Abstract
Patients with low baseline low-density lipoprotein cholesterol (LDL-C) but experiencing recurrent coronary revascularization events have been rarely investigated. In this retrospective cohort study, we enrolled patients undergoing percutaneous coronary intervention (PCI) with baseline LDL-C <55 mg/dL at the First Affiliated Hospital of Xi’an Jiaotong University between January and December 2017. Subsequent ischemia-driven coronary revascularization events and all-cause death were documented during a 4-year follow-up. Cox analysis was used to evaluate the association between baseline clinical characteristics and long-term events. As a result, among 388 patients (mean age 63 years; 79.1% male) enrolled, 32 patients underwent recurrent revascularization events, and 38 patients occurred all-cause death. After adjustment for age, diabetes mellitus, multi-vessel disease, and lipoprotein(a), multivariate Cox analysis showed that baseline serum triglyceride (TG) (HR 1.691, 95% CI 1.178 to 2.428, p=0.004) was an independent predictor of recurrent coronary revascularization events. Kaplan-Meier analysis revealed that a higher TG level (≥1.17 mmol/L, determined by receiver operating characteristic curve) was associated with increased risk of recurrent revascularization events than lower TG level (<1.17 mmol/L) (p=0.021). Female (HR 2.647, 95% CI 1.350 to 5.190, p=0.005) and previous atrial fibrillation (HR 3.163, 95% CI 1.403 to 7.132, p=0.006) were associated with increased risk of all-cause death. In conclusion, for patients undergoing PCI with baseline LDL-C <55 mg/dL, higher baseline TG can predict recurrent coronary revascularization events.
WHAT IS ALREADY KNOWN ON THIS TOPIC
Patients undergoing percutaneous coronary intervention (PCI) still have the risk of recurrent coronary events even with low level of baseline low-density lipoprotein cholesterol (LDL-C).
WHAT THIS STUDY ADDS
Baseline triglyceride is associated with recurrent revascularization events in patients undergoing PCI with baseline LDL-C <55 mg/dL.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Our study suggests that those patients may gain additional benefits from triglyceride-lowering therapy.
Introduction
Low-density lipoprotein cholesterol (LDL-C) is one of the most critical risk factors for atherosclerotic cardiovascular disease (ASCVD). Consistent evidence proves that LDL-C lowering provides incremental cardiovascular benefits. Since PCSK9 inhibitor is verified to strongly reduce LDL-C to an extremely low level and bring further cardiovascular benefits, the current guideline has updated and set a new LDL-C goal of <55 mg/dL in patients at very high risk of ASCVD for secondary prevention.1
However, regardless of which lipid-lowering agent is used, the clinical benefits depend on the baseline LDL-C level and the absolute magnitude of LDL-C reduction.2 The higher the baseline LDL-C is, the more benefits derived from lipid-lowering therapy. Cardiovascular benefit from intensified LDL-C lowering was expected less in patients with baseline LDL-C <100 mg/dL.3 4 Serial intravascular ultrasound analysis also indicated that statin therapy in inducing coronary plaque regression was less effective in patients with low LDL-C.5 However, in clinical practice, a challenging problem is that a group of patients develop ASCVD despite low LDL-C level and continue experiencing recurrent ischemic events even under statin therapy.6–8 In addition to LDL-C, what other risk factors are involved in this specific patient group have been scarcely studied. Therefore, our study aimed to explore which baseline risk factor could be associated with recurrent revascularization events in patients undergoing percutaneous coronary intervention (PCI) with baseline LDL-C <55 mg/dL.
Materials and methods
Population
This is a retrospective cohort study. Consecutive patients with coronary artery disease (CAD) undergoing PCI from January to December 2017 at the First Affiliated Hospital of Xi’an Jiaotong University were screened. Patients with successful PCI and baseline LDL-C <55 mg/dL were included in our study. The exclusion criteria were as follows: (1) no statin therapy at discharge; (2) occurring in-hospital death; (3) the occurrence of recurrent revascularization due to withdrawal of anti-platelet or statin treatment; (4) loss of follow-up.
Baseline clinical information was collected from standard medical records, including demographic data, diagnosis at presentation, and detailed previous histories. Fasting blood tests including alanine aminotransferase (ALT), serum albumin (ALB), serum creatinine (CRE), HbA1c, LDL-C, high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), total cholesterol (TC), and lipoprotein(a) were collected. Platelet (PLT) and hemoglobin tested at admission were recorded. Left ventricular ejection fraction (LVEF) measured by Simpson’s method was collected.
The manifestations of coronary angiography (CAG) were characterized by the affected number of three major epicardial arteries (stenosis of the lumen diameter >50%), defined as one-vessel, two-vessel, and multi-vessel diseases.
Clinical outcomes
During a 4-year follow-up, all-cause death, acute myocardial infarction (AMI), angina, any recurrent coronary revascularization (unplanned PCI or coronary artery bypass graft (CABG)), and stroke were documented. The endpoint was any unplanned coronary revascularization due to recurrent ischemic events and all-cause death. All follow-up information was obtained in April 2021 by telephone interview or by checking patient visits to the outpatient clinic or readmission medical records.
Statistical analysis
Patients were stratified into two groups according to the occurrence of recurrent revascularization events. Continuous normally distributed data were presented as mean with SD, and non-normally distributed data were shown as median with 25th and 75th percentiles; unpaired t-test and Mann-Whitney U test were used as appropriate. For discrete variables, differences were expressed as counts and percentages and were analyzed with χ2 or Fisher exact test.
Cox regression analysis was used to estimate the adjusted HRs and 95% CIs for revascularization events and all-cause death predictors. When analyzing the independent predictors of recurrent revascularization, we put the variables with p value ≤0.2 obtained in the univariate Cox regression (including age, TG, lipoprotein(a)) and established risk factors (diabetes mellitus and multi-vessel disease) into stepwise forward selection multivariate Cox analysis. Kaplan-Meier analysis was used to compare the cumulative hazard of recurrent revascularization events by log-rank test.
When analyzing the independent predictors of all-cause death, we put the variables with p value ≤0.1 obtained in the univariate Cox regression (including age, sex, hemoglobin, and history of atrial fibrillation and multi-vessel disease) into the multivariate analysis.
A two-tailed p value ≤0.05 was considered statistically significant. Statistical analysis involved the use of SPSS V.25.0.
Results
Study population
From January to December 2017, a total of 2955 patients undergoing successful PCI and receiving stating therapy at discharge were screened; 2530 patients with LDL-C ≥55 mg/dL were excluded, and the remaining 425 patients (14.3%) with LDL-C <55 mg/dL and statin therapy at discharge were enrolled. One patient experiencing recurrent PCI due to withdrawal of statin was excluded; 36 patients were lost to follow-up. At last, 388 patients were included in this study (figure 1). At presentation, 287 patients (74.0%) were diagnosed with unstable angina (UA), 63 patients (16.2%) with ST-elevation myocardial infarction (STEMI), 29 patients (7.5%) with non-ST elevation myocardial infarction (NSTEMI), and 9 patients (2.3%) with ischemic cardiomyopathy.
Study flowchart. LDL-C, low-density lipoprotein cholesterol; PCI, percutaneous coronary intervention.
Follow-up clinical events
During a 4-year follow-up, 32 patients (8.2%) underwent recurrent ischemia-driven revascularization procedures (29 PCI and 3 CABG), and 38 patients (9.8%) occurred all-cause death. The comparison of clinical, laboratory, and angiographic characteristics and follow-up information between the revascularization group and the non-revascularization group are listed in table 1. Patients in the revascularization group presented higher serum CRE (p=0.03), more multi-vessel disease (p=0.03), and more events of AMI and angina in follow-up (both p<0.001).
Comparison of clinical, laboratory, and angiographic characteristics and clinical outcomes between two groups
Predictors of recurrent revascularization and all-cause death
Table 2 lists the results of univariate Cox analysis for recurrent revascularization events and all-cause death.
Univariate Cox regression for predictors of recurrent revascularization and all-cause death
Univariate Cox regression showed that only TG was statistically associated with recurrent revascularization events (HR 1.691, 95% CI 1.178 to 2.428, p=0.004). When analyzing the independent predictors of recurrent revascularization events, we put the variables with p value ≤0.2 obtained in the univariate analysis (including age, lipoprotein(a), TG) and established risk factors (diabetes mellitus and multi-vessel disease) into multivariate Cox analysis. As a result, baseline TG (HR 1.691, 95% CI 1.178 to 2.428, p=0.004) was still the only independent predictor for recurrent revascularization in patients undergoing PCI with baseline LDL-C<55 mg/dL.
Since there is no established cut-point for TG, we used receiver operating characteristic curve (ROC) analysis to acquire the optimal cut-off value. Patients were further divided into two groups: higher TG group (≥1.17 mmol/L) and lower TG group (<1.17 mmol/L). Kaplan-Meier analysis demonstrated that a higher TG level was associated with a higher risk of recurrent revascularization events than a lower TG level (p=0.021 by log-rank test) (figure 2).
Kaplan-Meier analysis demonstrated that a higher triglyceride (TG) level (≥1.17 mmol/L) resulted in a higher risk of recurrent revascularization events than a lower TG level (<1.17 mmol/L) (p=0.021 by log-rank test).
When analyzing the potential predictors of all-cause death, we put the variables with p value ≤0.1 obtained in the univariate Cox regression (including age, sex, hemoglobin, history of atrial fibrillation, and multi-vessel disease) into the multivariate analysis. The results showed that female (HR 2.647, 95% CI 1.350 to 5.190, p=0.005) and previous atrial fibrillation (HR 3.163, 95% CI 1.403 to 7.132, p=0.006) were associated with higher risk of all-cause death in patients undergoing PCI with baseline LDL<55 mg/dL.
Discussion
The main findings of the current study are as follows: (1) despite baseline LDL-C <55 mg/dL and statin therapy, the risk of recurrent ischemia-driven revascularization events in patients undergoing PCI remained high (8.2%); (2) baseline TG was an independent predictor of recurrent revascularization events in those patients; (3) female and previous atrial fibrillation were associated with a higher risk of all-cause death in those patients.
An LDL-C <70 mg/dL was the previous target goal in secondary prevention for patients with ASCVD before the PCSK-9 inhibitor came out. However, ASCVD can occur in individuals even with low LDL-C levels. Patients with AMI with baseline LDL-C <70 mg/dL occupied 7.1% in the KAMIR study.9 In the TERCET study, the proportion rose to 20.7% among patients with acute coronary syndrome (ACS).10 In a PCI registry study, the ratio reached 41.9%.11 Even with low baseline LDL-C, statin therapy improves clinical prognosis.6–9 However, the benefit is less prominent as compared with high LDL-C, and recurrent vascular events continue to occur,3 4 which suggests that other risk factors, rather than LDL-C, are involved in atherosclerosis progression for those patients.
Numerous studies have shown an association between baseline serum TG and ASCVD. Elevated TG is related not only to subclinical atherosclerosis and vascular inflammation despite normal LDL-C12 but also equally to residual cardiovascular risk among patients receiving statin therapy,13 especially those with diabetes mellitus.14 Among patients with ACS with all baseline levels of LDL-C and treated effectively with statins, studies have found that TG was associated with recurrent ischemic events after ACS.15 16 Our study focused on patients with baseline LDL-C <55 mg/dL and got consistent results.
The American Heart Association suggests that optimal fasting TG level should be defined as <1.2 mmol/L.17 It points out that TG-rich lipoproteins and the remnants accumulate in the plasma when TG >1.2 mmol/L, while efficient lipolysis results in limited accumulation of remnant particles when TG <1.2 mmol/L.18 Our study used ROC analysis to acquire a similar cut-off value of 1.17 mmol/L and found that patients with TG ≥1.17 mmol/L had a statistically higher risk of recurrent revascularization than TG <1.17 mmoL/L. The 2019 European Society of Cardiology/European Atherosclerosis Society guideline suggests that TG-lowering drugs could be prescribed in high-risk patients only when TG is >2.3 mmol/L1. The recent REDUCE-IT trial demonstrated that icosapent ethyl, one TG-lowering agent, could reduce the need for first and subsequent coronary revascularizations in statin-treated patients with LDL-C <100 mg/dL and fasting TG >1.52 mmol/L.19 20 The optimal cut-point for initiating TG-lowering therapy in patients with different LDL-C level may need further exploration.
Although higher TG was related to a higher risk of revascularization, it was not associated with all-cause death in our study. This conclusion was not consistent with the previous research,21 which could be explained by the different baseline characteristics of the enrolled patients. Patients with low baseline LDL-C usually present worse clinical profiles, such as more comorbidities and older age.10 22 Our study showed females and patients with AF faced a higher risk of all-cause death. By comparing baseline characteristics, we found that patients with atrial fibrillation were older, more often with lower LDL-C and hemoglobin levels, presenting higher creatinine (all p<0.05) than those without. Older age and worse baseline conditions would be a reasonable explanation for AF contributing to all-cause death.
In conclusion, we explored why ischemia-driven revascularization events recurrently occurred in patients with low LDL-C levels (<55 mg/dL) and found that baseline TG was an independent risk factor. Whether TG-lowering agent can yield additional cardiovascular benefits in addition to statin therapy in those patients is under investigation.
Limitations
The present study had some limitations. First, patients with baseline LDL-C <55 mg/dL had two situations: receiving statin therapy or being born this way, which could potentially affect the results concluded in our study. However, if patients can easily reach the target goal under statin therapy but continue to suffer recurrent events, they should be paid equal attention. Second, in addition to TG, other risk factors are also involved in the residual cardiovascular risk, such as C reactive protein. We could not study it because of data deficiency. Third, the study was a retrospective cohort design with inherent prejudice.
Data availability statement
Data are available on reasonable request. Data are available from the corresponding author on reasonable request.
Ethics statements
Patient consent for publication
Ethics approval
The study was approved by the ethics committee of our institution. Written informed consent was waived due to a retrospective design. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki.
Footnotes
XF and XW contributed equally.
Presented at The abstract of this article was preprinted on ResearchGate (DOI:10.21203/rs.3.rs-1385123/v1).
Contributors Conceptualization: XF, YW. Data collection and analysis: XF, XN, YL, XW, WX, TZ. Writing—original draft preparation: XF. Writing—review and editing: XW, YW. Supervision: JS, YW. All authors have read and agreed to the published version of the manuscript. YW is responsible for the overall content as guarantor.
Funding This study was supported by the National Key R&D Program of China (2019YFA0802300, 2021YFA1311505), the National Natural Science Foundation of China (92049203,81970351, 81941005), the Key Project of Research and Development Plan of Shaanxi (2021ZDLSF02-04) and the Clinical Research Award of the First Affiliated Hospital of Xi'an Jiaotong University, China (No. XJTU1AF-CRF-2019-011).
Competing interests None declared.
Provenance and peer review Not commissioned; internally peer reviewed.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, an indication of whether changes were made, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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