Comparison of Provisional 1-Stent and 2-Stent Strategies in Diabetic Patients With True Bifurcation Lesions: The EES Bifurcation Study

Abstract: Background. Percutaneous coronary intervention (PCI) of true bifurcation lesions (Medina classification 1, 1, 1; 1, 0, 1; or 0, 1, 1) is challenging and may involve either a 1-stent strategy with provisional side branch stenting, or a 2-stent strategy. Diabetes mellitus is associated with greater atherosclerotic burden and higher incidence of bifurcation lesions, and unfavorable outcomes after PCI. It is unknown whether use of newer everolimus-eluting stent (EES) implantation impacts relative outcomes of 1-stent and 2-stent strategies in patients with diabetes. Methods. We performed a retrospective analysis of consecutive patients with diabetes mellitus and complex true bifurcation lesions (side branch diameter >2.0 mm) who underwent PCI with EES between February 2010 and December 2011. We grouped subjects based on initial treatment to a 1-stent (n = 81) or 2-stent (n = 54) strategy, and compared baseline characteristics, quantitative coronary angiography, and 1-year major adverse cardiovascular event (MACE) rates, defined as death, myocardial infarction, target lesion revascularization (TLR), or target vessel revascularization (TVR). Results. Baseline characteristics were well matched. A 2-stent strategy was associated with larger side-branch reference vessel diameter at baseline and post PCI. In-hospital events included 1 periprocedural myocardial infarction in each group and no deaths. At 1 year, there was no significant difference between 1-stent and 2-stent strategies in TVR rates (6.2% vs 3.7%; P=.53), TLR (both 3.7%; P>.99), or MACE (7.4% vs 3.7%; P=.37). Conclusion. In this series of diabetic patients undergoing complex bifurcation PCI using EES implantation, there was no difference between 1-stent and 2-stent strategies with respect to ischemic events at 1 year.

J INVASIVE CARDIOL 2014;26(12):619-623

Key words: percutaneous coronary intervention, bifurcation lesion, EES, diabetes mellitus

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Patients with diabetes mellitus have a higher prevalence of complex coronary artery disease (CAD), including bifurcation lesions.¹ Optimal management of complex CAD in diabetic patients recently has come under intense scrutiny, spurred by results of the FREEDOM trial, which demonstrated inferior outcomes of multivessel PCI, in comparison with coronary artery bypass graft (CABG) surgery, in diabetic patients with extensive CAD, in whom bifurcation lesions accounted for 22% of treated lesions.²

Among complex lesions, bifurcation lesions pose several technical challenges to PCI, including proximal-distal vessel mismatch, complex angulation, calcification, and tendency to plaque shift.³ Historically, bifurcation lesions have been associated with reduced procedural success and increased restenosis. This is particularly the case for true bifurcation lesions, defined as involvement of both the main vessel (MV) and side branch (SB), as described by Medina classifications (1, 1, 1), (1, 0, 1), or (0, 1, 1).⁴ The best approach to PCI for true bifurcation lesions is controversial; to date, evidence has not shown benefit for a 2-stent strategy over a 1-stent strategy with provisional SB stenting, even in the era of drug-eluting stent (DES) implantation.^5-7 

Available published data on complex PCI in diabetic patients principally includes experience with first-generation DESs. It is unknown whether the relative efficacy of 1-stent and 2-stent strategies differs with newer DESs, in particular everolimus-eluting stent (EES) platforms. In the SPIRIT-IV randomized controlled trial, second-generation EESs, in comparison with first-generation (paclitaxel-eluting) DESs, resulted in lower rates of target lesion failure, with similar benefits in simple and complex lesions.⁸ These findings were extended to an all-cause mortality benefit in a recent meta-analysis.⁹ Although benefits of EES over the first-generation paclitaxel-eluting stent in SPIRIT-IV appeared to be attenuated in diabetic patients, regardless of insulin use,¹⁰ a recent large meta-analysis of 42 trials of DES suggested a high likelihood that among DESs, the EES platform is most efficacious in diabetic patients.¹¹ We compared outcomes of 1-stent and 2-stent strategies in diabetic patients in the EES Bifurcation registry.

Methods 

Study design and participants. The EES Bifurcation registry was a single-center, retrospective, observational study of consecutive patients undergoing PCI for true bifurcation lesions using EES implantation between February 2010 and December 2011 at a single academic medical center. Treatment strategies of either an initial 2-stent strategy or an initial 1-stent strategy with provisional SB stenting were determined retrospectively based on angiographic and procedure documentation reviews. Inclusion criteria for enrollment in the registry included: (1) PCI of a true bifurcation lesion, defined as ≥50% luminal diameter stenosis of both MV and SB, within 5 mm of the bifurcation carina, in a major epicardial vessel, with reference vessel diameters >2.5 mm (MV) and >2.0 mm (SB) based on quantitative coronary angiography (QCA); (2) exclusive use of EES; (3) age ≥18 years at the time of PCI; and (4) written informed consent to undergo PCI. The study was approved by the institutional review board. For the present study, analysis was limited to subjects with a history of diabetes mellitus, as documented in medical records (Epic Systems).

Quantitative coronary angiography. QCA was performed for target bifurcation lesions before and after PCI using dedicated software (QCA-QAngioXA 7.3; Medis). Three independent analysts initially reviewed all angiograms. All angiograms were subsequently read by an experienced interventional cardiologist (GDD). Interpretations by this experienced reviewer were used for all analyses. Measurements of bifurcation lesions were made using two segments: (1) a combined MV, comprised of the proximal MV (PMV) and distal MV (DMV), with boundaries defined by the 5 mm proximal and distal to the implanted stent; and (2) the SB, with boundaries defined by the ostium and 5 mm distal to the ballooned or stented area. QCA measurements included angulation between the DMV and SB, reference vessel diameter (RVD), minimal lumen diameter (MLD), percent diameter stenosis (%DS), and lesion length.

Study definitions and clinical endpoints. Clinical outcomes were determined for the index hospitalization and at 1 year via the institutional PCI database. Deaths were determined via the Social Security Death Index. The primary efficacy endpoint was major adverse cardiovascular event (MACE) rate at 1 year, defined as a composite of death, myocardial infarction (MI), target lesion revascularization (TLR), or target vessel revascularization (TVR). Q-wave MI was defined as new pathologic Q-waves in >2 contiguous leads (excluding periprocedural MI). Non-Q-wave MI (NQWMI) was defined as a rise in creatine kinase-MB isoform (CK-MB) mass >8x the upper limit of normal together with clinical signs of MI, in the absence of pathologic Q-waves. TLR was defined as repeat revascularization by PCI or surgery of the target segment (inclusive of 5 mm proximal or distal to the stent) for clinical indications and/or demonstration of inducible myocardial ischemia. TVR was defined as repeat revascularization by PCI or surgery of the target vessel for ischemia (excluding TLR). In-hospital serious adverse events were defined as periprocedural MI, death, TVR by PCI or CABG surgery, hemodialysis, congestive heart failure, cerebrovascular accident, and blood transfusion. Periprocedural MI was defined as an increase in CK-MB mass ≥3x the upper limit of normal within 24 hours of the index PCI. Stent thrombosis (ST) was defined using the Academic Research Consortium definition.¹² Acute gain from PCI was defined as the change in the minimum lumen diameter from baseline to the final procedural angiogram.

Statistical analysis. Statistical analysis was performed with STATA version 12.1 (StataCorp LP). Categorical data are presented as frequencies. Continuous data are presented as mean ± 1 standard deviation (SD) and compared using Fisher’s exact test or log-rank test. P-values <.05 were considered significant.

Results

Of the 524 patients who had a true bifurcation lesion treated with EES between February 2010 and December 2011, a total of 319 patients (60.9%) had SB RVD >2.0 mm. Within this sample, 135 patients (25.8 %) had a history of diabetes mellitus (Figure 1). Among diabetic patients, 81 (60%) received a 1-stent strategy and 54 (40%) received a 2-stent strategy.

Baseline characteristics. Diabetic patients treated with a 2-stent strategy were more likely to report smoking (13% vs  3.7%; P=.04) and less likely to use aspirin at the time of admission (77.8% vs 90.1%; P=.05). Treatment groups were well matched with respect to baseline characteristics, including previous revascularization, family history of CAD, and left ventricular ejection fraction (Table 1).

Angiographic and procedural characteristics. A majority of lesions in both groups involved the PMV, DMV, and SB, corresponding to Medina classification (1, 1, 1) (Table 2). Patterns of lesion modification prior to stenting differed between the two groups, with a higher frequency of pretreatment of both MV and SB in patients receiving a 2-stent strategy (80% vs 51%; P=.01).  Among patients treated with a 2-stent strategy, the most common technique employed was V-stenting (43%), followed by simultaneous kissing stenting (SKS; 24%) and crush stenting (19%). Contrast volume use with a 2-stent technique was lower, but the difference was not statistically significant (137 ± 42 mL vs 159 ± 61 mL; P=.06).

Quantitative coronary angiography. Treatment with a 2-stent strategy was associated with significantly longer SB lesion length (13.6 ± 6.7 mm vs 7.6 ± 3.6 mm; P<.001) and larger SB RVD at baseline (2.4 ± 0.5 mm vs 2.2 ± 0.4 mm; P=.01) and following PCI (2.3 ± 0.5 mm vs 2.0 ± 0.5 mm; P<.001) (Table 3). Bifurcation angle, MV RVD and lesion length, and measures of MV and SB stenosis (%DS, MLD) were otherwise similar at baseline. Following PCI, a 2-stent strategy was associated with significant reduction in SB stenosis, as reflected in both %DS (22.4 ± 8.2% vs 36.1 ± 19.4%, P<.001) and MLD (1.9 ± 0.4 mm vs 1.4 ± 0.5 mm; P<.001).

Outcomes. In-hospital serious adverse events included only 1 periprocedural MI for 1-stent and 2-stent strategies (1.2% vs 1.9%; P=.80).

At 1 year, there was no significant difference between 1-stent and 2-stent strategies in rates of TVR (6.2% vs 3.7%; P=.53), TLR (both 3.7%; P=1.0), or MACE (7.4% vs 3.7%; P=.37) (Figure 2). There were no recorded deaths or episodes of definite or probable ST.

Discussion

In this study of diabetic patients undergoing PCI with EES for true bifurcation lesions, a 2-stent strategy was associated with superior immediate angiographic outcomes in the SB, as determined by QCA, but no difference in ischemic endpoints at 1 year in comparison with an initial 1-stent strategy and only provisional SB stenting. This result is consistent with findings using older stent platforms (BMSs and first-generation DESs),^5-7,13 as well as with use of EES implantation in broader patient populations.¹⁴

It is intuitive that a 2-stent strategy should provide superior immediate angiographic outcomes in the SB, in comparison with an initial 1-stent strategy in which only provisional SB stenting is performed. Acknowledging limitations inherent to retrospective analysis, our findings corroborate this intuition.  Based on rigorous QCA, a 2-stent strategy was associated with a statistically significant, large difference in acute lumen gain and reduction in %DS. Selection bias in post hoc designation to 1-stent or 2-stent strategies would be expected to accentuate the importance of this superior angiographic result, noting that patients treated with a 2-stent strategy tended to have larger SB vessels.

Despite this difference in immediate angiographic outcomes, there was no difference between strategies in ischemic events at 1 year. Logically, there are three main hypotheses to explain this discordance. The first hypothesis is that acute differences in SB stenosis did not translate into long-term differences in SB stenosis, and in turn, MACE rate. Our study did not have routine angiographic follow-up, prohibiting a comparison of restenosis in the two groups. A second hypothesis is that acute differences in SB stenosis did translate into long-term differences in SB stenosis, but that the degree of difference was irrelevant to MACE rate. In general, treated SB vessels were small to moderate caliber vessels (mean RVD, 2.4 ± 0.5 mm for the 2-stent strategy group) with only intermediate degrees of stenosis at baseline (60.7 ± 18.3% for the 2-stent strategy group). If treated SB lesions were not associated with hemodynamic significance (as reflected by fractional flow reserve) or inducible ischemia (as reflected by non-invasive study), routine stenting may not have conferred benefit for clinical ischemic events. Objective assessments of the physiologic significance of SB lesions were not available in our study.  A third hypothesis is that differences in SB acute lumen gain did confer reduction in MACE, but that our study was underpowered to detect this difference. 

In the context of consistent prior experience showing no added benefit, counting a recent quality-of-life analysis from the BBC One group showing no difference in angina-related health status with either stent strategy at 9 months post PCI and increased periprocedural complications of routine SB stenting as part of a 2-stent strategy, including 6-month and 9-month follow-up data from the Nordic-Baltic Bifurcation IV and TRYTON studies, respectively, we are inclined to accept the null hypothesis in this study.^15-17  This “negative” result contributes new knowledge to the body of literature on bifurcation PCI, showing that in diabetic patients with complex, true bifurcation lesions, even with EES implantation, a 2-stent strategy, when compared to a provisional 1-stent strategy, is not associated with improved outcomes. It is remarkable in our analysis, however, that there was no evident difference in periprocedural complications, including MI, with a 2-stent strategy, as has been reported elsewhere.

Study limitations. Our study had several limitations. First, as a single-center study, conducted at an academic referral center with specialty expertise in complex PCI, the EES Bifurcation registry is not generalizable to all PCI facilities. Second, retrospective observational design confers problems of selection bias in treatment with stenting strategies, along with unmeasured confounding. Although these biases prohibit inferences about the relative benefits of a routine 2-stent strategy, our data nonetheless provide insight into real-world practice in the treatment of complex bifurcation lesions in diabetic patients, and outcomes in patients treated with different approaches. Third, this study exclusively evaluated diabetic patients treated with EES, and results may not be generalizable to other second-generation DES platforms, such as zotarolimus and biolimus-eluting stents, or novel bioabsorbable stents. Fourth, our sample size may introduce the possibility of a type II statistical error. Fifth, in the absence of routine angiographic follow-up, it was not possible to compare angiographic restenosis in the two groups. Sixth, this study did not distinguish diabetic patients based on treatment with insulin. Finally, we did not capture proximal optimization treatment (POT) for the 1-stent strategy, and it has recently been shown that POT is beneficial for long-term angiographic success in bifurcation treatment.^18,19

Conclusion

In this registry of diabetic patients undergoing complex bifurcation PCI with EES, there was no apparent advantage of a 2-stent strategy over a 1-stent strategy with only provisional SB stenting, despite superior acute SB angiographic outcomes on QCA.

References

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From the ¹Mount Sinai School of Medicine, New York, New York; and the ²Humanitas Clinical and Research Center, Milan, Italy.

Disclosures: Dr Mehran reports institutional research grant support from The Medicines Co., Bristol-Myers Squibb/Sanofi-Aventis, and Lilly/Daiichi Sankyo; consulting fees from Abbott Vascular, AstraZeneca, Boston Scientific, Covidien, CSL Behring, Janssen Pharmaceuticals, Maya Medical, Merck, and Regado Biosciences. Dr Dangas serves on the advisory board and has received lecture honoraria from Bristol-Myers Squibb/Sanofi-Aventis. Dr Kini serves on the speakers bureau of the ACC and has received consulting fees from WebMD. Dr Sharma serves on the speakers bureau of Abbott Vascular, Angioscore, Boston Scientific, Lilly/Daiichi Sankyo, and The Medicines Co. Dr Kovacic has received honoraria from AstraZeneca and research support from the National Institutes of Health (K08HL111330), The Leducq Foundation (Transatlantic Network of Excellence Award), and AstraZeneca. The remaining authors report no relevant conflicts of interest.

Manuscript submitted July 14, 2014, and accepted August 11, 2014.

Address for correspondence: Prof Roxana Mehran, Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1030, New York, NY 10029-6574. Email: roxana.mehran@mssm.edu