Single Versus Double Stenting for Unprotected Left Main Coronary Artery Bifurcation Lesions: A Systematic Review and Meta-Analysis

Abstract: Objectives. We conducted a meta-analysis to assess outcomes for a single-stent (SS) strategy versus a double-stent (DS) strategy in treatment of distal unprotected left main coronary artery (ULMCA) lesions in the drug-eluting stent (DES) era. Background. Routine use of DES implantation has contributed to improved outcomes in patients undergoing percutaneous coronary intervention (PCI) for disease involving the ULMCA. However, PCI for ULMCA bifurcation lesions continues to be technically demanding and is an independent predictor of poor outcomes. While a number of stenting techniques have been described, the optimal strategy remains unknown. Methods. SS treatment was defined as stenting of the main branch alone and DS treatment as stenting of both the main and side branches. Our co-primary endpoints were major adverse cardiovascular events (MACE), and its individual components. Results. We identified 7 observational studies involving 2328 patients. Mean duration of follow-up was 32 months. We adopted the random effect model when computing the combined odds ratio (OR). There was decreased risk of MACE with SS strategy (20.4%) versus DS strategy (32.8%) (OR, 0.51; 95% confidence interval [CI], 0.35-0.73). There was also decreased target vessel/target lesion revascularization (TLR/TVR) with SS strategy (10.1%) versus DS strategy (24.3%) (OR, 0.35; 95% CI, 0.25-0.49). Conclusion. Compared to the DS strategy of percutaneous ULMCA bifurcation intervention, an SS approach may be associated with better outcomes.  

J INVASIVE CARDIOL 2014;26(6):229-233

Key words: left main coronary artery, percutaneous coronary intervention, drug-eluting stent

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The interest in unprotected left main coronary artery (ULMCA) percutaneous coronary intervention (PCI) has been steadily growing. Significant left main coronary artery (LMCA) disease occurs in 3%-9% of all patients who undergo coronary angiography¹ and around 60% of these lesions involve the distal vessel (ie, involve the bifurcation).² Despite advances in device technology and refinement of PCI techniques, bifurcation interventions continue to be a challenge for interventional cardiologists and are still associated with increased rates of complications when compared with non-bifurcation lesion interventions. In the drug-eluting stent (DES) era, several randomized studies are available comparing a provisional approach of implanting one stent in the main branch only versus a two-stent approach in both the main branch and side branch of non-left main bifurcations.^3-7 The general consensus from these studies is that there is no systemic advantage to a double-stent (DS) strategy and that provisional single-stent (SS) strategy should be the default approach for most non-left main bifurcations.⁸ However, the approach for treating ULMCA bifurcation lesions remains largely dependent on operator preference. In the setting of a paucity of clinical data to guide decision making, we performed this meta-analysis in an effort to compare the outcomes of SS versus DS for treatment of ULMCA bifurcation lesions in the DES era.

Methods

Search strategy. Pubmed, the Cochrane Databases, the Clinical Trials registry (www.clinicaltrials.gov), and the datasets of presentations at the major meetings of the American Heart Association, the American College of Cardiology, and Transcatheter Cardiovascular Therapeutics were searched from April 2002 to May 2012. Search terms included: “left main coronary artery,” “stenting,” “bifurcation,” and “double stent.” Two investigators (NM and WK) independently screened the search results at the abstract level, and relevant studies were retrieved as full manuscripts. Differences were resolved by consensus with input from a third reviewer (AD). Inclusion criteria were: (1) involving ULMCA disease; (2) involving DES; (3) involving at least 50 patients in the overall study cohort; and (4) at least 6-month follow-up duration. Exclusion criteria were defined as: (1) non-English studies; (2) involving bare-metal stent (BMS) implantation; and (3) studies not reporting relevant clinical outcomes. Data regarding patient demographics and clinical outcomes were then entered into a database. 

Endpoints. The primary endpoints were major adverse cardiovascular event (MACE) rate and its individual components (cardiovascular death, myocardial infarction, and target vessel/target lesion revascularization [TVR/TLR]). 

Statistical analysis. Summary odds ratio (OR) and the corresponding 95% confidence interval (CI) were calculated using raw data. These were converted to natural log ORs as well as standard errors using the method outlined in the Cochrane Handbook.⁹ These were combined using the generic inverse-variance method. A 2-sided P-value <.05 was considered to be statistically significant. Results for individual studies and summary results are expressed as an OR with 95% CI. We did not perform multivariate regression analysis to adjust for potential confounders, as we did not have access to patient-level data. Heterogeneity in our analysis was assessed by examining the forest plots and then calculating a Q-statistic, which was compared to the I² index. A random effects model was used irrespective of the findings for heterogeneity. Studies were rated according the Newcastle-Ottawa scale (NOS) used for assessing non-randomized observational studies. Statistical calculations were performed with Review Manager (RevMan version 5.1; The Nordic Cochrane Centre, The Cochrane Collaboration, 2011).

Results

Database searches retrieved an initial 219 studies, of which 16 were deemed relevant; 9 of these studies were eventually excluded and a final 7 studies meeting inclusion/exclusion criteria were included in the analysis (Figure 1).^10-16 Among these 7 studies, 5 were prospective and 2 were retrospective in nature. No randomized studies were identified that satisfied our inclusion criteria.

The included studies comprised 2328 patients with a mean follow-up of 32 months (range, 12-48 months). Table 1 shows the characteristics of studies included in our meta-analysis. The mean age of patients ranged from 65-72 years, and the majority were men. Based on the NOS, all of the included studies scored high in terms of selection and outcome assessment. However, in comparability, 5 out of 7 scored high (Table 2). The procedural characteristics of our population are presented in Table 3. Out of the total 2328 patients, 1368 (58.8%) underwent SS of the ULMCA bifurcation stenosis while 960 (41.2%) underwent DS covering both the main vessel and the side branch. In most studies, the stent strategy (SS or DS) was made a priori. Different DS techniques were utilized (crush, culotte, T-stent, or V-stent), with most operators preferring the crush technique (range, 17%-50% of patients). True bifurcation lesions (Medina 1,1,1; 1,0,1; 0,1,1) ranged from 41%-90% across included studies. Paclitaxel- and sirolimus-eluting stents were used across studies. None of the studies used dedicated bifurcation stents. Intravenous GPI use ranged from 6%-48%. Final kissing-balloon inflation was commonly used, especially in the DS arm. Most of the included studies did not report the number of patients who crossed over from one stenting strategy to the other. Studies were noted to be heterogeneous in regard to MACE and TLR/TVR (Q-test P >.05 for both; I² was 71.5% and 36.5%, respectively).

Estimates of rates for MACE, cardiac death, MI, and TVR/TLR as stratified by stent technique are displayed in Table 4. The event rates are numerically higher for patients treated with DS for most endpoints. Using the OR as our risk estimate, the OR clearly favored SS strategy for MACE (0.51; 95% CI, 0.35-0.73; P<.001) (Figure 2) and TLR/TVR (0.35; 95% CI, 0.25-0.49; P<.001) (Figure 3). The OR for MI (0.79; 95% CI, 0.49-1.27; P=.31) (Figure 4) and death (0.95; 95% CI, 0.59-1.51; P=.74) (Figure 5) did not reach statistical significance. There was no evidence of publication bias for the included studies for both endpoints based on visual inspection of the funnel plot.

Discussion

To date, there have been no randomized studies that specifically address the best percutaneous approach for treatment of ULMCA bifurcation lesions and current evidence is derived from several observational studies. In this study, we performed a meta-analysis of these studies comparing the outcomes for SS versus DS techniques for the treatment of ULMCA bifurcation lesions in the DES era. We demonstrated that in comparison with DS strategy, SS treatment is associated with a 50% reduction in MACE and a 63% reduction in TLR/TVR. 

Despite the tremendous developments that have been made in the field of interventional cardiology over the past few decades, the treatment of bifurcation lesions remains challenging. During the BMS era, treatment of non-LM bifurcation lesions demonstrated unacceptably high rates of restenosis, approaching 60% in some series.¹⁷ Even though outcomes have improved with the use of DESs, bifurcation lesions are generally still associated with worse outcomes.^18-20 Multiple approaches for performing DS technique to treat bifurcation lesions have been developed and can generally be classified according to whether or not the side-branch ostium is adequately covered.^21,22 However, recent data from randomized controlled trials on treatment of non-LM bifurcation lesions using DES implantation do not support the routine use of the DS approach.^3-8 Thus, there is consensus that provisional SS strategy should be the default approach for most non-LM bifurcations. Unlike non-LM bifurcations, the side branch in LM bifurcations is more likely to be of large size and therefore supplies a large amount of myocardium. This makes protecting the side branch in ULMCA bifurcations of utmost importance and questions the generalizability of findings from non-LM bifurcations. Our findings support that a provisional SS strategy may be the preferred approach for stenting of ULMCA bifurcation lesions. 

There are multiple potential explanations for the worse outcome associated with DS in comparison to the SS technique. First, the complexity and technical difficulties inherent in deploying two versus one stent can increase procedural time, contrast volume and radiation exposure, and increase the risk of procedure-related myocardial injury.⁴ Incomplete ostial coverage of the side branch with subsequent suboptimal drug release, excessive metal concentration with multiple layers of overlapping stents, and stent fractures could also lead to worse outcomes. Stent fracture in the circumflex simultaneous kissing stent at the bend leaving the LM, resulting in severe focal restenosis at this location, has been described.²³ On the other hand, not treating apparently significant angiographic lesions at the origin of side branches has not been associated with excessive subsequent MI or revascularization.²² This is probably because ostial side-branch lesions after stenting are frequently pseudolesions.⁶ Consistent with these observations are the findings from a fractional flow reserve study by Koo et al, which showed that only 30% of side-branch lesions that appear >75% on quantitative coronary angiography are in fact physiologically significant.²⁴

Study limitations. Our study has multiple limitations, including those that are well known of the meta-analytical approach²⁵ (especially with observational data).²⁶ Our results, particularly the crude event rates, are prone to confounding and selection bias. We did not have access to patient data from the included studies; therefore, we were not able to perform multivariate regression analysis to adjust for potential confounders. Most of the included studies adopted an a priori strategy to SS versus DS, which may reflect a selection bias given that the patients treated with the DS technique likely have more complex atherosclerosis involving the origins of both vessels. Operator preference likely had an influence on the selection of stenting strategy and thus is a major confounder. In addition, it is also possible that the operator preference might have affected the reported outcomes. The majority of the included studies adopted an intention to treat model. Different definitions for MI were adopted in different studies and individual outcomes (death, MI, and stent thrombosis) were not consistently reported among the different studies. There may be some degree of overlap between the studies included — the individual studies did not report the institutions involved consistently and most were based on multicenter registries across the United States and Europe; as such, it would be difficult to determine what percentage of the patient population overlapped.

Conclusion

An SS strategy may be associated with fewer long-term adverse outcomes compared to a DS strategy for treatment of ULMCA bifurcation lesions; thus, our findings support a provisional approach of implanting one stent on the main branch as the default technique. There is need for randomized clinical trials to confirm these observations.

References

1. El-Menyar AA, Al Suwaidi J, Holmes DR Jr. Left main coronary artery stenosis: state-of-the-art. Curr Probl Cardiol. 2007;32(3):103-193.
2. Morice MC, Serruys PW, Kappetein AP, et al. Outcomes in patients with de novo left main disease treated with either percutaneous coronary intervention using paclitaxel-eluting stents or coronary artery bypass graft treatment in the Synergy Between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery (SYNTAX) trial. Circulation. 2010;121(24):2645-2653.
3. Colombo A, Moses JW, Morice MC, et al. Randomized study to evaluate sirolimus-eluting stents implanted at coronary bifurcation lesions. Circulation. 2004;109(10):1244-1249.
4. Steigen TK, Maeng M, Wiseth R, et al. Randomized study on simple versus complex stenting of coronary artery bifurcation lesions: the Nordic bifurcation study. Circulation. 2006;114(18):1955-1961.
5. Colombo A, Bramucci E, Sacca S, et al. Randomized study of the crush technique versus provisional side-branch stenting in true coronary bifurcations: the CACTUS (Coronary Bifurcations: Application of the Crushing Technique Using Sirolimus-Eluting Stents) study. Circulation. 2009;119(1):71-78.
6. Hildick-Smith D, de Belder AJ, Cooter N, et al. Randomized trial of simple versus complex drug-eluting stenting for bifurcation lesions: the British Bifurcation Coronary Study: old, new, and evolving strategies. Circulation. 2010;121(10):1235-1243.
7. Chen SL, Santoso T, Zhang JJ, et al. A randomized clinical study comparing double kissing crush with provisional stenting for treatment of coronary bifurcation lesions: results from the DKCRUSH-II (Double Kissing Crush versus Provisional Stenting Technique for Treatment of Coronary Bifurcation Lesions) trial. J Am Coll Cardiol. 2011;57(8):914-920.
8. Zhang F, Dong L, Ge J. Simple versus complex stenting strategy for coronary artery bifurcation lesions in the drug-eluting stent era: a meta-analysis of randomised trials. Heart. 2009;95(20):1676-1681.
9. Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions The Cochrane Collaboration. John Wiley & Sons, Ltd, West Sussex, England: 2011.
10. Valgimigli M, Malagutti P, Rodriguez Granillo GA, et al. Single-vessel versus bifurcation stenting for the treatment of distal left main coronary artery disease in the drug-eluting stenting era. Clinical and angiographic insights into the Rapamycin-Eluting Stent Evaluated at Rotterdam Cardiology Hospital (RESEARCH) and Taxus-Stent Evaluated at Rotterdam Cardiology Hospital (T-SEARCH) registries. Am Heart J. 2006;152(5):896-902.
11. Morice MC. The synergy between percutaneous coronary intervention with TAXUS and cardiac surgery: the SYNTAX study. Left main PCI treatment: technical considerations. Presented at Transcatheter Cardiovascular Therapeutics, 2008.
12. Palmerini T, Marzocchi A, Tamburino C, et al. Impact of bifurcation technique on 2-year clinical outcomes in 773 patients with distal unprotected left main coronary artery stenosis treated with drug-eluting stents. Circ Cardiovasc Interv. 2008;1(3):185-192.
13. Toyofuku M, Kimura T, Morimoto T, et al. Three-year outcomes after sirolimus-eluting stent implantation for unprotected left main coronary artery disease: insights from the j-Cypher registry. Circulation. 2009;120(19):1866-1874.
14. Godino C, Parodi G, Furuichi S, et al. Long-term follow-up (four years) of unprotected left main coronary artery disease treated with paclitaxel-eluting stents (from the TRUE registry). EuroIntervention. 2010;5(8):906-916.
15. Kim WJ, Kim YH, Park DW, et al. Comparison of single- versus two-stent techniques in treatment of unprotected left main coronary bifurcation disease. Catheter Cardiovasc Interv. 2011;77(6):775-782.
16. Takagi K, Ielasi A, Shannon J, et al. Clinical and procedural predictors of suboptimal outcome after the treatment of drug-eluting stent restenosis in the unprotected distal left main stem: the Milan and New-Tokyo (MITO) registry. Circ Cardiovasc Interv. 2012;5(4):491-498.
17. Sheiban I, Albiero R, Marsico F, et al. Immediate and long-term results of “T” stenting for bifurcation coronary lesions. Am J Cardiol. 2000;85(9):1141-1144, A9.
18. Ong AT, Hoye A, Aoki J, et al. Thirty-day incidence and six-month clinical outcome of thrombotic stent occlusion after bare-metal, sirolimus, or paclitaxel stent implantation. J Am Coll Cardiol. 2005;45(6):947-953.
19. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA. 2005;293(17):2126-2130.
20. Ge L, Airoldi F, Iakovou I, et al. Clinical and angiographic outcome after implantation of drug-eluting stents in bifurcation lesions with the crush stent technique: importance of final kissing balloon post-dilation. J Am Coll Cardiol. 2005;46(4):613-620.
21. Iakovou I, Ge L, Colombo A. Contemporary stent treatment of coronary bifurcations. J Am Coll Cardiol. 2005;46(8):1446-1455. Epub 2005 Sep 28.
22. Latib A, Colombo A. Bifurcation disease: what do we know, what should we do? JACC Cardiovasc Interv. 2008;1(3):218-226.
23. Baim DS, Mauri L, Cutlip DC. Drug-eluting stenting for unprotected left main coronary artery disease: are we ready to replace bypass surgery? J Am Coll Cardiol. 2006;47(4):878-881.
24. Koo BK, Kang HJ, Youn TJ, et al. Physiologic assessment of jailed side branch lesions using fractional flow reserve. J Am Coll Cardiol. 2005;46(4):633-637.
25. Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000;283(15):2008-2012.
26. Egger M, Schneider M, Davey Smith G. Spurious precision? Meta-analysis of observational studies. BMJ. 1998;316(7125):140-144.

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From the ¹UnityPoint Clinic – St Luke’s Hospital, Cedar Rapids, Iowa and the ²University of Iowa Carver College of Medicine, Iowa City, Iowa. 

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Cram reports NIH and NIAMS grants to his institution, as well as consultant fees for Vanguard Health and The Consumers Union.

Manuscript submitted September 3, 2013, provisional acceptance given November 4, 2013, final version accepted December 27, 2013.

Address for correspondence: Amandeep S. Dhaliwal, MDCM, 200 Hawkins Drive, Iowa City, IA 52242. Email: amandeepdhaliwal@uiowa.edu