Does the Target Vessel Impact on Results of Percutaneous Coronary Intervention for Bifurcation Lesions? Insights From the I-BIGIS Registry

Abstract: Background. Bifurcations remain a challenging subset for percutaneous coronary intervention (PCI). Specifically, it is unclear whether bifurcations on left anterior descending (LAD) coronary arteries have the same prognosis of bifurcations on left circumflex (LCX) or right coronary arteries (RCA). We compared the results of PCI for bifurcation lesions, focusing on target vessel. Methods. Patients undergoing bifurcation PCI on the LAD were compared to those undergoing bifurcation PCI on the LCX and on the RCA. The primary endpoint was the long-term major adverse cardiac event (MACE) rate, defined as death, myocardial infarction, or target lesion revascularization (TLR). Results. A total of 2376 subjects were included, with 71.1% treated on the LAD, 21.5% on the LCX, and 7.4% on the RCA. Early MACE rates were similarly uncommon in the LAD (2.0%), RCA (2.3%), or LCX (1.2%) groups (P=.46). Long-term outcomes (22.81 ± 2.7 months) were also similar, with MACE in 12.6%, 14.9%, and 12.4% (P=.39), death in 4.0%, 4.5%, and 4.5% (P=.83), myocardial infarction in 3.8%, 3.6%, and 3.0% (P=.23), and stent thrombosis in 1.5%, 2.2%, and 1.7% (P=.64), despite an apparent increase in TLR rates in the LCX group (12.4%) vs LAD (8.9%) or RCA (7.3%) groups (P=.04). However, after multivariable adjustment, the risk of all long-term adverse events was similar irrespective of target vessel. Conclusions. Bifurcations localized in the LCX and RCA are associated with event rates at least as high as those in the LAD. Thus, care should be taken to skillfully perform PCI and maximize post-PCI medical therapy wherever the bifurcation lesion is located. 

J INVASIVE CARDIOL 2013;25(12):660-665

Key words: bifurcation, coronary artery disease, percutaneous transluminal coronary angioplasty, stent

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Percutaneous coronary intervention (PCI) is a mainstay in the management of patients with coronary artery disease. Despite several advancements, including improvements in access sites,¹ techniques,² and devices,^3,4 patients with bifurcation lesions still represent a higher-risk subset.⁵ Indeed, procedural success is lower in coronary bifurcations, and adverse events more common even after an apparently successful procedure.^2,6,7 Several patient and procedural prognostic features have been identified, such as age, diabetes, renal function, cardiac systolic function, and vessel size,^6,8,9 whereas others have been challenged.¹⁰

A commonly shared belief among cardiologists is that a bifurcation lesion should be approached and managed differently depending on its location in the coronary tree. In other words, patients with bifurcation lesions of the left anterior descending (LAD), which often has large branches such as septal perforators and diagonals, are often considered at higher risk of early and late adverse events.¹¹ Conversely, bifurcation lesions in the left circumflex (LCX) or right coronary artery (RCA) are usually considered less clinically relevant, given the more limited amount of myocardium at risk. However, there is no clear evidence basis to support this stance. 

The Italian Multicenter Registry on Bifurcation Study (I-BIGIS) was a multicenter retrospective registry enrolling patients undergoing PCI for coronary bifurcation lesions, actually providing the largest ever dataset on bifurcation PCI.⁶ We thus performed a retrospective comparison of early and long-term outcomes of bifurcation PCI explicitly comparing patients with lesions in the LAD, the LCX, and the RCA, within the setting of the I-BIGIS registry.

Methods

Study design. The I-BIGIS was an Italian multicenter, retrospective, observational clinical study, independent of commercial funding, enrolling consecutive patients undergoing bifurcation PCI between January 2002 and December 2006.⁶ Percutaneous coronary revascularization at the site of a bifurcation lesion of a major epicardial vessel and eligibility for 1-year follow-up were required for inclusion, while no specific exclusion criteria were adopted. All patients provided written informed consent and ethical committee approval was waived given the observational design. We decided a priori to exclude patients undergoing PCI for left main bifurcation disease, those undergoing PCI on more than one bifurcation lesion or those receiving multivessel PCI, as these patients would have confounded the comparison according to target vessel.

Data collection. All decisions concerning treatment strategy and stent selection, as well as postprocedural aspects (eg, antiplatelet therapy duration) were at the operator’s discretion. Patients were discharged on oral thienopyridines for 3-12 months plus aspirin indefinitely, depending on admission diagnosis as well as stent choice. Patients were followed by direct check of hospital charts, patient visit, phone interview, or contact with referring physicians.

Clinical outcomes and definitions. Bifurcation lesions were defined as presence of >50% diameter stenosis in a major epicardial coronary vessel (eg, the LAD) involving a coronary bifurcation with a 2.5-4.5 mm reference vessel diameter in the main branch and 2.25-4.5 mm in the side branch. True coronary bifurcation lesions were defined as a stenosis >50% in both the main branch and the ostium of the side branch. The primary endpoint of the study was the long-term major adverse cardiac event (MACE) rate, ie, the composite of death, myocardial infarction, coronary artery bypass grafting (CABG), or target lesion revascularization (TLR). As secondary endpoints, we appraised individual components of MACE at 30 days and at long-term follow-up. Stent thrombosis was also assessed utilizing Academic Research Consortium definitions.¹²

Statistical analysis. Continuous variables are reported as mean ± standard deviation and categorical variables as n (%). Bivariate analyses were first performed to compare the LAD, LCX, and RCA groups, with continuous variables compared with analysis of variance, and categorical variables with the Chi-squared test. Survival analysis was performed with the Kaplan-Meier method and comparing those curves with the log-rank test. Subsequently, variables significantly or tending to be associated (P<.10) with target vessel at bivariate analysis were included in a Cox proportional hazard analysis in order to appraise the independent prognostic impact of target vessel on clinical outcomes. Statistical significance was set at the .05 2-tailed level, and computations performed with SPSS 20 (IBM).

Results

Population and procedures. From 4314 initial patients, a total of 1938 were excluded in keeping with the selection criteria for this substudy, yielding a final set of 2376 patients subjects. Of these patients, a total of 1689 (71.1%) were treated on the LAD or its branches, 510 (21.5%) were treated on the LCX or its branches, and 177 (7.4%) were treated on the RCA or its branches Patient characteristics when comparing included versus excluded patients were largely similar, except for a more extensive atherosclerotic burden among excluded patients (who by definition had left-main bifurcation disease or underwent PCI on multiple vessels or bifurcation lesions).

Patient features are reported in Table 1. The LAD group had a significantly lower prevalence of male gender, hypertension, dyslipidemia, diabetes, prior myocardial infarction, prior revascularization, multivessel disease, and ST-elevation myocardial infarction at admission (all P<.05). Lesion and procedural characteristics are reported in Table 2. The LAD group had a significantly higher rate of true bifurcation lesions, complex stenting technique, and drug-eluting stent implantation, but a significantly lower prevalence of multiple lesions on the same vessel (all P<.05). Moreover, main-branch size was smaller in the LCX and RCA groups, even if the opposite phenomenon occurred for side-branch size (all P<.05). Finally, intravascular ultrasound and kissing-balloon inflation were more common in patients undergoing bifurcation PCI in the LAD.

Clinical outcomes. Early (30-day) events were not significantly different between the groups (Table 3), with MACE in 33 (2.0%) in the LAD group vs 6 (1.2%) in the LCX group and 4 (2.3%) in the RCA group (P=.46), and death in 16 (0.9%), 3 (0.6%), and 3 (1.7%, P=.41), respectively. Similarly, long-term data after 22.8 ± 2.7 months of follow-up, showed non-significant differences in MACE rates (213 [12.6%] in the LAD group vs 76 [14.9%] in the LCX group and 22 [12.4%] in the RCA group; P=.39), as well as all other appraised clinical endpoints, with the notable exception of TLR, which appeared more common in the LCX group (63 [12.4%] vs 151 [8.9%] in the LAD group and 13 [7.3%] in the RCA group; P=.04). However, multivariable adjusted Cox proportional hazard analysis for late events showed that there was no statistically significant and independent association between any of the three target vessel groups and adverse event rates (Table 4).

Discussion

This work, stemming from the largest dataset available so far on bifurcation PCI in the current drug-eluting stent era, has several implications: (1) PCI for coronary bifurcation lesions is feasible and associated with favorable early results irrespective of the target vessel; (2) despite common prejudices that LAD lesions are more challenging and more commonly fraught with recurrences, long-term adverse events occur on average in 12%-15% of patients, without significant differences in patients with bifurcation lesions in the LAD, LCX, or RCA; and (3) thus, care should be taken to skilfully perform PCI and maximize post-PCI medical therapy wherever the bifurcation lesion is located.

Current research context. Notwithstanding the major and recent improvements in the early and late outlook of patients undergoing percutaneous coronary revascularization, several unmet needs remain. Intense research is focusing on intense antiplatelet therapy¹³ and novel devices such as bioresorbable vascular scaffolds, with the ultimate goal of applying them to unselected real-world patients.¹⁴ However, bifurcation lesions remain a rather common yet challenging subset.

The typical approach to bifurcation lesions is appraising them according to disease extent, thus distinguishing true versus pseudo-bifurcations, for instance applying the user-friendly Medina classification or minor modifications of this tool.^15,16 Another commonly used approach is based on the distinction between bifurcation with diffuse side-branch disease, versus those without extensive atherosclerotic involvement of the side branch, and thus less likely to require side-branch stenting.^5,17 These ways to tackle bifurcations share the common assumption that bifurcation lesions occurring on different coronary vessels share similar procedural challenges and long-term rates of adverse events.¹⁸ However, this concept has never been formally tested or proven.

Contributions of the present study. Our study, stemming from the large and well-known I-BIGIS registry, provides several important findings for practitioners managing patients with coronary bifurcation lesions in whom PCI is envisioned. First, bifurcation PCI most commonly involves the LAD and its branches, with LCX PCI still more common than RCA PCI. Moreover, patients with LAD bifurcations in our study usually had a lower-risk profile, including lower prevalence of prior myocardial infarction or prior revascularization. Accordingly, main-branch diameter was  smaller in the LAD group than in the LCX and RCA groups. These baseline differences are probably the simplest explanation of the fact that, despite obvious differences in the theoretical amount of ischemic myocardium, early and long-term event rates were similar in the three groups. Indeed, early MACE and mortality were unanimously uncommon, whereas long-term MACE rates ranged between 12% and 15% after almost 2 years of follow-up, without significant differences among the three groups at multivariable adjusted analyses. Accordingly, bifurcation PCI in the LCX or RCA should not be viewed per se at lower risk of early complications or late events in comparison to bifurcation PCI in the LAD.

Avenues for further research. Our results appear important to guide the management of patients with coronary bifurcation lesions, as well as the refinements in coronary devices. Since LCX and RCA bifurcations are still fraught with a clinically relevant risk of adverse events, and are typically characterized by smaller main branches yet larger side branches, a tailored approach could be considered in these patients. Indeed, we might envision a more liberal use of complex stenting techniques or dedicated devices in such cases.

Accordingly, the development of dedicated bifurcation stents should take into account the differences between coronary bifurcation lesions located in the LAD, LCX, or RCA. Moreover, differences in tortuosity and angulation (with RCA and distal LCX lesions typically requiring more manipulations) should be borne in mind. In particular, it appears from our work that true bifurcation lesions in the LCX and RCA most commonly have similar reference vessel diameters in both main and side branches, thus requiring devices that can easily accommodate such “symmetric” bifurcations. These might differ substantially from devices more suited for LAD bifurcations, in which the main branch often appears larger than the side branch. Finally, our results suggest that future trials focusing on coronary bifurcations should best exploit stratified randomization based on target vessel, to minimize the potentially biasing impact of this feature on the study results.¹⁹ Indeed, this has not been the case in several of the most important and recent studies on coronary bifurcations.^20-22

While substantial work has been so far devoted to the identification of predictors of early and long-term adverse events, much still needs to be done.^6,8 Specifically, prior analyses from this very dataset suggested that MACE rates were predicted by diabetes, reduced systolic function, restenotic lesion, stent type, and complex stenting strategy. Kissing-balloon inflation was not associated with fewer MACEs, but with a reduced risk of repeat revascularization in the side branch, albeit only in those receiving 2 stents. Further appraisal of the different patient, lesion, or procedural variables associated with clinical outcomes are nonetheless required, especially in the current era of novel generation stents.²⁵

Study limitations. This work has several drawbacks, including all those typical of observational studies.²³ Specifically, information and selection bias, with their confounding effects, cannot be completely taken care of and should be borne in mind. However, the use of extensive multivariable analyses may effectively reduce the impact of selection bias.²⁴ Another key limitation of this work is that details on coronary dominance were not available, and thus we cannot appraise the different prognostic impact of bifurcation PCI on a dominant versus non-dominant LCX or RCA. Finally, quantitative coronary angiography or detailed quantification of disease burden (eg, by means of SYNTAX score) were not available and thus cannot be exploited for further analyses.

References

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From the ¹Department of Medico-Surgical Sciences and Biotechnology, Sapienza
University of Rome, Latina, Italy, ²Division of Cardiology, University of Turin, Turin,
Italy, ³Division of Cardiology, Ospedale di Legnano, Milan, Italy, ⁴Division of
Cardiology, Ferrarotto Hospital, Catania, Italy, ⁵Division of Cardiology, Tor Vergata
University, Rome, Italy, and ⁶Division of Cardiology, Policlinico Casilino, Rome, Italy.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of
Potential Conflicts of Interest. Dr Biondi-Zoccai reports grants from Abbott Vascular; personal
fees and non-financial support from Abbott Vascular, Boston Scientific, Cordis, Medtronic,
and Terumo, outside the submitted work. The other authors report no disclosures.

Manuscript submitted May 31, 2013, provisional acceptance given October 8, 2013,
final version accepted October 17, 2013.

Address for correspondence: Dr Giuseppe Biondi-Zoccai, Department of Medico-
Surgical Sciences and Biotechnology, Sapienza University of Rome, Corso della
Repubblica 79, 04100 Latina, Italy. Email: gbiondizoccai@gmail.com