Comparison of Different Stenting Techniques of Coronary Bifurcation Lesions: A Network Meta-Analysis of 7601 Patients

Abstract

Background: Intervention on coronary bifurcations lesions (CBL) is challenging. While provisional side branch (PS) stenting is the recommended method in most cases, there is no consensus on the preferred 2-stent technique. Methods: We performed a network meta-analysis including randomized controlled trials (RCT) and observational studies comparing stenting techniques in CBL with reported clinical outcomes. A mixed treatment comparison model generation was performed to compare culotte, T and protrusion (TAP), crush and provisional techniques. Results: We included 14 RCT and 14 observational studies comprising 7,601 patients among whom 2,516 were treated with PS, 792 with TAP, 1,493 with culotte and 2,808 with crush. A Bayesian network meta-analysis showed a significant rate reduction of major adverse cardiovascular events (OR=0.73; 95%CI 0.52-0.99) and a trend for reduction in lesion revascularization (OR=0.72; 95%CI 0.48-1.11) and myocardial infarction (OR=0.62; 95%CI 0.3-1.08) with the crush technique, mainly driven by the double kissing (DK) crush, compared with all other stenting techniques. Other clinical outcomes, including mortality and stent thrombosis (ST) did not differ significantly between methods. Conclusion: The crush technique, and especially DKcrush, is associated with improved outcomes compared to culotte T and protrusion (TAP) and provisional techniques for CBL treatment. Further research is required to determine the optimal stenting technique for CBL. Pr ep rin t Introduction Coronary bifurcation lesions (CBL) account for 15-20% of all percutaneous coronary interventions (PCI) and constitute a major challenge for interventional cardiologists in terms of both procedural success and long-term major adverse cardiac events (MACE). Based on data from multiple randomized controlled trials (RCT) and registries, current guidelines advocate the use of provisional side branch (SB) stenting for the majority of CBL. However, an upfront double stent technique should be considered for complex CBL (long side branch lesions, difficult side branch access or high risk of side branch compromise) since a provisional strategy may potentially lead to acute or long-term occlusion of a significant side branch. In these cases, which account for 5 to 25% of CBL, a 2-stent technique may be needed for optimal results. Several dual-stenting techniques are recommended, including reverse provisional stenting, T-stenting and small protrusion (TAP) in which a second stent is being advanced through the struts of the MB stent into the SB and deployed with slight (1-2mm) protrusion into the MB, then both the MB balloon ant the SB stent balloon are simultaneously inflated. Culotte technique in which 2 stents are deployed in tandem, from the main vessel into each branch with strut opening to each branch by kissing balloon inflation leaving the proximal main vessel covered with two overlapped stents, and crush modification including mini-crush and double kissing crush (DK crush) which consists of stenting from the main vessel into the SB, balloon crushing from the MB, stenting from the main vessel into the MB and final kissing balloon inflation. The DKcrush modification is performed with a 2 kissing Pr ep ri t balloon inflations, both prior and following the second stent deployment . Nevertheless, due to the anatomical and technical complexity of these lesions and methods, treatment results may be affected by several factors such as the selected double stenting technique, operator’s experience and the use of intracoronary imaging during the PCI. Therefore, the optimal 2-stent technique for CBL remains controversial. Accordingly, we performed a network meta-analysis of RCT and observational studies comparing the clinical outcomes of various 2-stent techniques with provisional stenting in CBL. Methods The primary objective of this network meta-analysis was to compare the various 2 stents techniques for CBL, with a common comparator of a provisional technique, with regards to clinical outcomes including MACE defined in most studies as mortality, myocardial infarction and target vessel or lesion revascularization, target lesion revascularization (TLR), all-cause mortality, myocardial infarction (MI) and stent thrombosis (ST). Clinical outcomes and events rate are based on the definitions given and the reported incidents in each study. We included the recommended techniques such as crush, culotte, and TAP, but not simultaneous kissing stents which is no longer recommended (EBC statement). We included in the crush group all methods such as mini-crush, classic crush, and DK crush since the concept of the result was similar. Nevertheless, to assess the impact of DKcrush, we performed a separate analysis with DKcrush group as an independent group from other crush techniques. Two independent investigators (EK and LH) had systematically screened (January 2020) MEDLINE/PubMed for titles and abstracts containing the terms coronary bifurcation OR crush stenting OR provisional stenting OR culotte Pr pri nt stenting , reviewed the full-text articles and determined their eligibility. Included in the meta-analysis were RCTs and observational studies, comparing at least two of the listed PCI techniques for CBL with available clinical follow-up separately for each technique. Studies with inadequate outcome data, duplication of data and those available only in abstract form were excluded from the analysis. Data was abstracted by additional two investigators (OB and AD) in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Metaanalysis Of Observational Studies in Epidemiology (MOOSE) guidelines The type of study, year of publication, time of follow up, treatment allocation and stenting technique, patients age, gender, co-morbidities, left ventricular ejection fraction (LVEF) and outcome data for TLR, MACE, MI, ST and all-cause mortality at the longest available follow-up were extracted and recorded when available. We accepted the studies definitions for adverse events. Statistical analysis Dichotomous variables are expressed as percentages and continuous variables as mean ± standard deviation or median+ IQR (interquartile range) based on normal distribution. To compare directly and indirectly between the CBL interventional techniques: provisional, crash, culotte, and TAP we used a mixed treatment comparison model generation performed by GeMTC 0.14.3 software (GeMTC, http://drugis.org/software/r-packages/gemtc). Bayesian hierarchical random-effects model with directed acyclic graph model for general-purpose Markov chain Monte Carlo analysis was performed with 50,000 tuning iterations and 100,000 simulation iterations. Data is presented as odds ratios (OR) and 95% credible intervals (CrI). Convergence was appraised graphically according to Gelman and Rubin. Data from a Pr pri consistency model are presented, and the direction of findings were confirmed with an inconsistency model to serve as a sensitivity analysis. Additional sensitivity analysis was performed with removal of one study at a time to confirm directionality and magnitude of findings. Statistical significance was defined as a P-value <0.05. Results We screened and reviewed a total of 4,005 MEDLINE citations using the previously defined search terms. 212 abstracts which met the inclusion/exclusion criteria were evaluated, and from them 76 full-text publications were reviewed in detail. Finally, we entered 28 studies in the meta-analysis, including 14 RCTs 10,11,20– 23,12–19 and 14 observational studies . The study flow chart is shown in Figure 1. Characteristics of studies included in the meta-analysis are presented in Table 1. Among the 7,601 patients with CBL identified from the included articles, 1,493 were treated with culotte, 2,808 with crush, 792 with TAP and 2,516 with provisional stenting. Figure 2 represents the number of patients treated by each BCL technique. Mean follow-up was 28.6 months. Patients baseline characteristics are shown in Table 2. Mean age was 65.9± 9.9 years. Men comprised 76.3% of the population, 33% were smokers and 28% had diabetes mellitus. Prior MI was present in 24%, 28% of patients had undergone previous PCI and 4.8% had prior coronary artery bypass graft (CABG) surgery. The mean left ventricular ejection fraction (LVEF) was 54.5± 12%. Angiographic and procedural characteristics are shown in Table 3. True bifurcation lesions were present in over 90% of the patients, left main lesions were included in 18 studies and were recorded in 3,108 patients, kissing balloon inflation Pr pri nt (KBI) was performed in 81% of CBL and intracoronary imaging was used in 13 studies and 2,011 patients. The network plot for MACE with and without DKcrush is presented in figure 3. The Bayesian network meta-analysis demonstrated the superiority of the crush technique, but not culotte and TAP, over provisional stenting in reduction of MACE (OR=0.73; 95%CI 0.52-0.99) (Figure 4). This was mostly driven by lower TLR and MI rates, while mortality and ST did not differ significantly between stenting methods, possibly due to the low event rate and lack of statistical power. Rankings of therapies according to the probability of being the best, second, third and fourth based on the Bayesian network meta-analysis revealed similar results with the crush technique as a leading 2-stent treatment modality in all outcomes, as shown in Figure 5 When differentiating between double kissing crush (DKcrush) and other crush methods, the results indicate that the crush superiority was driven by the DKcrush technique (Figure 6). Ranking of treatment showed similar findings indicating that it is DKcrush which results in improved clinical outcome for patients with bifurcation lesions requiring 2 stents (figure 7). When limiting the analysis to RCTs, there was no statistically significant difference in any of the stated endpoints between provisiona