Long‐term outcomes after stent implantation in very small vessel coronary artery disease

Abstract Background Percutaneous coronary interventions (PCI) in very small vessel lesions represent an intriguing aspect of coronary artery disease (CAD). Uncertainty still exists in stent implantation in very small caliber vessels. This study aimed to evaluate the long‐term outcomes of patients treated with 2.0‐mm drug‐eluting stent (DES). Method This retrospective observational study included 134 patients undergoing PCI with 2.0‐mm zotarolimus DES from December 2016 to May 2020. The primary endpoint was major adverse cardiovascular events (MACE) at 2‐year follow‐up, which was composed of all‐cause mortality, target vessel myocardial infarction, and ischemia‐driven target lesion revascularization. Multiple logistic regression analysis was used to identify the independent predictors of MACE, and odds ratios (OR) and 95% confidence intervals (CI) were calculated. Result The lesions were diffuse (mean length 20.9 ± 5.51 mm) and belong to type B2/C lesions (90.3%). On follow‐up, the MACE rate was 20.1% and mostly driven by late lumen loss demanding revascularization (11.9%). In multivariable analysis, chronic kidney disease (CKD) (OR: 4.291, 95% CI: 1.574−11.704, p = 0.004) and calcified lesions (OR: 3.688, 95% CI: 1.311−10.371, p = 0.013) were the independent predictors of subsequent cardiovascular events, whereas statin was associated with better outcomes (OR: 0.335, 95% CI: 0.119−0.949, p = 0.040). Conclusion 2.0‐mm DES is a feasible option for treating very small vessel CAD in complex lesions. Patients with CKD and calcified lesions carry the hazard of worse outcomes, and careful consideration should be taken before stenting in this high‐risk population.


| INTRODUCTION
Up to one-third of patients undergoing percutaneous coronary intervention (PCI) have small vessel coronary artery disease (CAD), and it is especially prevalent in patients with diabetes mellitus (DM) and chronic kidney disease (CKD). 1-3 PCI of small vessel lesions presents technical challenges and is associated with increased risks of late lumen loss and adverse cardiovascular events. [4][5][6] The definition of small vessel CAD varies across trials until the Society for Cardiovascular Angiography recently published a literature suggesting a reference vessel diameter (RVD) < 2.5 mm as the cutoff value for classifying small coronary vessels. 5,7,8 The evolution of stent technology and the availability of 2.25-mm and 2.0-mm drug-eluting stents (DES) has led to very small vessel CAD being proposed to describe the lesions that are only amenable to these devices. 9,10 Although studies have indicated no significant difference in clinical outcome between 2.25 and 2.0-mm zotarolimus DES at 1year follow-up, 10 the long-term efficacy and safety of 2.0-mm DES remain unclear. No consensus exists on an optimal strategy for treating very small vessel CAD because the data is sparse. 11,12 Therefore, our study aimed to assess the long-term clinical outcomes of patients treated with 2.0-mm zotarolimus DES for very small vessel CAD.

| Interventional procedures
PCI was performed using standard procedure, and the specific revascularization technique was chosen based on the operator's judgment. All patients received a loading dose of aspirin (300 mg) and P2Y12 inhibitors (clopidogrel 300 mg for stable angina or ticagrelor 180 mg for acute myocardial infarction [AMI]) before the PCI. Unfractionated heparin (7500-IU bolus) was administered before the intervention to achieve an activated clotting time of >300 s. When a very small vessel lesion was considered hemodynamically significant, 400−800 µg of nitroglycerine was administered intracoronary to reassess the vessel size and distinguish it from coronary spasm. Lesions were treated with 2.0-mm zotarolimus DES if the following results were observed after predilated balloon angioplasty: flow-limiting dissection, thrombolysis in myocardial infarction (TIMI) flow < 3, or residual stenosis > 40%.
Following PCI, P2Y12 inhibitors were recommended to be continued (clopidogrel 75 mg/day or ticagrelor 90 mg twice daily) for at least 1 year and continue aspirin (100 mg/day) or P2Y12 inhibitor (if aspirin intolerant) indefinitely. Angiotensin-converting enzyme inhibitors and beta-blockers were prescribed for patients presenting with AMI unless contraindicated. Statin prescriptions were granted according to lipid guidelines in Taiwan and regulations of Taiwan's National Health Insurance Administration. 13 For patients undergoing PCI for stable angina, other medications, such as beta-blockers or nitrates, were administered at the attending physician's discretion.

| Angiographic analysis
Angiographic data were measured using quantitative coronary angiography analysis, including RVD, minimum lumen diameter, and percent of stenosis. The complexity of the lesions was defined according to the modified American College of Cardiology/American Heart Association grading system. 14,15 This modified classification divided the coronary lesions into three categories (A, B, and C) based on 11 angiographic criteria. Within the intermediate risk category B, subcategories B1 and B2 are distinguished by the number of unfavorable characteristics present. 14 Calcification was classified into none/mild, moderate, and severe. 16 Moderate calcification was defined as radiopacity apparent only during the cardiac cycle before contrast injection. Severe calcification was defined as apparent radiopacity without cardiac motion, affecting both sides of the arterial lumen. Postdilation was indicated by the presence of additional dilatations induced by a > 2.0-mm noncompliant balloon within the stent area following stent deployment. Lesion success was defined as residual stenosis < 30%, final TIMI flow grade of 3, and absence of significant side branch occlusion or flow-limiting dissection after the procedure. Follow-up coronary angiography was performed only in symptomatic patients with myocardial ischemia documented by a noninvasive test.

| Study definitions and endpoints
The primary endpoint of the study was the occurrence of major adverse cardiovascular events (MACE) at the second year, defined as a composite of all-cause death, nonfatal myocardial infarction (MI), and clinically-driven target lesion revascularization (TLR). TLR was defined as any repeated revascularization procedure performed for >50% angiographic narrowing of the treated lesion from 5 mm proximal to 5 mm distal to the stent. An additional endpoint included stent thrombosis, which was classified into early (within one month), late (between 1 and 12 months), or very late (after 12 months).

| Angiographic findings and procedure characteristics
Results on lesion characteristics and procedures are displayed in  12.6 mm). 10,[18][19][20] Because the very small vessel lesions are commonly found in patients with DM or CKD and are manifested with diffuse lesions in nature, our study might better reflect the outcome of very small vessel stenting in routine clinical settings. 21,22 Stent delivery is technically difficult in coronary interventions for smaller vessel sizes because manipulation of the stent is usually hampered by calcification, vessel tortuosity, and the distal location of the lesion. 23 Dislodgment of 2.0-mm DES was reported in a study comparing different strategies for treating CAD with very small vessel sizes. 24 The same study also found a higher incidence of stent thrombosis at 1 year (2%), which could be attributed to malposition or stent underexpansion. 24 However, the findings from other studies and our study indicate that 2.0-mm zotarolimus DES provides appropriate lesion crossability and a low rate of stent thrombosis (≤1%). 10,25 In these studies, almost all very small vessel lesions were Although stenting has the advantage of acute lumen gain, longterm efficacy is a major concern. Studies have indicated that a vessel diameter < 2.50 mm could serve as a threshold for small target vessels to predict higher rates of 2-year MACE (10.8%) and restenosis (4.8%), and studies have found no significant association between outcomes and vessel diameter. 5 Another pooled analysis reported no significant difference in long-term outcomes between vessel diameters of ≤2. 25  This study has the following limitations. First, the retrospective study design, lack of randomization, lack of control group, and limited sample size made it impossible to control for all confounders and might have led to inherent selection bias. The patients' background parameters also varied to a certain extent, and there were no planned sensitivity analyses to assess the findings of the primary analysis.

| Clinical outcomes
Therefore, the risk model identified in our study should still be interpreted with caution due to the width of 95% CI and the potential effects of other undetected variables. Second, routine follow-up coronary angiography was not performed because of cost and ethical considerations. The potential in-stent late loss was not comprehensively assessed. Third, although our hospital is a tertiary medical center and disease management accords with current standards of clinical practice, the result of this single-center study may not be generally applicable to other health facilities.

| CONCLUSION
Our study reports that 2.0-mm zotarolimus DES for very small vessel CAD is feasible on the basis of findings obtained at 2-year follow-up.
Statin therapy was associated with fewer incidences of MACE. CKD and calcified lesions were independent predictors of long-term MACE rate in patients treated with 2.0-mm zotarolimus DES. The decision to stent very small coronary vessels in these high-risk patients should be tailored to each patient's unique clinical characteristics, and clinicians should ensure adequate lesion preparation and optimal stent deployment if revascularization by PCI is required.

ACKNOWLEDGMENTS
The authors express their appreciation to the Department of Medical

Education and Research Center of Medical Informatics in Kaohsiung
Veterans General Hospital for inquiries and assistance in data processing. The authors also would like to thank Mei-Chi, Wang for her expert statistical assistance.

CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to legal restrictions imposed by the government of Taiwan in relation to the "Personal Information Protection Act." ORCID En-Shao Liu http://orcid.org/0000-0001-6469-3051