Abstract: Background. Percutaneous coronary intervention (PCI) of coronary bifurcation lesions (CBLs) remains a challenge in contemporary practice due to the procedural and technical difficulties involved. We sought to review the current evidence on the safety and clinical outcomes of dedicated bifurcation stent (DBS) implantation in comparison with established treatment strategies for CBL-PCI. Methods. We conducted a comprehensive search to identify randomized control trials (RCTs) reporting 1-year clinical and angiographic outcomes of patients undergoing CBL-PCI with DBS vs conventional CBL-PCI strategies. Random-effects meta-analyses were performed to estimate the effect of DBS compared with conventional CBL-PCI using aggregate data. Results. A total of 5 RCTs comprising 1249 participants met the inclusion criteria. The use of DBS was comparable to conventional stenting techniques in terms of major adverse cardiovascular event (MACE) rate (odds ratio [OR], 1.28; 95% confidence interval [CI], 0.90-1.82; I2=0%), all-cause mortality (OR, 0.80; 95% CI, 0.31-2.07; I2=0%), cardiac mortality (OR, 0.16; 95% CI, 0.02-1.39; I2=0%), myocardial infarction (OR, 1.26; 95% CI, 0.84-1.89; I2=0%), definite stent thrombosis (OR, 1.75; 95% CI, 0.36-8.52; I2=0%), cumulative target-lesion revascularization (OR, 1.39; 95% CI, 0.85-2.27; I2=0%), clinically driven target-lesion revascularization (OR, 1.23; 95% CI, 0.68-2.22; I2=0%), or target-vessel revascularization (OR, 1.43; 95% CI, 0.92-2.22; I2=0%). Conclusion. The present analysis suggests that CBL-PCI with DBS may be associated with similar 1-year clinical and angiographic outcomes compared with conventional CBL-PCI strategies. However, the low quality of evidence and limited follow-up warrant further studies to ascertain any significant differences in patient-important outcomes before the adoption of DBS into routine CBL-PCI practice.
J INVASIVE CARDIOL 2019;31(12):E344-E355.
Key words: coronary bifurcations, dedicated bifurcation stents, efficacy, meta-analysis, outcomes, percutaneous coronary intervention
Coronary bifurcation lesions (CBLs) comprise one of the more complex lesion subsets routinely faced in interventional cardiology and account for up to 20% of all percutaneous coronary interventions (PCIs).1,2 While provisional side-branch (SB) stenting is currently the preferred strategy,1,2 potential complications of CBL stenting include loss of the SB and potential stent deformation, malposition, or fracture. On the other hand, a double-stent strategy implies that multiple layers overlap, resulting in neocarina formation, and therefore increased risks for periprocedural myocardial infarction (MI), stent thrombosis (ST), and need for reintervention.1-4
Dedicated bifurcation stents (DBSs) are designed to overcome such technical challenges and simplify the CBL treatment technique. Nonetheless, the use of DBS implantation for the treatment of CBL has only been investigated in studies with small sample sizes that are under-powered for the endpoints studied and, thus, subject to selection biases. Therefore, we conducted a comprehensive systematic review and meta-analysis to assess the safety and efficacy of DBS implantation in clinical trials.
Search strategy. We conducted a search of Medline, Embase, Google Scholar, Science Direct, Web of Science, and conference abstracts, using OvidSP (Ovid Technologies) from conception to August 2018. The terms used were “dedicated bifurcation stent, coronary bifurcations, AND randomized trials.” Furthermore, we manually screened the retrieved publications and pertinent reviews for further appropriate study inclusions. Institutional review board approval and patient consent were not required because of the systematic review and meta-analysis nature of this study.
Study selection. The titles and abstract yielded by the search were screened independently and in duplicate by two investigators (MOM and VN) against the inclusion criteria. Additional studies were retrieved by checking the bibliography of included studies and relevant reviews. The full reports of potentially relevant studies were retrieved, and data were independently extracted on study design, participant characteristics, treatment groups, outcome events, follow-up, and results. Any discrepancies between reviewers were resolved by discussion after consulting a third investigator (RB).
Eligibility criteria. We only included English-written studies evaluating randomized-controlled trials (RCTs) reporting outcomes on DBS implantation. The included studies were all similar in design, with DBS being the main intervention and an alternative CBL stenting strategy as the control group. The main inclusion criteria were studies reporting procedural success and at least one of the following outcomes: major adverse cardiac event (MACE); periprocedural MI; mortality; MI, definite ST, or angiographic outcomes at follow-up to evaluate DBS device safety and efficacy in comparison with conventional CBL treatment techniques.
The outcomes of interest were also independently extracted on a preformatted table. As mentioned above, disagreements were resolved by consensus. The reporting of outcomes had to include either crude event rates in each group or any risk/odds estimate (risk ratio, odds ratio [OR]) with 95% confidence intervals (CIs). The main exclusions included studies of non-randomized design, case reports/case series (≤3 participants), reviews, and editorials. The study utilized a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol (Figure 1).5
Risk of bias and quality assessment. Study quality was assessed using the updated Cochrane Risk of Bias 2.0 tool for randomized studies,6 which addresses selection bias, allocation bias, performance bias, detection bias for patient-reported outcomes and all-cause mortality, the completeness of outcome data, and selectivity of reporting (Figure 2). Risk of bias was independently assessed by two investigators (MM and VN) and discrepancies were resolved by group discussion and additional adjudication (RB). The Grading of Recommendation Assessment, Development, and Evaluation (GRADE) system7 was used to appraise the strength of evidence. A summary of quality of evidence was constructed in an evidence profile using GRADEpro software (McMaster University and Evidence Prime).
Data analysis. We used RevMan, version 5.3 (Nordic Cochrane Centre) to perform pairwise random-effects meta-analysis using the Mantel-Haenszel method to obtain a pooled OR for binary data or mean difference (MD) for continuous data, and its corresponding 95% CI. The I2 statistic was used to assess the consistency among studies, with I2<25% considered low, I2=50% considered moderate, and I2>75% considered high heterogeneity.8 Subgroup analysis was performed to determine whether treatment effect was influenced by different stent designs. In addition, sensitivity analyses were performed to assess the potential influence of any estimates on treatment effect or association that were derived from the mean by excluding a study considered to be an outlier (ie, a double-stent strategy, instead of provisional SB stenting as comparator or DBS as opposed to bare-metal stents). Two-sided P-values of <.05 were considered statistically significant.
Trials, stents design, comparators, and study population. A total of five RCTs9-13 met the inclusion criteria, comprising 1249 participants of which 627 were treated with DBS (Figure 1).
Cervinka et al9 conducted a randomized trial comparing bare-metal DBS (Twin-Rail; Invatec) to classic bare-metal stents (Liberté; Boston Scientific) for the treatment of CBLs in patients who were unsuitable for drug-eluting stent (DES) implantation.
The TRYTON (Prospective, Single Blind, Randomized Controlled Study to Evaluate the Safety & Effectiveness of the Tryton Side Branch Stent Used With DES in Treatment of de Novo Bifurcation Lesions in the Main Branch & Side Branch in Native Coronaries) trial was designed to evaluate the Tryton bifurcation stent compared with SB balloon angioplasty, with DES in the main vessel (MV) for the treatment of de novo true CBLs.10 The Tryton SB stent (Tryton Medical) is a dedicated SB non-DES composed of a cobalt-chromium alloy with three zones: SB zone (5.5 to 6.5 mm) deployed within the SB; transition zone (4.5 mm) at the SB ostium; and MV zone (8 mm).10
The POLBOS I (POLish Bifurcation Optimal Stenting I) trial was designed to compare CBL treatment with any regular DES versus stenting with the coronary-dedicated bifurcation Expert stent (BiOSS), a balloon-expandable stent coated with a biodegradable polymer that elutes paclitaxel.11 Furthermore, the trial was designed to assess the effect of final kissing-balloon inflation (KBI) on clinical outcomes in patients receiving DES treatment. There were no restrictions on the type of DES used. The POLBOS II (POLish Bifurcation Optimal Stenting II) trial was similar in design and aims to the POLBOS I trial. However, the DBS examined in POLBOS II was the Lim coronary-dedicated balloon-expandable bifurcation stent (BiOSS), which is coated with a biodegradable sirolimus-eluting polymer.12
The COBRA (COmplex coronary Bifurcation lesions: RAndomized comparison of a strategy using a dedicated self-expanding biolimus-eluting stent versus a culotte strategy using everolimus-eluting stents) trial13 compared the Axxess biolimus-A9 eluting stent (Biosensors) in combination with two BioMatrix DESs (Biosensors) vs culotte stenting using two Xience Prime DESs (Abbott Vascular).13 The Axxess device is a self-expanding, conically shaped nickel-titanium (nitinol) DES.14 Further study details are provided in Table 1.
Coronary bifurcation lesions and procedure-related characteristics. The left anterior descending (LAD) coronary artery and diagonal branch was the most common CBL and accounted for 90% of the cases, followed by the left main (LM) and LAD, and LM and circumflex.11-13 Medina classification5 1,1,1 lesions were present in 40%-73% of cases.11-13 The mean MV lesion length ranged from 7.35-16.8 mm and SB lesion length ranged from 2.9-9.17 mm. The MV diameter ranged from 2.9-3.74 mm and the SB diameter stenosis was mostly around 50%. Further CBL characteristics of the included RCTs are summarized in Table 2.
Radial access was used in 38%-81% of cases. The use of final KBI in the POLBOS I and II trials was as low as 30% of cases,11,12 but >80% in 2 other studies.10,13 The procedural success rates were similar across the 2 POLBOS arms. The rates of periprocedural MI were similar across the 2 POLBOS cohorts; however, Dubois et al13 reported rates as high as 45%. Further procedural characteristics are provided in Table 3.
Risk of bias and quality of evidence. Ascertainment of outcomes was prospective and reported loss to follow-up was <5% in the 5 studies.9-13 Risk of bias assessment according to the updated Cochrane Risk of Bias 2.0 tool for randomized studies indicated that most of the studies were at high or moderate risk of bias (Figure 2). The strength of the evidence for clinical and angiographic outcomes as appraised by the GRADE tool is detailed in Table 4.
Periprocedural and adverse clinical events at 9-month and 12-month follow-up. Periprocedural variables showed no statistically significant differences in point estimates between procedures involving DBS as compared to conventional stenting strategies in terms of fluoroscopy time (MD, 1.16; 95% CI, -2.07-4.38; I2=80%), procedure duration (MD, 0.12; 95% CI, -18.05-18.29; I2=94%), or contrast volume (MD, 11.18; 95% CI, -11.59-33.94; I2=82%), although with a high degree of heterogeneity (Figure 3).
Four studies reported on MACE during follow-up, of which 1 study10 included follow-up to 9 months and 3 studies9,12,13 included follow-up to 12 months. The crude MACE rate was higher in the DBS group when compared with conventional stenting (16.6% vs 13.5%, respectively). Data on follow-up for all-cause mortality and cardiac mortality were available for 9 months of follow-up in 1 study10 and for 12 months of follow-up in 3 studies.11-13 The crude rates of all-cause mortality and cardiac mortality were both higher in the conventional stenting group (1.6% vs 1.3% and 0.9% vs 0%, respectively). Four studies reported data on MI and definite ST, with 9-month follow-up in 1 study10 and 12-month follow-up in 3 studies.11-13 At follow-up, MI occurred in 10.6% of the DBS group vs 8.7% of the comparator group, and definite ST occurred in 0.7% of the DBS group vs 0.3% of the comparator group.
Meta-analyses evaluating clinical outcomes showed no statistically significant differences in effect estimates between DBS as compared with conventional stenting technique in terms of MACE (OR, 1.28; 95% CI, 0.90-1.82; I2=0%), all-cause mortality (OR, 0.80; 95% CI, 0.31-2.07; I2=0%), cardiac mortality (OR, 0.16; 95% CI, 0.02-1.39; I2=0%), and MI (OR, 1.26; 95% CI, 0.84-1.89; I2=0%) (Figure 4). Overall rating of confidence in estimates was very low, due to risk of bias, indirectness, and imprecision (Table 4).
Angiographic assessment of device efficacy. A total of 4 studies reported data on cumulative target-lesion revascularization (TLR), clinically driven TLR, and target-vessel revascularization (TVR). One study10 reported 9-month follow-up, while 3 studies11-13 reported 12-month follow-up. Cumulative TLR rates were 6.7% vs 4.9%, clinically driven TLR rates were 4.4% vs 3.6%, and TVR rates were 8.6% vs 6.3% in the DBS group vs the comparator group, respectively.
Meta-analyses evaluating angiographic outcomes could not confirm or exclude differences in effect estimates between DBS and conventional stenting strategies in terms of definite ST (OR, 1.75; 95% CI, 0.36-8.52; I2=0%), cumulative TLR (OR, 1.39; 95% CI, 0.85-2.27; I2=0%), clinically driven TLR (OR, 1.23; 95% CI, 0.68-2.22; I2=0%), or TVR (OR, 1.43; 95% CI, 0.92-2.22; I2=0%) (Figure 5). Overall, our confidence in estimates was very low, due to risk of bias, indirectness, and imprecision (Table 4).
Subgroup and sensitivity analyses. Subgroup analysis was performed to determine whether the stent design influenced the relative treatment effect. These results suggested no differences in effect estimates for clinical and angiographic outcomes and absence of significant interaction (Pinteraction<.05 for all analyzed variables). With regard to periprocedural variables, significant interaction (Pinteraction>.001) and high degree of heterogeneity (I2>80%) were found between the analyzed subgroups (Table 5).
Although most of the included studies were small, Dubois et al13 reported outcomes comparing the DBS with culotte stenting; thus, a double-stent strategy was used instead of provisional SB stenting for the comparator group. However, sensitivity analysis excluding this study could not confirm or exclude a difference in the effect estimates for clinical and angiographic outcomes (Table 6). Further sensitivity analysis was performed excluding 1 study9 that reported outcomes for bare-metal stents. However, this study did not report events for the majority of outcomes (all-cause mortality, MI, definite ST, cumulative TLR and TVR) and did not report cardiac mortality and clinically driven TLR. Therefore, these outcomes remained unchanged. The effect estimates for outcomes such as MACE, fluoroscopy time, procedure duration, and contrast volume did not change when the bare-metal stent study was excluded (Table 6).
The main finding of this meta-analysis of 5 RCTs is that DBSs show similar overall rates of periprocedural as well as clinical and angiographic outcomes at 12 months of follow-up. While these results suggest that DBSs are comparable with conventional stenting strategies in the short-term with regard to the analyzed outcomes of interest, the CIs are wide due to the small event rates. Hence, we rated the quality of evidence as very low due to risk of bias, indirectness, and imprecision. The current evidence also underpins the paucity of existing data, as well as the need for further large-scale randomized clinical trials with longer follow-up to support the role of DBS use in current CBL-PCI.
It is well-known that CBL stenting is associated with increased MACE rate and worse angiographic outcomes as compared with non-CBL stenting.16 The two main interventional strategies for managing CBL include a single-stent strategy, consisting of stenting the MV with provisional stenting to SB, and a double-stent strategy, comprising stenting both the MV and SB.17,18 The double-stent strategy has also been associated with higher odds of MACE and worse angiographic endpoints;19,20 therefore, as mentioned above, provisional SB stenting is the preferred strategy.1,2
The choice of stent diameter for MV stenting is crucial and is usually selected according to the distal MV reference diameter. The drawback is inadequate proximal MV stent apposition,21 which can be corrected by the proximal optimization technique (POT).1 The decision to treat the SB after POT depends on the angiographic assessment of the SB ostium as >75% stenosis or TIMI flow <3. Notably, when balloon dilation in the SB ostium is performed, it may cause stent distortion in the MV and attraction of the struts opposite to the SB in the MV lumen,22,23 thus requiring KBI, which allows SB ostium treatment and enables correcting for stent distortion and inadequate apposition in the MV stent struts at the SB ostium.18,24 The final KBI is mandatory in any double-stent technique18,21-24 and is thus a foundation of CBL treatment. Importantly, KBI implies that the 2 overlapping balloons can exceed the MV reference diameter and elicit an asymmetrical (oval- or elliptical-shaped) stent expansion.25 This can lead to over-stretching of the proximal MV stent, and risk for dissection of the proximal MV and SB vessels.23,25-27 Proximal MV asymmetrical deformation and enhancement at the level of the carina can again be corrected by a final POT, which is also known as a re-POT.28,29
The rationale behind DBS use is to allow operators to simplify the interventional treatment of CBLs by providing an easier access to the SB, protect its ostium (ie, due to angulations), and match the MV stent configuration while avoiding its deformation. Moreover, it would be logical to think that performing CBL-PCI with a DBS would potentially be associated with reductions in fluoroscopy time, procedural time, and contrast volume; however, our results do not support this hypothesis. Of note, the lack of availability of different DBS sizes and the complexity of the procedure itself might be impediments to its widespread use. It is important to appreciate that we used aggregate data from studies comparing completely different DBS designs (balloon vs self-expandable), different stent platforms in the comparator group (bare-metal stent vs DES and limus vs paclitaxel), the use of different CBL-PCI techniques with provisional vs double-stent strategy in the control arm, and unclear antiplatelet regimes; each of these would result in significant clinical (or technical) heterogeneity30 that, beyond statistical heterogeneity, may contribute to the findings.
Importantly, the mean SB diameter appears to be <2.5 mm in all of the included trials, raising the question of whether these SBs are significant in terms of amount of supplied myocardium and, consequently, the overall prognosis. Finally, it should also be highlighted that our results may not necessarily be generalized to all patients undergoing CBL-PCI, since the majority of patients included in the trials presented with stable angina and very few presented with acute coronary syndromes. Hence, the choice of CBL-PCI strategy is not only dependent on the CBL anatomy, but on other factors such as clinical presentation as well.
Study limitations. The present study has several limitations. The main limitation lies in the small number of studies, patients, and events informing each outcome, as well as the differences in primary endpoints between included studies. Individual patient data were not available, precluding the adjustment for any differences in baseline clinical characteristics, type of CBL (including or excluding LM bifurcation), type of DBS device used, and the different coronary stent platforms used in the CBL-PCI arm. Moreover, there is a high risk of bias in the included trials, particularly regarding blinding and outcome bias, as operators are directly involved in performing the interventions and therefore blinding would not be possible. Another limitation is the exclusion of patients with acute coronary syndromes, which makes our findings only generalizable to patients with stable ischemic heart disease. Finally, differences in the length of follow-up between trials warrant caution with regard to long-term efficacy (or lack thereof) of DBS use. Nevertheless, we believe that our findings provide insight into the acute and short-term outcomes between DBS implantation and CBL-PCI.
This analysis suggests that CBL stenting with DBS may be associated with similar procedural variables as well as 1-year clinical and angiographic outcomes as compared with conventional CBL-PCI strategies. However, the included studies have very low quality of evidence and limited follow-up. Hence, further studies are needed to ascertain significant differences in patient-important outcomes before DBS use is incorporated into routine treatment for CBL-PCI.
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From the 1Keele Cardiovascular Research Group, Centre for Prognosis Research, Institutes of Applied Clinical Science and Primary Care and Health Sciences, Keele University, Keele, United Kingdom; 2Wayne State University, Detroit Medical Center, Detroit Heart Hospital, Detroit, Michigan; 3Department of Interventional Cardiology and Endovascular Therapeutics, Instituto, Cardiovascular de Buenos Aires, Buenos Aires, Argentina; 4London Health Sciences Centre, London, Ontario, Canada; and 5Department of Epidemiology and Biostatistics, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Manuscript submitted May 18, 2019, final acceptance May 29, 2019.
Address for correspondence: Rodrigo Bagur, MD, PhD, FAHA, University Hospital, London Health Sciences Centre, 339 Windermere Road, N6A 5A5, London, Ontario, Canada. Email: firstname.lastname@example.org