matching if the difference of the estimated propensity score between TR and TF groups was ≤0.001. Propensity-adjusted survival analysis was then performed again with the Kaplan-Meier method and log-rank test.

All P-values are two-sided and P<.05 was considered statistically significant. All analyses were conducted in SPSS version 22 (SPSS, Inc).

Results

Clinical, angiographic and procedural characteristics. Overall, a total of 936 patients were admitted in the two centers for ULMS-PCI during the investigation period. Of them, 467 (49.9%) underwent ULMS-bifurcation PCI with DES implantation. Figure 1 shows the study flow chart for patient selection. In total, 221 patients (47.3%) were treated via TF and 246 (52.7%) via TR approach.

Notably, over a 9-year period, the absolute number of ULMS-bifurcation PCIs and the rate of TR adoption dramatically increased (Figure 2A). Indeed, at these institutions, the TR ULMS-bifurcation PCI rate went up from 9.1% in 2005 to 90.6% in 2013 (P<.001) (Figure 2B). Furthermore, the increasing operators’ confidence with the TR approach is evidenced by the significant increase of complex cases done transradially over time (9.1% in 2005 vs 44.7% in 2013; P=.02) (Figure 2C). Notably, in the TR group, the procedural success rate remained stable over the study period, despite the significantly increased proportion of complex PCIs (Figure 2D).

Patient clinical and angiographic characteristics are reported in Tables 1 and 2, and are stratified according to the access site chosen for the procedure.

Notably, the two groups were well matched in terms of cardiovascular risk factors, previous history of surgical or percutaneous coronary revascularization, and type of presenting coronary syndrome. Of note, however, a significantly higher proportion of patients with cardiogenic shock on admission were treated via TF approach (Table 1). In the TR group, clopidogrel was used less often (90.6% vs 96.4%; P=.01) in favor of new antiplatelet agents; similarly, a wider use of bivalirudin was observed (8.9% vs 0.9%; P<.001). Glycoprotein IIb/IIIa inhibitor adoption was more frequent in the TF group (15.8% vs 5.3%; P<.001). 

Regarding the angiographic characteristics, the two groups were well matched in terms of atherosclerotic burden, as evidenced by both the similar involvement of other vessels and by the SYNTAX score (Table 2). Conversely, a significantly higher proportion of patients with true bifurcation disease (Medina 1,1,1; Medina 1,0,1; and Medina 0,1,1) was treated via TF approach (60.2% vs 40.2%; P<.001). 

Procedural characteristics are summarized in Table 3. Femoral access approach led to a significantly higher adoption of larger guiding catheter size and was associated with a lower screening time (16.2 minutes [IQR, 10.5-25.1] vs 20.3 minutes [IQR, 13.2-30.2]; P<.001) and radiation dose exposure (6151 cGy/cm² [IQR, 4973-7879] vs 7700 cGy/cm² [IQR, 5990-8891]; P<.001). However, the simultaneous treatment of other vessels was more commonly performed in TR procedures, which probably affected resource consumption measures (Table 3). 

Double-stent technique was mainly employed in cases of true bifurcation disease (36.2% vs 5.9%; P<.001) with similar 1-year mortality (13.5% vs 11.1%; P=.64) and 1-year MACCE rate (20.9% vs 20.5%; P=.95) for double-stent and single-stent techniques, respectively. Patients in the TF group were treated more frequently with a double-stent strategy (25.8% vs 16.7%; P=.02).

The two groups did not differ in the use of intravascular imaging guidance or rotational atherectomy. Both overall (22.2% vs 9.3%; P<.001) and preventive LV support (12.7% vs 6.9%; P=.03) were used more frequently in the TF group. 

Predictors of access site selection. In the multivariate model, the year of procedure (OR, 1.72; 95% CI, 1.55-1.92; P=.01), PCI on true bifurcation (OR, 0.39; 95% CI, 0.24-0.63; P<.001), and presentation with cardiogenic shock (OR, 0.22; 95% CI, 0.10-0.55; P<.001) were independently associated with TF approach (Figure 3). In order to detect any change over time in the parameters influencing the choice between TR and TF approaches, the same model was repeated in patients undergoing PCI to ULMS bifurcation before and after 2010 (the year in which TR and TF approach rates were equal) (Figure 2B).

Before 2010, the year of the procedure (OR, 1.61; 95% CI, 1.17-2.21; P=.01), PCI on true bifurcation (OR, 0.45; 95% CI, 0.21-0.96; P=.04), intravascular imaging adoption (OR, 0.24; 95% CI, 0.10-0.60; P=.01), and preventive LV support (OR, 0.11; 95% CI, 0.08-0.92; P=.04) were independently associated with TF approach. Notably, no patients admitted with cardiogenic shock or requiring rotational-atherectomy assisted ULMS-bifurcation PCI were treated via TR approach (Figure 3).

Interestingly, after 2010, only year of the procedure (OR, 2.09; 95% CI, 1.60-2.73; P=.01), PCI on true bifurcation (OR, 0.42; 95% CI, 0.23-0.75; P=.01), and admission with cardiogenic shock (OR, 0.25; 95% CI, 0.10-0.92; P=.01) were independently associated with access-site choice.

Clinical outcomes. Procedural success was achieved in similar proportions in both TF and TR groups (95.9% vs 98.4%); similarly, no differences were observed in terms of coronary-related and arrhythmic complications between the two groups (Table 3). Notably, a lower rate of access-related complications was reported in the TR group (6.3% vs 2.0%; P=.02), which was principally driven by a lower occurrence of minor vascular complications (5.9% vs 0.8%; P=.04). No differences in terms of in-hospital (5.1% vs 2.1%; P=.09), 30-day (7.4% vs 3.4%; P=.06), 180-day (8.5% vs 6.5%; P= 0.43), and 1-year mortality (9.8% vs 10.7%; P=.79) were detected between the TF and TR groups (Table 4). Similarly, no difference was detected in MACCE rates or in each MACCE component at the same time points between the two groups (Table 4). Interestingly, TR approach was associated with a lower incidence of 30-day NACE (6.9% vs 15.7%; P=.01) (Table 4). These results were also confirmed by survival analysis showing a nearly overlapped trend for 1-year mortality and MACCE rates in the two groups (log-rank P=.84 and P=.51, respectively) (Figure 4, top panels). 

Using all the variables independently associated with TR approach, plus age, sex, and coronary syndrome as background variables, a propensity score model was derived, obtaining 106 matched patient pairs. All the variables were equally distributed between the two groups and the C-statistic for the entire model was 0.7. After propensity-matching, TR and TF groups maintained the same trends for both 1-year mortality and MACCE rate (propensity-adjusted log-rank P=.73 and P=.52, respectively) (Figure 4, bottom panels). Also, in the propensity-score matched population, TR continued to be associated with a lower risk of access-site related complications (3.7% vs 6.6%; P=.03). 

Discussion

This study describes the ULMS-bifurcation experience of two high-volume PCI tertiary centers. The main findings of the study are: (1) the TR approach for the treatment of ULMS-bifurcation disease is feasible and associated with good procedural results and fewer access-site related complications; (2) the rate of both overall and complex ULMS-bifurcation PCIs performed transradially has dramatically increased in the 9-year study period; (3) treatment of a true ULMS bifurcation, presentation with cardiogenic shock, and the year of the procedure still continue to be factors favoring the choice of the TF route in case of ULMS-bifurcation PCI; (4) after propensity-score adjustment, the TR approach offers similar results in terms of 1-year mortality and MACCE rate as compared with the TF approach.

Following the introduction of DES implantation, ULMS-PCI has become a potential alternative to CABG, particularly in those with low to mid tertile SYNTAX scores^7,20 and some contraindication to surgery. Left main intervention remains challenging, especially when there is direct involvement of the bifurcation. Patients with ULMS-bifurcation disease are usually older and have a higher likelihood of chronic kidney disease and multivessel disease, and in the setting of an unstable presentation may be at higher risk of hemodynamic instability.¹⁰ In this regard, data from the DELTA registry demonstrated a higher MACE rate at follow-up in patients having distal LM-PCI compared with those having PCI to the LM ostium or shaft.¹⁰

ULMS-bifurcation PCI is known to require complex techniques (with simultaneous use of stents and balloons) and adjunctive devices (such as rotational atherectomy), favoring the selection of larger-sized guiding catheters. As a consequence, many operators may be influenced by such issues to favor the TF route during access-site selection. 

Previous retrospective studies have already reported similar results for TR and TF approaches in LM-PCI in terms of procedural success and long-term outcomes (Table 5),^13-16 confirming in this specific LM setting the benefits related to the TR approach already demonstrated in previous large, randomized, non-LM PCI trials.^19,21 In this regard, Yang et al reported a significantly shorter in-hospital stay and a 0.6% rate of combined major and minor bleeding in the radial group, compared with 2.8% in the TF group (P=.02).¹⁵ This was in line with Ziakas et al’s study, which described a 5.7% access-site complication rate in the TF group, with no events at all in the TR cohort.¹³ 

Although these retrospective studies also included patients having ULMS-bifurcation PCI, there were no specific data addressing the feasibility of the TR approach in this particular setting. To our knowledge, our study is one of the largest series of ULMS-bifurcation PCI, and so far is the first to analyze the procedural and long-term outcomes in a well-selected population of patients specifically undergoing ULMS-bifurcation treatment.

Moreover, by including patients presenting with ST-elevation myocardial infarction and cardiogenic shock, we provide real-world data and our analysis extends to a more complex group of patients known to present generally worse outcomes.²²

Our results fit with the previous literature about LM^13-16 and non-LM bifurcation PCI,²³ by reporting no difference in mortality and MACCE rates at long-term follow-up between the TR and TF approaches. In comparison with previous reports, inclusion of cardiogenic shock patients accounts for the overall greater mortality detected in our study in both groups. Notably, even if at higher risk of CVA for evident anatomical reasons, in this specific context we noticed a similar rate of CVA in both TR and TF groups. 

Finally, in keeping with previous observations in other PCI settings,¹⁹ we observed a benefit in terms of reduced rate of access-site related complications associated with the TR approach. This difference is related to reduced minor vascular complications and drives for a superiority in the composite NACE endpoint for TR approach compared with TF.

Previous studies have shown that the access site does not impact on radiation dose and screening time in high-volume TR-PCI centers;²⁴ however, we detected a longer screening time and higher radiation dose exposure in the TR group, probably related to the higher rate of multivessel PCI in this group. 

A novelty of our analysis is the identification of clinical, anatomical, and procedural characteristics associated with TR and TF approaches. Indeed, besides a progressive increase in the number of complex and non-complex TR ULMS-bifurcation PCIs over the investigation period, we detected that presentation with cardiogenic shock and treatment of a true bifurcation were significantly associated with the TF route. It means that patients with hemodynamic instability or with a foreseeably challenging LM anatomy are usually treated transfemorally. This is in line with data reported in the RADIAL PUMP UP registry, in which nearly two-thirds of the patients undergoing intraaortic balloon-pump assisted PCI were treated by TF approach.²⁵ 

Not surprisingly, the year of the procedure, reflecting the phase of the learning curve for both TR and LM-PCI, was associated with a TF approach. Also, these data conform to previous evidence showing that in all comers, the main predictor of TR approach was the volume of TR-PCIs performed per center and per operator.²⁶ 

Interestingly, we detected a change in the parameters associated with the preference of the access site over time. Indeed, intravascular imaging adoption and preventive LV support appeared to be used more frequently with the TF approach only in the first years of the investigation period, but not recently when perhaps improved skills and familiarity allowed more complex ULMS-bifurcation PCIs to be undertaken by the radial approach. The data regarding double-stent technique adoption seem to further confirm this. Indeed, we observed an overall higher rate of double-stent technique in the TF group. However, while the double-stent technique proved to be a predictor of femoral approach before 2010, albeit only at the univariate model, it was not related to access site preference at all thereafter. 

Moreover, no cases of rotational-atherectomy supported PCI were performed transradially in the first years of the investigation period. The change can be explained by the progressively increased routine adoption of sheathless guiding catheters, making rotational atherectomy feasible by the radial route.²⁷ 

Study limitations. Despite propensity-score adjustment, comparisons from this analysis are limited by the retrospective and non-randomized design. No comparison in terms of in-hospital stay was performed between the two groups in view of different discharge policies between the two centers, as only one of them had a “day-case” service that allowed shorter stays. Moreover, even different types of access-related complications were taken in consideration, and even if main differences were detected in terms of minor hemorrhages, no “validated scale” such as TIMI, GUSTO or BARC was used to grade bleeding.

Conclusion

The present larger registry on patients with ULMS bifurcation undergoing PCI shows the safety, feasibility, and clinical efficacy of TR approach. Notably, large-volume TR PCI centers have shifted toward exponential adoption of TR access in ULMS-bifurcation PCI, rendering it the standard approach in daily clinical practice. Cardiogenic shock and unfavorable bifurcation anatomy are the only variables favoring selection of the TF approach.

Acknowledgments. The authors want to thank the team of the catheterization laboratory of the John Radcliffe Hospital (Oxford, United Kingdom) and Policlinico A. Gemelli (Rome, Italy). A special thanks to the consultants Prof Keith M. Channon, Dr Bernard D. Prendergast, Dr John Colin Forfar, Prof Robin C. Choudhry, Dr Oliver Ormerod, Dr Mario A. Mazzari, Dr Rocco Mongiardo and Prof Antonio G. Rebuzzi for their invaluable help and support. 

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From the ¹Oxford Heart Centre, Oxford University Hospitals, Oxford, United Kingdom; and ²Department of Cardiovascular Sciences, Catholic University of the Sacred Heart, Rome, Italy.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Manuscript submitted July 24, 2014, provisional acceptance given September 22, 2014, final version accepted January 26, 2015.

Address for correspondence: Adrian P. Banning MD, Oxford Heart Centre, John Radcliffe Hospital, Headley Way, Oxford OX39DU, United Kingdom. Email: adrian.banning@ouh.nhs.uk