A Sex-Based Analysis From the RAIN-CARDIOGROUP VII Study (VeRy Thin Stents for Patients With Left MAIn or BifurcatioN in Real Life) on Left Main Stenting

Abstract: Introduction. There is a lack of data on clinical outcomes of percutaneous coronary intervention (PCI) with ultrathin stents on unprotected left main (ULM) coronary artery comparing women and men. Methods. All patients treated with ULM-PCI with ultrathin stents (struts ≤81 µm) enrolled in the RAIN-CARDIOGROUP VII study were analyzed according to a sex-assessment evaluation. Major adverse cardiovascular event (MACE, a composite of all-cause death, myocardial infarction, target-lesion revascularization [TLR], and stent thrombosis) was the primary endpoint, whereas single components of MACE were the secondary endpoints. Results. Out of a cohort of 793 patients, a total of 172 women (21.7%) and 621 men (78.3%) were included. Compared with men, women were older and less frequently smokers, had more frequently a history of previous PCI, and presented more frequently with an acute coronary syndrome. Among women, ostial lesions were more prevalent and mean stent diameter was lower compared with men. After 13.4 months (range, 8.4-21.6 months), 32 women (18.6%) and 106 men (17.1%) experienced MACE (P=.64). Censoring follow-up data at 3 years, no differences were observed in MACE (16.9 vs 14.7 per 100•patient-years; log-rank P=.61) and their single components between women and men. At multivariate analysis, chronic kidney disease (hazard ratio [HR], 1.91: 95% confidence interval [CI], 1.23 to -2.95; P<.01) and acute coronary syndrome presentation (HR, 1.84; 95% CI, 1.22-2.77; P=.01) were independent predictors of MACE overall. Larger stent size (HR, 0.65; 95% CI, 0.48-0.89; P<.01) and longer dual-antiplatelet therapy duration (HR, 0.95; 95% CI, 0.90-0.99; P=.03) were associated with a reduced risk of MACE during the subsequent follow-up. Conclusion. Ultrathin stents offer low rates of MACE and TLR in the overall population without significant differences between sexes.

J INVASIVE CARDIOL 2020;32(9):342-346. Epub 2020 June 22.

Key words: coronary artery disease, drug-eluting stents, gender medicine, left main, percutaneous coronary interventions

Surgical coronary revascularization has long been the standard of care for unprotected left main (ULM) disease.^1,2 However, more recently, percutaneous coronary intervention (PCI) has been widely adopted and demonstrated to be non-inferior to surgery in selected patients.³ Previous studies have shown differences in outcomes between women and men undergoing PCI,^4,5 mainly attributed to different risk profiles between genders. 

The technological evolution of coronary stents, along with the wider use of intracoronary imaging tools, allowed PCI to be competitive with surgical revascularization for patients with ULM coronary artery disease and true bifurcation lesions.^6,7 In particular, the progressive reduction in stent strut thickness allows for faster endothelialization, with lower rates of revascularization and stent thrombosis compared with first-generation stents.^8,9 Previous studies have been conducted with the Synergy stent (Boston Scientific) and Xience stent (Abbott Vascular) to test the effects of thin-strut coronary stents in ULM treatment.¹⁰ Drug-eluting stent (DES) options with very thin struts have demonstrated excellent clinical results in randomized studies; however, data in real-world populations are scarce. To bridge this gap of knowledge and implement available data, we performed a sex-based analysis of the RAIN (VeRy Thin Stents for Patients With Left MAIn or BifurcatioN in Real Life) CARDIOGROUP VII study to better evaluate incidence of cardiovascular events following ULM-PCI in a female cohort of patients in a real-world setting. 

Methods

The present is a retrospective multicenter study including patients from June 2015 to January 2017 (NCT03544294).

Inclusion criteria. All consecutive patients presenting with a critical ULM lesion at our centers were included, if treated with one of the following stents: (1) Promus Element platinum-chromium coated stent with a permanent polymer loading everolimus and a strut thickness of 81 µm in diameters from 2.25 to 3.5 mm (Boston Scientific); (2) Xience Alpine cobalt-chromium coated stent with a permanent polymer loading everolimus and a strut thickness of 80 µm in diameters from 2.25 to 4.0 mm (Abbott Vascular); (3) Ultimaster cobalt-chromium coated stent with a biodegradable polymer loading sirolimus and a strut thickness of 80 µm in diameters from 2.25 to 4.0 mm; (Terumo Corporation); (4) Synergy platinum-chromium coated stent with a biodegradable polymer loading everolimus with a strut thickness of 74 µm for diameters in the range of 2.25 to 2.75 mm, 79 µm for diameters in the range of 3.00 to 3.50 mm, and 81 µm for diameters of 4.0 mm (Boston Scientific); or (5) Resolute Onyx platinum-chromium coated stent with a biodegradable polymer loading zotarolimus and a strut thickness of 81 µm for diameters from 2.25 to 4.0 mm (Medtronic).

Baseline and procedural data. Data about cardiovascular risk factors, clinical presentation, and angiographic features were collected, along with characteristics of implanted stents. Data were derived from electronic charts at each center on prespecified forms and recorded online (https://www.cardiogroup.org/RAIN/index.php?cat=home). The use of intravascular ultrasound or optical coherence tomography and stenting technique choice (provisional vs double stenting), were left to the physician’s discretion. Follow-up was performed through dedicated clinical assessment, telephone follow-up, or formal query by primary care physicians. 

Study endpoints. Major adverse cardiovascular event (MACE; a composite of all-cause death, myocardial infarction [MI], and target-lesion revascularization [TLR]) was the primary endpoint of the present analysis. Individual MACE components and stent thrombosis (ST) represented the secondary endpoints. The analysis was performed according to a gender-based assessment. 

Statistical analysis. Continuous variables were expressed as mean ± standard deviation or median (interquartile range [IQR]) and compared with non-parametric Mann-Whitney U-test. Qualitative variables were reported as number (percentage) and compared with Pearson’s Chi-square test or Fisher’s Exact test, as appropriate.

Events were censored at 36 months; event rates per 100•patient-years were calculated, whereas survival estimates were computed by Kaplan-Meier methods; group comparisons were conducted using the log-rank test. Predictors of MACE were identified using a univariable Cox regression analysis. Hazard ratio (HR) was reported with 95% confidence interval (CI). A multivariable model was built to identify the parameters independently associated with the occurrence of MACE at follow-up; all covariables with a statistically significant association with MACE at the univariable analysis (with a two-tailed P-value <.10) and clinically relevant covariables were included in the final model. Analyses were conducted using SPSS software, version 2.1 (IBM Corporation). A two-tailed P<.05 was considered statistically significant. 

Results

The final study population treated for ULM disease included 793 patients, of which 172 (21.7%) were female. Baseline clinical features are presented in Table 1. Women were older than men (73 ± 11 years vs 70 ± 10 years, respectively; P<.001) and less frequently active smokers than men (10.7% vs 15.3%, respectively; P<.001). Stable angina was the most frequent clinical presentation in men (52% vs 41.3% in women), while ULM-PCI was mainly performed for acute coronary syndromes in women (58.7% vs 48% in men; P=.01). Overall, dual-antiplatelet therapy prescription did not differ in duration between women and men, while men withdrew DAPT before 12 months more frequently than women (13.1% vs 9.1%, respectively; P=.04). Prevalence of distal ULM stenosis was similar (63.4% women vs 66.6% men; P=.46), whereas a higher ostial lesion location was observed in women (22.2% vs 13.8% in men; P=.01). A true bifurcation lesion treatment was equally performed in women and men (48.4% vs 42.1%, respectively; P=.27), with a planned or bail-out two-stent technique used in 26% of cases (T-stenting, crush and minicrash, and culotte techniques were equally adopted). Radial access and intracoronary imaging guidance were similar in both groups. Complete procedural data are reported in Table 2. 

Study endpoints. MACE occurred in 32 women (18.6%) and 106 men (17.1%; P=.64) (Table 3), with an event rate of 16.9 per 100•patient-years and 14.7 per 100•patient-years, respectively (Supplemental Table S1; supplemental materials available at www.invasivecardiology.com). No differences emerged when performing Kaplan-Meier analysis. Incidence of single components of MACE was similar between women and men, both in crude event incidence and in time-adjusted rates (Table 3; Supplemental Table S1). Ultrathin DESs were associated with similar rates of any ST (definite, probable, or possible) in women and men (P=.24) (Supplemental Table S2).

At multivariable analysis, chronic kidney disease (HR, 1.87; 95% CI, 1.22-2.85; P<.01) and acute coronary syndrome presentation (HR, 1.76; 95% CI, 1.18-2.63; P<.01) were strong predictors of MACE overall. Stents sized ≥3.5 mm (HR, 0.65; 95% CI, 0.48-0.89; P<.01) and longer (>6 months) DAPT duration (HR, 0.95; 95% CI, 0.90-0.99; P=.03) were associated with a reduced risk of MACE during the subsequent follow-up. However, female gender failed to be an independent predictor of MACE (Table 4). 

Discussion

Several studies have addressed the topic of gender, showing a worse clinical outcome in women undergoing ULM stenting when compared with men;¹¹ these results in randomized controlled trials (RCTs) proved to be inconsistent in Asian countries, but were confirmed with a higher rate of adverse events in the female population in Western countries.^12-14 A recent study by Trabattoni et al, conducted on a consecutive series of ULM stenoses treated with everolimus-eluting stent in 122 women and 467 men, confirmed a higher rate of MACE in women, primarily guided by higher mortality and explained by a prevalence of unstable clinical setting and older age in the female group.¹⁵ A recent network meta-analysis by Waksman et al evaluated 80,885 patients receiving DESs with different strut thicknesses, enrolled in 69 randomized clinical trials. DES options with thinner struts were associated with a significant reduction in ST and myocardial infarction compared with thicker-strut options.¹⁶ Thinner struts allow greater flexibility and deliverability, but also reduce stent-induced vessel wall injury and inflammation to promote faster endothelialization. These technical features also improve the rheologic behavior, with low shear stress and decreased thrombogenicity.¹⁷ Ultrathin struts had significantly less ST and myocardial infarction (odds ratio, 0.43; credible interval, 0.27-0.68 and odds ratio, 0.73; credible interval, 0.62-0.92, respectively). Our study aimed in particular to assess gender-related differences regarding the outcomes of patients treated with ultrathin stents in the ULM. According to the results obtained in the IRIS-MAIN registry, women in our study were older and more commonly presented with acute coronary syndromes than men. They had different clinical presentation, but similar lesion characteristics and long-term outcomes after ULM stenting. 

To the best of our knowledge, this is one of the largest patient samples for ultrathin stents in the ULM evaluated in a sex-based analysis. The main results are: (1) TLR is an infrequent event at mid-term follow-up in both sexes; (2) ULM disease is more frequently treated for an unstable clinical presentation in women; and (3) ostial lesion location is more commonly observed in women; this did not affect the stenting technique choice (provisional vs double-stent technique), which was equally represented in women and men.

TLR has been confirmed to be an infrequent event at mid-term follow-up, inferior to second-generation DES options. The NOBLE trial showed a TLR rate of 11% at 5 years, while the EXCEL TLR rate was 9.5% at 3-year follow-up.^12,13 In a recent meta-analysis by Bangalore et al,¹⁸ newer-generation ultrathin DES (not selected for lesion site) were associated with a net 16% reduction in target-lesion failure (relative risk, 0.84; 95% CI, 0.72-0.99) at 1-year follow-up when compared with contemporary second-generation thicker-strut stents. The estimated relative risk reduction in target-lesion failure was consistent with what might be expected with a reduction in strut thickness by ≈10 μm. 

In this sex-based analysis of the RAIN-CARDIOGROUP VII study, we did not test for subgroup effects according to stent type and permanent or biodegradable polymer. However, a recent meta-analysis assessing patients treated with DES options with <100 μm struts found no difference in MACE between biodegradable polymer DES and permanent polymer DES at 2-year follow-up.¹⁹ 

It has to be acknowledged, however, that given the retrospective setting, some unknown confounding might have contributed to these differences in outcomes.²⁰ From a procedural standpoint, no significant differences were observed between women and men in terms of lesion characteristics, number, length, and type of very thin DES stents, one- vs two-stent strategy in ULM lesion treatment, high-pressure stent postdilation, or use of intracoronary imaging guidance.

Study limitations. First, this is not a randomized controlled trial; consequently, inferential aim related to performances of different stent types are limited. Second, a retrospective design, together with lack of randomization, might limit the detection of potential known and unknown confounders despite the performance of multivariable adjustment. Third, testing was not performed for subgroup effects according to stent type and permanent or biodegradable polymer. 

Conclusion

Very-thin strut stents can be safely adopted for ULM percutaneous revascularization with low MACE rate at 3-year follow-up. The use of very-thin strut DES options may have contributed in overcoming the previously described worse clinical outcomes of ULM stenting in women. Further prospective clinical evaluations on very-thin strut DES options in bifurcation lesions are needed.

From the ¹Department of Invasive Cardiology, Centro Cardiologico Monzino, IRCCS, Milan, Italy; ²Division of Cardiology, Department of Internal Medicine, Città della Salute e della Scienza, Turin, Italy; ³Department of Cardiology, Infermi Hospital, Rivoli, Italy - Department of Cardiology, San Luigi Gonzaga Hospital, Orbassano, Turin, Italy; ⁴Division of Cardiology, University Hospital of Zurich, Zurich, Switzerland; ⁵Division of Cardiology, Cardio-Thoracic-Vascular Department, Azienda Ospedaliero Universitaria “Policlinico-Vittorio Emanuele,” Catania, Italy;  ⁶Department of Cardiology, Hospital Clinico San Carlos, Madrid, Spain; ⁷Structural Interventional Cardiology, Careggi University Hospital, Florence, Italy; ⁸Department of Cardiology, Medical University of Silesia, Katowice, Poland; ⁹Coronary Care Unit and Catheterization Laboratory, A.O.U. Maggiore della Carità, Novara, Italy; ¹⁰Pierre and Marie Curie University, Paris, France; ¹¹PolitoBIOMed Lab, Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Turin, Italy; ¹²University Clinical Hospital, Warsaw, Poland; ¹³Division of Cardiology, S. Giovanni Evangelista Hospital, Tivoli, Rome, Italy; ¹⁴Pederzoli Hospital, Peschiera del Garda, Italy; ¹⁵San Raffaele Scientific Institute, Milan, Italy; and ¹⁶Dipartimento di Cardiologia, Ospedale San Giovanni Bosco, Turin, Italy.

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 February 17, 2020, provisional acceptance given February 24, 2020, final version accepted February 28, 2020.

Address for correspondence: Daniela Trabattoni, MD, FESC, FACC, Director, Invasive Cardiology Unit 3, Centro Cardiologico Monzino, IRCCS, Via Parea, 4 – 20138 Milan, Italy. Email: Daniela.trabattoni@ccfm.it

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