Methods

Literature search and selection criteria

We performed an electronic search of the US National Library of Medicine (PubMed, at www.pubmed.gov), the US National Institutes of Health clinical trials registry (www.clinicaltrials.gov), the Cochrane Central Register of Controlled Trials (www.mrw.interscience.wiley.com/cochrane/cochrane_clcentral_articles_fs.html), abstracts from scientific meetings of major cardiology societies (American College of Cardiology, American Heart Association, European Society of Cardiology and Cardiovascular Research Foundation), as well as internet-based sources of information on clinical trials in cardiology (www.tctmd.com, www.theheart.org, www.clinicaltrialresults.com and www.cardiosource.com/clinicaltrials). The key words used included “bifurcation”, “bifurcational”, “bifurcated”, “coronary”, “drug-eluting stent”, “sirolimus-eluting stent”, “paclitaxel-eluting stent”, “clinical trial” and “randomised”. We also identified relevant reviews and editorials from major medical journals published within the last few years and assessed for possible information on trials of interest. The last search was performed in December 2008.

To be selected for this meta-analysis, studies comparing a simple bifurcation treatment strategy with a complex strategy using DES had to be randomised and have their results reported or made available by the trial investigators for a minimum follow-up period of at least 6 months. All studies meeting the requirements, regardless of the language or form of publication, were considered to be eligible for this meta-analysis. Articles were searched and reviewed independently by two of the authors (ZF and DL); those meeting the inclusion criteria were selected for further analysis. A total of six trials were initially identified.9 10 11 12 13 14 The Sirius bifurcation study9 was excluded because the results were reported according to the actual treatment received and not by the intention to treat. Finally, five trials were included in this meta-analysis.10 11 12 13 14

Study outcomes and data abstraction

The clinical endpoints of this meta-analysis included cardiac death, myocardial infarction (MI), target lesion revascularisation (TLR) and stent thrombosis (ST). In the present study, MI was defined as elevation of cardiac enzymes (data for cardiac enzymes >2 times the upper normal limit (UNL) in the CACTUS trial13 and ⩾3 times the UNL in the remaining studies10 11 12 14 were available and used for this analysis), either with or without new pathological Q waves. The cardiac enzymes, assessed for this purpose, varied among the studies, being total creatine kinase (CK), creatine kinase MB isoenzyme (CK-MB) or troponin T or I. In addition, we evaluated binary angiographic restenosis (defined as ⩾50% diameter stenosis of the treated lesion at follow-up) of both the MV and the SB.

Two investigators (ZF, DL) independently performed data abstraction. Differences were resolved by discussion. In addition to pertinent data on the outcomes of interest, we gathered information on trial names, first author, year of publication or report, and number of patients enrolled. The information was collected regarding main clinical characteristics as well as angiographic characteristics. We recorded the length and rate of clinical and angiographic follow-up in each study included in this analysis. Patients were analysed according to the intention-to-treat principle and outcomes were evaluated by blind assessors.

Statistical analysis

Data were expressed as relative ratio (RR) and 95% confidence interval (CI) for dichotomous variables. The presence of the heterogeneity across trials was evaluated with Cochran’s test. We also calculated the I² statistic to measure the heterogeneity among trials.16 The results of individual trials were combined with the Mantel Haenszel method according to a fixed effect model,17 as no heterogeneity across trials was found in terms of all endpoints in the present study. We assessed publication bias using the Begg adjusted rank correlation test according to the method of Begg and Mazumdar18 and the regression asymmetry test by Egger et al.19 A sensitivity analysis was performed by comparing the treatment effects obtained with each trial removed consecutively from the analysis with the overall treatment effects. Results were considered statistically significant at two-sided p<0.05. Statistical analyses were performed with the Revman 5 freeware package program (The Cochrane Collaboration, Oxford, UK) and the Stata version 9 statistical package.

Results

Five randomised studies of patients with simple versus complex strategy for the DES treatment of bifurcation lesions were selected for this meta-analysis. A total of 1553 patients were included in these studies: 777 of them were treated with the simple strategy, and 776 were treated with the complex strategy. The sirolimus-eluting stent was the study stent in four studies10 11 12 13 and the paclitaxel-eluting stent was used in the remaining one.14 All patients were preprocedurally treated with aspirin and thienopyridines (a loading dose of 300–600 mg of clopidogrel or 500 mg of ticlopidine). Post-intervention anti-platelet therapy consisted of aspirin and thienopyridines for at least 6 months. Length of clinical follow-up varied between 6 months and 12 months, and length of angiographic follow-up between 6 months and 9 months after the index procedure. The main baseline clinical and procedural characteristics of these trials are summarised in table 1.

The fixed-effect model was used for each of the clinical and angiographic endpoints because of the lack of heterogeneity across trials included in this meta-analysis. The risk of follow-up MI was lower in patients treated with the simple strategy compared to patients treated with the complex approach (RR 0.54, 95% CI 0.37 to 0.78, p = 0.001) (fig 1). There was no significant heterogeneity (χ² = 4.56, p = 0.34, I² = 12.3%) or publication bias using the Begg adjusted correlation test (z = 0.24, p = 0.81) and regression asymmetry test by Egger (t = 0.43, p = 0.70). The simple strategy was associated with a reduced early (in-hospital or 30-day) MI (RR 0.52, 95% CI 0.35 to 0.78, p = 0.002) in comparison with complex strategy (fig 1). There was no significant heterogeneity (χ² = 4.48, p = 0.34, I² = 10.8%) or publication bias (z = −0.24, p = 1.0, Begg’s test; t = 0.24, p = 0.83, Egger’s test) across trials. Omission of individual trials from the analysis did not have any relevant influence on the overall results of the analysis. Among the early MI events, the risk of non-Q-wave MI in the simple strategy was significantly lower than that in the complex strategy (RR 0.63, 95% CI 0.39 to 0.99, p = 0.049), while no significant difference in the risk of Q-wave MI was found between the two groups (RR 0.54, 95% CI 0.15 to 1.95, p = 0.35). The risk of cardiac death at follow-up was not significantly different (RR 0.68, 95% CI 0.21 to 2.25, p = 0.53; χ²0.52, p = 0.92, I² = 0%), and the risk of TLR was similar (RR 0.93, 95% CI 0.62 to 1.41, p = 0.74; χ²1.86, p = 0.76, I² = 0%) in the simple strategy group compared to the complex strategy group. No publication bias was found for cardiac death (z = 1.02, p = 0.31, Begg’s test; t = −1.23, p = 0.34, Egger’s test) or TLR (z = 0.73, p = 0.46, Begg’s test; t = 0.31, p = 0.78, Egger’s test) across trials. The incidence of definite ST was 0.6% with the simple strategy and 1.4% with the complex strategy, and no difference was observed between the two groups (RR 0.50, 95% CI 0.19 to 1.32, p = 0.16; χ²2.11, p = 0.72, I² = 0%) (fig 2). No publication bias was found for ST (z = 0.24, p = 0.81, Begg’s test; t = 0.47, p = 0.67, Egger’s test).

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Figure 1

Relative ratios of follow-up myocardial infarction and early (in-hospital or 30-day) myocardial infarction associated with simple versus complex strategy from individual trials and overall population. *In the Nordic trial, procedure-related cardiac enzyme release, the main diagnostic reference of early myocardial infarction was evaluated in 279 of 413 patients (126/206 patients in the complex strategy group and 153/207 in the simple strategy group). BBC ONE, The British Bifurcation Coronary study: Old, New and Evolving strategies; CACTUS, Coronary Bifurcations: Application of the Crushing Technique Using Sirolimus-Eluting Stents Study.

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Figure 2

Relative ratios of definite stent thrombosis associated with the simple versus complex strategy from individual trials and overall population. BBC ONE, The British Bifurcation Coronary study: Old, New and Evolving strategies; CACTUS, Coronary Bifurcations: Application of the Crushing Technique Using Sirolimus-Eluting Stents Study.

With respect to the angiographic endpoints, we excluded the BBC ONE study,14 because of the absence of scheduled angiographic follow-up. Pooling the remaining four studies, the restenosis rates of both MV and SB were similar in the simple strategy group compared to the complex strategy group (RR 1.15, 95% CI 0.66 to 2.00, p = 0.63 and RR 1.12, 95% CI 0.80 to 1.57, p = 0.50, respectively) (fig 3). No significant heterogeneity or publication bias was found for the restenosis risk of MV (χ² 3.63, p = 0.30, I² = 17.3%, heterogeneity test; z = 0.34, p = 0.73, Begg’s test; t = −0.88, p = 0.47, Egger’s test) or SB (χ² 5.54, p = 0.14, I² = 45.9%, heterogeneity test; z = 1.70, p = 0.09, Begg’s test; t = −2.91, p = 0.10, Egger’s test) across trials. Omission of individual trials from the analysis did not have any relevant influence on the overall results of the analysis.

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Figure 3

Relative ratios of main vessel and side branch restenosis associated with the simple versus complex strategy from individual trials and overall population. BBC ONE, The British Bifurcation Coronary study: Old, New and Evolving strategies; CACTUS, Coronary Bifurcations: Application of the Crushing Technique Using Sirolimus-Eluting Stents Study.

Discussion

In this study, we performed a meta-analysis of five randomised trials comparing two different strategies for the DES treatment of bifurcation lesions. We found no significant differences in the risk of cardiac death, TLR, or ST between the simple and complex strategy. However, bifurcation treatment with the simple strategy was associated with a 46% reduction in the hazard of follow-up MI compared with complex strategy, mainly because of the significantly reduced rate of early MI. With regard to the angiographic endpoints, the restenosis risk of either MV or SB at follow-up did not differ between the two strategy groups.

The optimal strategy for bifurcation treatment utilising current stent platforms has already been widely discussed. Studies from the bare-metal stent (BMS) era consistently demonstrated that a simple strategy was superior to a complex strategy.20 21 22 23 However, in the current era of DES, it remains an unsolved problem whether routine stenting of the SB could improve outcome and whether strategies recommended in the BMS era should be changed. The present meta-analysis allows an evaluation of clinical and angiographic benefits and drawbacks associated with the two different bifurcation strategies.

Clinical outcomes

In the present meta-analysis, there was a 46% reduction in the risk of MI with the simple strategy for bifurcation treatment using DES, which was mainly due to the lower risk of early non-Q-wave MI compared with the complex strategy. According to the MI definition in the enrolled studies, most diagnoses of early non-Q-wave MI were established on the basis of a procedure-related elevation of cardiac biomarkers. Although the clinical and prognostic significance of procedure-related biomarker elevation is ambiguous, an association could be established between the complexity of an interventional procedure and the risk of procedure-related myocardial injury. Except for the MI, other adverse events were few and at a similar level in both groups. Independent of stenting strategy, the cardiac mortality was low and comparable to that reported in previous studies with DES treatment for simple de novo lesions.2 3 In addition, the incidence of TLR in the follow-up period did not differ between the different strategy groups, and was relatively lower using DES compared with that using BMS in historical studies. Using the complex stenting strategy for bifurcation lesions, the increased risk of ST has been a concern.9 In our meta-analysis, the incidence of definite ST at mid-term follow-up was similar among patients treated with the simple strategy versus complex strategy. Recently, Jensen et al reported the 14-month follow-up results of the Nordic Bifurcation Study, showing that the rates of ST and major adverse cardiac events (MACE) were low and independent of treatment complexity.24 These findings suggest the parallel safety of these two different strategies in DES treatment of bifurcation lesions.

Angiographic outcomes

The risk and site of restenosis within the stented bifurcation is a further point of interest when DES are used in such a special type of lesions. Irrespective of the stenting strategy assigned, the use of DES in bifurcation lesions was associated with a low risk of MV restenosis in the present meta-analysis. In the past, many authors were concerned about the deformation of the MV stent after dilating or stenting the SB. The balloon dilation of angulated SB may produce metal protrusion of the MV stent into the lumen while the routine stenting of both bifurcated branches would leave double or triple layers of stent struts in the proximal MV segment, resulting in a narrowing of the MV diameter at this level. However, DES-induced inhibition of neointimal proliferation is so powerful that even with imperfect final stent geometry, restenosis appears very infrequently at this site of the bifurcation. In the present meta-analysis, the rate of binary restenosis in the SB was similar between the two strategy groups at scheduled angiographic follow-up, and it was more than two times higher than that in the MV regardless of stenting SB or not. Previous studies showed that the restenosis mechanisms differed in the case of stented and unstented SB. The remodelling due to elastic recoil and late vessel shrinkage is the predominant mechanism of post-procedural lumen loss after plain balloon angioplasty,25 26 whereas the neointima formation accounts for 90% of the lumen loss because of incomplete coverage of the SB ostium or excess distorted metal at the level of the carina in cases of SB stenting.27 28 29 30 Although the complex strategy with routine stenting of SB achieved a better result compared to the simple strategy, it could not provide a more favourable outcome in terms of follow up binary restenosis rate in the SB. Moreover, a focal stenosis or restenosis at the SB was very frequently clinically silent and there were no significant differences in terms of major events between the two strategies.10 Thus, a conservative strategy with regard to treatment of SB stenosis can be advocated if normal blood flow can be maintained in the SB. Previous studies have demonstrated the important role of the final kissing balloon to decrease the SB restenosis in bifurcation intervention when using the complex or simple strategy.12 31 32 33 34 35 In the present study, the rate of the final kissing balloon was relatively high overall with a small inter-study variability (ranging from 74% to 100%) in the complex strategy arm, but it varied widely (ranging from 29% to 100%) in the simple strategy arm. Although favourable, the outcome may be improved further by increasing the rate of the final kissing balloon.

Limitations

In the present study, various techniques (Culotte, routing T, crush stenting and so on) have been used in the complex strategy arm, and outcomes of individual technique were not available. The different technique may have a different impact on the outcome and further studies are needed to detect a possible difference between these techniques. In addition, the follow-up period of all studies enrolled into this analysis was restricted to <12 months. With the use of DES, the events such as restenosis and ST may occur beyond one year. Thus, longer follow-up data will certainly provide important additional information before final conclusions can be drawn. Finally, this meta-analysis was not based on individual patient data and the time-to-event analyses could not be performed.

Conclusions

The results of this meta-analysis show that the simple strategy was associated with a lower risk of early MI and a similar rate of angiographic restenosis at follow-up in comparison with the complex strategy for DES treatment of coronary bifurcation lesions. Since the complex strategy (with routine stenting of both branches of a bifurcation) seems to provide no further advantage, the simple stenting strategy comprising systematic MV stenting and balloon dilation together with provisional stenting for SB can be recommended as a preferred bifurcation stenting technique.