Cardiovascular Outcomes in Patients with Initial Diagnosis of Obstructive Coronary Artery Disease and LDL-C below 1.8 mmol/L

Background To investigate individuals at high risk for atherosclerotic cardiovascular disease (ASCVD), but, without previous events and with low-density lipoprotein cholesterol(LDL-C)<1.8 mmol/L should be treated with statin. Methods: We studied 1330 patients with LDL-C <1.8 mmol/L at the initial diagnosis of obstructive coronary atherosclerotic disease (OCAD) by angiography. Of 1330, 782 had not received prior statin therapy and 548 were treated with statin. Incidence of subsequent major adverse cardiac and cerebral event (MACCE) during a median of 25-month follow-up were identied and compared between patients with LDL-C <1.8 mmol/L without any prior statin [prior statin(-)] and those with LDL-C <1.8mmol/L achieved by prior statin therapy [prior statin(+)]. Results ACS occurred in 93.4% of individuals with LDL-C <1.8 mmol/L as an initial diagnosis of OCAD. Prior statin(+), comparing to prior statin(-) who displayed similar ASCVD risk burden including 71.6% with hypertension, 39.1% with diabetes and 76.1% with ≥ 3 risk factors, had signicantly lower incidence of acute myocardial infarction(AMI) (10.4% vs. 28.8%, P<0.001), higher left ventricular ejection fraction(LVEF)(0.67±0.07 vs. 0.64±0.09, P <0.001), lower incidences of subsequent MACCE (4.7% vs. 10.4%, P =0.001), total mortality (2.4% vs. 6.8%, P =0.001) and cardiovascular(CV) death (1.5% vs. 4.3%, P =0.006) during follow-up. After multivariable adjustment, no prior statin therapy was signicantly and independently associated with subsequent CV death, particularly in the subgroups of age ≥ 65 years and hypertension. Conclusions intensively treated in the PROVE IT-TIMI 22 (The Pravastatin Atorvastatin Infarction 22) LDL-C ≤ 40 mg/dL and 40–60 mg/dL groups fewer (death, MI, stroke, recurrent ischemia or revascularization) than LDL-C > 60–80 mg/dL groups 19 The recent trials with Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition conrmed that further LDL-C reduction to 30–50 mg/dl with combination of PCSK9 inhibitor and statin can lead to further reduction of ASCVD events comparing 7,8,20


Background
Obstructive coronary atherosclerotic disease (OCAD) is the leading cause of death worldwide 1,2 . It is well established that elevated levels of low-density lipoprotein cholesterol (LDL-C) is associated with an increased risk of OCAD and its related major adverse cardiac and cerebral event (MACCE) 3,4 . Randomized clinical trials have demonstrated that LDL-C lowering therapies can reduce risk of OCAD and MACCE [5][6][7][8][9] .
Currently, LDL-C lowering with statin therapy has been recommended as a corner stone of primary and secondary preventions by multiple practice guidelines [10][11][12][13] .
For secondary prevention, it is clear that statin therapy should be initiated regardless of baseline LDL-C levels. The target level of LDL-C < 1.8 mmol/L (70 mg/dL) or a reduction of at least 50% if the baseline is between 1.8 and 3.5 mmol/L (70 and 135 mg/dL) should be achieved with LDL-C lowering therapies. In primary prevention setting, guidelines recommended initiation of LDL-C lowering therapy in LDL-C > 1.8 mmol/L, and recently added risk assessment algorithm and imaging and biomarker assessment with objective of improving identi cation of high-risk population. 2019 European Society of Cardiology(ESC)guidelines showed that in patients with type 2 diabetes mellitus(T2DM) at very-high risk, an LDL-C reduction of ≥ 50% from baseline and an LDL-C goal of < 1.4 mmol/L (< 55 mg/dL) is recommended 14 . In the real-world practice, acute coronary syndrome (ACS) can develop in individuals with LDL-C < 1.8 mmol/L and it is not clear whether individuals with LDL-C < 1.8 mmol/L and at high risk for atherosclerotic cardiovascular disease (ASCVD), but, without previous clinically established ASCVD related events, should also be treated with statin. To address this critical unanswered clinical question, we performed a retrospective analysis with objective to identify incidence of subsequent MACCE in patients with LDL-C < 1.8 mmol/L without any prior statin use and to compare these outcomes to a cohort of patients with LDL-C < 1.8 mmol/L achieved by prior statin therapy.

Study population
Study subjects were identi ed in the database at the Cardiovascular Center of Beijing Friendship Hospital. As shown in Figure  1, a total of 11137 patients underwent coronary angiography from January 2013 to September 2019. Of these 11137, 9339 were diagnosed with OCAD. Of the 9339 patients, 8009 were excluded according to the exclusion criteria including prior diagnosis of OCAD; LDL-C ≥1.8 mmol/L; triglycerides (TG) > 4.5mmol/L; acute infections; malignant tumor; missing clinical or follow-up data. Finally, a total of 1330 patients were included in this analysis, and 782 were identi ed not treated with statin prior to the initial diagnosis of OCAD and 548 were con rmed to receive statin for at least 1 month prior to the diagnosis. The median duration of statin use was 24.0 (IQR: 3.0, 60.0) months. All patients were followed up to December 31, 2019 with a median follow up of 25.0 (IQR: 11.8, 48.6) months.
The study data collections were approved by the Institutional Review Board of Beijing Friendship Hospital a liated to Capital Medical University and were in accordance with the Declaration of Helsinki.

Data collections and de nitions
Patient demographic information, medical and medication history, laboratory measurements, echocardiographic and angiographic evaluations, and clinical outcomes during the hospitalization of initial diagnosis of OCAD were collected and con rmed through electronic medical records. The subsequent outcomes on MACCE were collected and recorded through clinical follow-up visits.
OCAD was de ned as atherosclerotic lesion(s) in coronary arteries causing >50% of the lumen obstruction by coronary angiography, which causing myocardial ischemia or necrosis.
MACCE included all-cause death, non-fatal myocardial infarction (MI) and non-fatal stroke. Non-fatal MI was de ned as chest pain with new ST-segment changes and elevation of myocardial necrosis markers to at least twice of the upper limit of the normal range. Non-fatal stroke included ischemic and hemorrhagic stroke, was de ned as cerebral dysfunction caused by cerebral vascular obstruction or sudden rupture, and was diagnosed based on signs of neurological dysfunction or evidence of brain imaging.

Statistical analysis
Continuous variables were expressed as mean value± SD or median and interquartile range (IQR), depending on the distribution of the data. Comparisons between the study groups were performed by Student t-test or Mann-Whitney U-test. Categorical variables were expressed as number and percentage, and compared using the Pearson chi-square test or Fisher's exact test. The cumulative incidence of MACCE was estimated by Kaplan-Meier survival Curves, and the groups were compared using the log-rank test. A multivariable Cox regression analysis was performed in order to determine whether no prior statin therapy was an independent predictor for all-cause mortality, cardiovascular (CV) death and composite MACCE. Baseline variables that were signi cantly correlated with outcomes by univariate analysis and clinically relevant were entered into the multivariate model. In model 1, we adjusted for age, gender and body mass index. In model 2, we further adjusted for history of current/ex-smoker, hypertension, antiplatelet agent use prior admission and angiotensin-converting-enzyme inhibitors/angiotensin receptor blockers/beta-blocker (ACEI/ARB/β-blocker) use prior admission. In model 3, we further included left ventricular ejection fraction(LVEF). All analyses were two-tailed and P value <0.05 was considered statistically signi cant. Data were analyzed using SPSS statistical package version 24.0 (SPSS Inc., Chicago, IL, USA).

Patient characteristics
As shown in Figure 1, of 9339 subjects undergoing coronary angiography(CAG), 1330(14.2%) patients were diagnosed to have OCAD for the rst time. Patient demographic, medical and clinical, laboratory, echocardiographic and angiographic characteristics are presented and compared between prior statin(-) and (+) groups as shown in Table 1.
Comparing to prior statin(+), subjects in the prior statin(-) group showed signi cantly lower body mass index(BMI), higher percent of male gender and smokers, lower percent of hypertension, signi cantly less likely to receive antiplatelet therapy, ACEI/ARBs, or β-blocker prior to the current admission. The prevalence of ACS as a clinical presentation of the initial diagnosis of OCAD was 93.4% and similar between prior statin(-) and (+) groups (93.9% vs 92.7%, P =0.402). Among ACS, 22.7% (282/1242) was con rmed as acute myocardial infarction(AMI). However, incidence of AMI was signi cantly higher in the prior statin(-) group than prior statin(+) (28.8% vs. 10.4%, P <0.001). Furthermore, among patients who suffered AMI, peak troponin I level was signi cantly higher in the prior statin(-) group than prior statin(+)

Independent association of subsequent MACCE and mortality
Multivariate analysis included variables that were identi ed to be signi cantly associated with MACCE, total mortality and CV death in the univariate model. Also, intercorrelations among variables were taken into consideration in the multivariate analysis, for example, LVEF<0.50 and diagnosis of AMI at admission were found signi cantly associated with MACCE by univariate analysis. However, LVEF<0.50 was signi cantly correlated with AMI (r=0.38, P <0.001), therefore, LVEF<0.50 was the variable entered in the multivariate analysis. As shown in Table 2, no prior statin therapy was signi cantly and independently associated with CV death (HR=2.47, 95%CI 1.13-5.36, P =0.023). In addition, no prior statin therapy showed a trend in association with an increased risk of all-cause death (HR=1.76, 95%CI 0.92-3.37, P =0.090) and composite MACCE (HR=1.47, 95%CI 0.91-2.38, P =0.112).

Discussion
The present study involved 1330 patients with LDL-C levels < 1.8 mmol/L who were rst diagnosed with OCAD and 58.8% of these patients did not receive prior statin therapy. There are 2 important observations: (1) The risk of AMI occurrence remained high in individuals with LDL-C < 1.8 mmol/L, especially in those without prior statin therapy. (2) We found that prior statin therapy for lowering LDL-C to < 1.8 mmol/L comparing to LDL-C < 1.8 mmol/L without statin was signi cantly associated with lower incidences of subsequent MACCE (4.7% vs. 10.4%, P = 0.001), total mortality (2.4% vs. 6.8%, P = 0.001) and CV death (1.5% vs. 4.5%, P = 0.006) during a median of 25-month follow-up. The multivariate analysis revealed that no prior statin therapy remained an independent and strong predictor of CV death, particularly in the subgroups of age ≥ 65 years and hypertension.
Populations studies and randomized clinical trials have established that increased levels of LDL-C are associated with increased risk of ASCVD and subsequent MACCE 3,4 and every 1 mmol/L LDL-C lowering with interventions is associated with 20% MACCE risk reduction 5,15 , even in people who were considered to be at low risk. Genetic studies in the recent years have demonstrated that genetic mutation associated lower levels of LDL-C are correlated with further reduced risk for coronary heart disease 3,16−18 . Data from the intensively treated patients in the PROVE IT-TIMI 22 (The Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22) trial showed that LDL-C ≤ 40 mg/dL and 40-60 mg/dL groups had fewer major cardiac events (death, MI, stroke, recurrent ischemia or revascularization) than LDL-C > 60-80 mg/dL groups 19 . The recent trials with Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition con rmed that further LDL-C reduction to 30-50 mg/dl with combination of PCSK9 inhibitor and statin can lead to further reduction of ASCVD events comparing statin alone 7,8,20 . The cumulated evidence in the past 50 years has impacted the development of practice guidelines recommending LDL-C as the primary treatment target for people at different ASCVD risk levels [10][11][12][13]21 .
Initiation of LDL-C therapy is recommended in people with established vascular diseases (secondary prevention) at any levels of LDL-C. If ASCVD risk management is entirely based on LDL-C levels, LDL-C lowering therapy is commonly recommended when LDL-C > 1.8 mmol/L (70 mg/dL) in individuals without previous vascular events (primary prevention). Indeed, physicians have initiated statin therapy in a group of high-risk subjects with LDL-C > 1.8 mmol/L to achieve LDL-C < 1.8 mmol/L. Not surprised, in our study, this group with prior statin comparing to subjects with LDL-C < 1.8 mmol/L without statin displayed a lower incidence of AMI, lower levels of peak troponin I for less myocardium ischemic damage when MI was not prevented, and decreased risk of subsequent MACCE and mortality, which are consistent with results seen in the previous primary prevention trails [22][23][24] and also can be explained by improved plaque stability with statin therapy demonstrated in the previous imaging studies 25-28 .
The lower incidence of AMI and less myocardium ischemic damage with statin-induced LDL-C < 1.8 mmol/L comparing to "naturally" LDL-C < 1.8 mmol/L suggest that non-lipid effects of statin 29-31 and a greater LDL-C toxicity 5,32 . Importantly, the higher incidence of AMI and the increased risk of subsequent MACCE and mortality in subjects with LDL-C < 1.8 mmol/L without prior statin raise a question whether statin therapy should be given to high-risk individuals without previous vascular events regardless of LDL-C levels because LDL-C < 1.8 mmol/L did not offer cardiovascular protection in this population.
The most recent guidelines began to suggest that ASCVD risk assessment and initiation of statin therapy should not limited to LDL-C levels. In our study, patients treated with and without prior statin showed high and similar ASCVD risk burden (76.3% vs. 76.1%) with ≥ 3 risk factors. Statin therapy was obviously given to patients with LDL-C > 1.8 mmol/L. However, among subjects not treated with prior statin, 39.1% of them had type-2 diabetes, despite LDL-C level < 1.8 mmol/L, should receive statin therapy according to guideline recommendations, and 7.0% with chronic kidney disease also should be treated with statin. Furthermore, 76.1% of subjects displayed ≥ 3 ASCVD risk factors in our study could have bene ted from statin therapy as HOPE-3 demonstrated that rosuvastatin 10 mg daily signi cantly lowered risk of ASCVD events than placebo in an intermediate-risk and ethnically diverse population with 1-2 risk factors without established cardiovascular disease 25 . Furthermore, the bene ts of rosuvastatin were consistent across all subgroups de ned based on LDL-C level, blood pressure, C-reactive protein level, cardiovascular risk at baseline, age, sex, and race or ethnic group. However, the baseline LDL-C in HOPE-3 was > 1.8 mmol/L. The role of lowering LDL-C with statins in the primary prevention among people without clinically established cardiovascular disease, regardless of lipid levels, in ammatory markers, hypertension status, or diabetes status, has not been established. Our subgroup analyses emphasized the importance of early statin therapy for the population with age ≥ 65 years or hypertension.
Further investigations, in light of our study ndings, are needed to determine whether statin or other LDL-C lowering therapy would reduce ASCVD events in patients with multiple risk factors, but, LDL-C < 1.8 mmol/L. The present study found that 1231 (92.6%) patients with initial diagnosis of OCAD and LDL-C < 1.8 mmol/L presented as ACS at admission. The underutilization of statin was also led by under diagnosis of OCAD prior to the rst presentation of ACS in our study. At the time of initial diagnosis of OCAD, about 80% of patients already had multivessel or left main coronary disease and near 10% had chronic total occlusion by angiography. If the OCAD was fully recognized prior to the rst presentation of ACS, at least 80% of patients should have given statin therapy and bene ted from the treatment. These ndings, on one hand, support the potential role of using coronary CT angiography and coronary artery calcium scoring to detect the underlying coronary atherosclerosis in patients with low LDL-C. On the other hand, these data also present challenges in the real-world practice given the high burden of ASCVD worldwide, cost of imaging test for OCAD diagnosis and complexity of proper use of imaging test. In this situation, the risk score calculation recommended by guidelines [10][11][12] can help to identify individuals at increased risk for ASCVD despite of LDL-C < 1.8 mmol/L.

Limitations
There are limitations with this study. First, this is a single-center study, although with a large sample size, but, limited number of MACCE, which limits the generalization of the ndings and statistical power to account for all possible confounders. Second, it is a retrospective analysis with potential unmeasured bias. Prospective cohort studies are needed to con rm our ndings. Future randomized clinical trials will be able to investigate the effects of statin or other lipid therapies on reduction of MACCE in high-risk patients with LDL-C < 1.8 mmol/L.

Conclusion
Prior statin therapy for lowering LDL-C to < 1.8 mmol/L comparing to LDL-C < 1.8 mmol/L without statin was signi cantly and independently predictive of subsequent CV death. Statin therapy was largely underutilized in this high-risk population with multiple ASCVD risk factors despite of LDL-C < 1.8 mmol/L. These ndings suggest that statin therapy for primary prevention of OCAD should be considered based ASCVD risk assessment, not driven by LDL-C level only.

Competing interests
The authors declare that they have no competing interests.

Ethics approval and consent to participate
The study data collections were approved by the Institutional Review Board of Beijing Friendship Hospital a liated to Capital Medical University, and written informed consent was obtained from all patients.

Consent for publication
Not applicable.

Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request Authors' contributions WPL, XQZ and HWL contributed to the conception or design of the work. WPL, XQZ, YZ, XSD, DDL and HC contributed to the acquisition, analysis, or interpretation of data for the work. WPL, XQZ and YZ drafted the manuscript. All authors critically revised the manuscript. All authors gave nal approval and agree to be accountable for all aspects of the work ensuring integrity and accuracy.  Model 2 included age, gender, body mass index, current/ex-smoker, hypertension, antiplatelet agent use prior admission and ACEI/ARB/β-blocker use prior admission.
Model 3 included age, gender, body mass index, current/ex-smoker, hypertension, antiplatelet agent use prior admission, ACEI/ARB/β-blocker use prior admission and LVEF<0.5. Figure 1 The study subject selection ow chart. CAG: Coronary angiography; OCAD: Obstructive coronary atherosclerotic disease; TG: Triglycerides; LDL-C: Low-density lipoprotein cholesterol.  Forest plot of CV death according to subgroups. The dashed vertical line represents the hazard ratio for the overall study population. The box sizes are proportional to the precision of the estimates (with larger boxes indicating a greater degree of precision). Adjusted model included age, gender, BMI, current/ex-smoker, hypertension, antiplatelet agent use prior admission, ACEI/ARB/β-blocker use prior admission and LVEF<0.5. BMI, body mass index; HT, hypertension; DM, diabetes mellitus; eGFR, estimated glomerular ltration rate; CV, cardiovascular.