Impact of an Intensive Lipid-Lowering Therapy Protocol on Achieving Target Low-Density Lipoprotein Cholesterol Levels in Patients With Acute Coronary Syndrome

Abstract

Background: Intensive lipid-lowering therapy (ILLT) is crucial for preventing secondary acute coronary syndrome (ACS). However, achieving target low-density lipoprotein cholesterol (LDL-C) levels remains challenging in clinical practice.

Methods and Results: This retrospective study included 534 patients with ACS who underwent primary percutaneous coronary intervention (PCI) between September 2016 and August 2022. The ILLT protocol, wherein ezetimibe and statins are prescribed, was introduced in September 2019. We compared the rate of achievement of the LDL-C target of <70 mg/dL at the first outpatient visit and the incidence of cardiovascular events during the 3-year observation period after PCI between the conventional therapy (n=226) and ILLT (n=308) groups. The ILLT group had a higher achievement rate than the conventional therapy group (71.8% vs. 48.7%; P=0.001). In the ILLT group, 17% of statin-naïve patients did not achieve the LDL-C target, and the cutoff value of LDL-C on admission for predicting non-achievement of this target was 146 mg/dL. Patients in the ILLT group showed a significantly lower incidence of cardiovascular events than those in the conventional therapy group (hazard ratio 0.57; 95% confidence interval 0.34–0.97).

Conclusions: Implementing the ILLT protocol using statins and ezetimibe helped achieve the target LDL-C level early in patients with ACS and may consequently improve prognosis. However, patients with LDL-C levels ≥146 mg/dL on admission may need more intensive treatment.

Coronary artery disease (CAD) is the leading cause of death worldwide.¹ It is well known that dyslipidemia is a major cause of atherosclerosis, with acute coronary syndrome (ACS) reported to have a high mortality rate.^2,3 The European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines recommend a target low-density lipoprotein cholesterol (LDL-C) level of <1.4 mmol/L (<55 mg/dL) in patients with ACS.⁴ In Japan, the 2022 Guidelines for the Prevention of Atherosclerotic Cardiovascular Disease recommend a target LDL-C level of <70 mg/dL for secondary prevention.⁵ High-dose statins have been shown to reduce cardiovascular events compared with moderate-dose statins.^6–8 In addition to statins, ezetimibe and PCSK9 inhibitors have been reported to be effective in lowering LDL-C levels in patients at high risk of CAD.^9,10 Early introduction of PCSK9 inhibitors has been reported to reduce rehospitalization.^11,12

Although the importance of lipid-lowering therapy has been increasingly recognized, the achievement of target LDL-C levels remains inadequate. Only 34.3% of patients with ACS in Japan achieve LDL-C levels of <70 mg/dL 1 month after discharge, possibly owing to concerns regarding the side-effects of increasing doses of statins.¹³

Therefore, in September 2019, we developed and implemented a new protocol for intensive lipid-lowering therapy (ILLT) using high-dose statins and ezetimibe in patients undergoing primary percutaneous coronary intervention (PCI) for ACS at our hospital. This study aimed to investigate whether the ILLT protocol increased the rate of LDL-C target achievement at the first outpatient visit (4–6 weeks after PCI) and to determine whether clinical outcomes improved. Furthermore, we sought to identify patients who failed to achieve the LDL-C target using the ILLT protocol.

Methods

Study Design and Participants

This retrospective study included 534 out of 885 patients diagnosed with ACS who underwent emergency PCI at our hospital between September 2016 and August 2022 (Figure 1). Patients who received PCSK9 inhibitors during hospitalization and those whose LDL-C levels could not be measured on admission or at the first outpatient visit after discharge (4–6 weeks after PCI) were excluded. A total of 534 patients were then included in the analysis and divided into 2 groups: a conventional therapy group (CT group; n=226), and an ILLT group (n=308), based on protocol implementation before and after (Figure 1).

Figure 1.

Study protocol. LDL-C, low-density lipoprotein cholesterol.

Definition of ACS and Methods of Examination

ACS was defined as high-risk unstable angina pectoris, non-ST-elevation myocardial infarction, and ST-elevation myocardial infarction as previously described,¹⁴ and LDL-C levels were measured using direct methods in our laboratory. According to the Japanese Society for Arteriosclerosis Guidelines,⁵ the target LDL-C level was considered to be <70 mg/dL at the initial outpatient visit.

Ethical Issues

This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of our hospital (Approval no. 1192). Because this was an observational study without intervention or invasive procedures and did not involve the use of human biological specimens, the requirement for written informed consent from patients was considered exempt, in accordance with the ‘Ethical Guidelines for Medical and Health Sciences Research Involving Human Subjects’. Relevant information regarding the study was made available to the public, and individuals were provided with the opportunity to refuse to provide data.

Lipid-Lowering Therapy Protocol

The lipid-lowering treatment protocol (hereinafter referred to as ‘protocol’) was as follows (Figure 2):

Figure 2.

Study flowchart. CT, conventional therapy; ILLT, intensive lipid-lowering therapy; LDL-C, low-density lipoprotein cholesterol; PCI, percutaneous coronary intervention.

(1) Patients not taking statins on admission: If baseline LDL-C was ≥120 mg/dL, high-dose statin plus 10 mg ezetimibe was initiated. If baseline LDL-C was <120 mg/dL, high-dose statin was started.

(2) Patients already on statins on admission: If baseline LDL-C was ≥70 mg/dL, high-dose statin plus ezetimibe 10 mg was initiated. If baseline LDL-C was <70 mg/dL, high-dose statin was started. At the first outpatient visit (4–6 weeks after PCI), if the LDL-C level was >70 mg/dL, patients who were not already taking ezetimibe were prescribed ezetimibe 10 mg. If patients were already taking high-dose statins and ezetimibe, a PCSK9 inhibitor was recommended.

Statins and ezetimibe were prescribed within 24 h of PCI according to the aforementioned protocol. The cutoff value of 120 mg/dL LDL-C was set based on the reported rate of change in LDL-C after statin administration.¹⁵ High-dose statins were defined as atorvastatin 20 mg, rosuvastatin 5 mg, and pitavastatin 4 mg in this study. To confirm adherence to the protocol, we reviewed medical records.

Outcome

The primary outcome was to determine the rate of LDL-C target attainment at the initial outpatient visit compared with the conventional therapy group in patients with ACS, while the secondary outcome was the cumulative incidence of major adverse cardiac events (MACE) during the 3-year observation period after PCI. MACE was defined as a composite of cardiovascular death, non-fatal myocardial infarction, coronary revascularization, and non-fatal stroke. Coronary revascularization was performed if new 90% stenotic lesions were found at the time of coronary angiography, or if lesions were more advanced than at the time of ACS and more than 90% stenosis was found. The decision to perform coronary angiography was made by the attending physician based on outpatient symptoms and the results of coronary computed tomography, myocardial scintigraphy, and exercise stress electrocardiogram. Stroke was also diagnosed based on computed tomography and magnetic resonance imaging findings after the patient presented with cranial nerve symptoms.

Safety Evaluations

Drug-related serious adverse events included liver dysfunction (alanine aminotransferase/aspartate aminotransferase >3×upper limit of normal [ULN]), myopathy (creatine kinase >10×ULN), rhabdomyolysis (creatine kinase >10,000×ULN), gallbladder-related adverse events, and cancer.¹⁶ These measurements were evaluated at the initial outpatient visit.

Statistical Analysis

The Mann-Whitney U test was used for non-normally distributed data, whereas the t-test was applied for normally distributed data. Continuous variables were expressed as median (interquartile range [IQR]) and mean ± SD, respectively. Categorical variables were analyzed using the chi-squared test. The chi-square test was used to compare the proportion of patients who achieved the LDL-C target (LDL-C <70 mg/dL) at the first outpatient visit (after 4–6 weeks) before and after the introduction of the protocol. Receiver operating characteristic (ROC) curve analysis was performed to identify the optimal cutoff value for predicting patients who did not achieve the target LDL-C level. Logistic regression was also used to examine baseline factors in patients who failed to achieve their LDL-C goals. The Kaplan-Meier curve and log-rank test were used to examine MACE. To evaluate the impact of the ILLT protocol, a multivariable Cox proportional hazards model was performed. This model was adjusted for clinically relevant risk factors, including ILLT protocol, age, sex, hypertension, diabetes, and chronic kidney disease. Statistical significance was defined as P<0.05. All calculations were performed using the IBM SPSS Statistics version 28.0J (IBM, Armonk, NY, USA).

Results

Patient Characteristics at Baseline

Table 1 presents the baseline characteristics of patients in this study. The prevalence of previous acute myocardial infarction in the CT group was significantly higher than in the ILLT group (P=0.026), whereas the prevalence of acute myocardial infarction and hypertriglyceridemia in the ILLT group was significantly lower than in the CT group (P=0.018). Statin use at admission was 27.9% in the CT group and 28.9% in the ILLT group (P=0.796). Median LDL-C values were not significantly different (110.0 mg/dL vs. 116.0 mg/dL; P=0.107) at the time of admission.

Table 1.

Patient Characteristics

	CT group (n=226)	ILLT group (n=308)	P value
Age (years)	71.0 [62.0–80.0]	70.0 [61.0–76.0]	0.075
Male	171 (75.7)	238 (77.3)	0.664
BMI (kg/m2)	23.9 [21.4–26.5]	24.1 [21.3–26.8]	0.687
Type of ACS
AMI	133 (58.8)	210 (68.2)	0.026
UAP	–	–
Previous PCI	57 (25.2)	49 (15.9)	0.008
Previous CABG	7 (3.1)	6 (1.9)	0.395
Previous MI	29 (12.8)	21 (6.8)	0.018
Previous stroke	14 (6.2)	12 (3.9)	0.052
Previous or current smoking	136 (60.2)	183 (59.4)	0.859
Diabetes	87 (38.5)	116 (37.7)	0.845
Hypertension	166 (73.5)	215 (69.8)	0.357
Familial hypercholesterolemia	12 (5.3)	18 (5.8)	0.791
Hemodialysis	8 (3.5)	10 (3.2)	0.853
eGFR (mL/min/1.73 m2)	69.7±21.0	68.6±20.9	0.445
Total cholesterol (mg/dL)	179.0 [151.5–201.5]	186.5 [159.0–216.0]	0.020
Triglycerides (mg/dL)	70.5 [44.0–119.0]	91.0 [6.0–160.0]	0.000
HDL-C (mg/dL)	42.0 [36.0–52.0]	45.0 [37.0–54.0]	0.090
LDL-C (mg/dL)	110.5 [86.0–133.0]	116.0 [89.0–140.0]	0.107
Medications for dyslipidemia
Statin	63 (27.9)	89 (28.9)	0.796
Ezetimibe	12 (5.3)	17 (5.5)	0.916
EPA	21 (9.3)	20 (6.5)	0.158
PCSK9 inhibitors	0 (0)	0 (0)

Data are presented as n (%), mean (SD), or median [IQR]. ACS, acute coronary syndrome; AMI, acute myocardial infarction; BMI, body mass index; CABG, coronary artery bypass grafting; CT, conventional therapy; eGFR, epidermal growth factor receptor; EPA, eicosapentaenoic acid; HDL-C, high-density lipoprotein cholesterol; ILLT, intensive lipid-lowering therapy; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; PCI, percutaneous coronary intervention; PCSK9, protein convertase subtilisin/kexin type 9; UAP, unstable angina pectoris.

Achievement of Target LDL-C in All Patients

The median duration between the date of PCI and the first outpatient visit was 38 (IQR 31–44) days. The LDL-C target attainment rate was significantly higher in the ILLT group than in the CT group (48.7% vs. 71.8%; P=0.001; Figure 3). The median LDL-C values in the ILLT group were significantly lower than those in the CT group (71.5 mg/dL and 57.0 mg/dL; P<0.001). The decrease in LDL-C in the ILLT group was significantly greater than in the CT group (47.8% vs. 34.9%; P=0.001). The percentage of patients taking statins at discharge was similar in both groups (96.0% vs. 97.7%; P=0.252); however, the percentage of patients taking high-dose statins was significantly higher in the ILLT group (14.2% vs. 90.9%; P<0.001; Supplementary Figure 1). The rate of patients taking ezetimibe at discharge in the ILLT group was also higher than that in the CT group (18.6% vs. 58.7%, P<0.001; Supplementary Figure 1). The adherence rate of the ILLT protocol was 57.6% in the first year (September 2019 to August 2020), but gradually increased to 80.5% in the last year (September 2021 to August 2022).

Figure 3.

Achievement rate of target low-density lipoprotein cholesterol (LDL-C; <70 mg/dL) at the first outpatient visit. The intensive lipid-lowering therapy (ILLT) group achieved the target LDL-C at 71.8%, which was significantly higher than the conventional therapy (CT) group.

Clinical Outcome

During follow up (median 988 [IQR 795–1,095] days), 55 patients had MACE during the subsequent 3-year observation period after PCI (Supplementary Table 1). The cumulative incidence of MACE was significantly lower in the ILLT group (log-rank test P=0.036; Figure 4). Multivariable Cox proportional hazard analysis revealed that the ILLT protocol was significantly associated with a lower incidence of MACE (hazard ratio 0.57 [95% confidence interval 0.34–0.97]; P=0.04; Table 2).

Figure 4.

Cumulative incidence of major adverse cardiac events (MACE) during the 3-year observation period after percutaneous coronary intervention. Patients in the intensive lipid-lowering therapy (ILLT) group showed a significantly lower incidence of cardiovascular events than those in the conventional therapy group.

Table 2.

Cox Proportional Hazard Model of Major Adverse Cardiovascular Events

	Crude HR	95% CI	P value	Adjusted HR	95% CI	P value
ILLT protocol	0.57	0.33–0.97	0.04	0.57	0.34–0.97	0.04
Age ≥75 years	1.27	0.75–2.18	0.38	0.99	0.54–1.66	0.96
Male	1.72	0.81–3.63	0.16	1.70	0.81–3.71	0.17
Hypertension	1.66	0.86–3.21	0.13	1.29	0.70–2.64	0.46
Diabetes	2.16	1.27–3.68	0.005	1.97	1.21–3.54	0.01
Chronic kidney disease	2.81	1.64–4.83	<0.001	2.81	1.60–4.86	<0.001

CI, confidence interval; ILLT, intensive lipid-lowering therapy; OR, odds ratio.

Safety Evaluations

Adverse events considered to be drug-related in this study were liver dysfunction, myopathy, rhabdomyolysis, gallbladder-related adverse events, and cancer. However, there were no significant differences in the occurrence of adverse events between the ILLT and CT groups (1.6% vs 1.3%; P=0.78; Supplementary Table 2).

Exploratory Analysis to Identify Patients Who Need More ILLT

The present study also examined a patient population in which more intensive therapy, in addition to high-dose statins and ezetimibe, may be considered to achieve an LDL-C level of <70 mg/dL. Among those in the ILLT group, 116 patients who had not taken statins or ezetimibe on admission but received both medications at discharge were further analyzed. Table 3 presents the baseline characteristics of the non-achieving (n=20) and achieving (n=96) groups. Age, sex, body mass index, and other risk factors did not differ significantly between the 2 groups. There were no significant differences in the levels of triglycerides and HDL-C, whereas LDL-C levels in the non-achieving group were significantly higher than those in the achieving group (P=0.02). Based on the ROC curve analysis, the cutoff value of LDL-C levels to predict an unachieved LDL-C target of <70 mg/dL at the first outpatient visit was 146 mg/dL (area under the curve [AUC]=0.72; Supplementary Figure 2). Multivariable analysis showed that an LDL-C level ≥146 mg/dL on admission was an independent predictor of the inability to achieve a target LDL-C level of <70 mg/dL (P=0.018; Table 4).

Table 3.

Baseline Characteristics of Patients Without Statin Treatment on Admission

	Non-achieving group (n=20)	Achieving group (n=96)	P value
Age (years)	63.5 [50–79.5]	68.5 [59.0–76.0]	0.428
Male	14 (70.0)	73 (76.0)	0.570
BMI (kg/m2)	25.0 [20.5–29.0]	24.9 [22.2–27.6]	0.844
Type of ACS
AMI	17 (85.0)	67 (69.8)	0.166
UAP	–	–
Previous PCI	0 (0)	2 (2.1)	0.515
Previous CABG	0 (0)	2 (2.1)	0.487
Previous MI	1 (5.0)	2 (2.1)	0.455
Previous stroke	2 (10.0)	3 (3.1)	0.168
Previous or current smoking	11 (55.0)	55 (57.3)	0.851
Diabetes	6 (30.0)	28 (29.2)	0.941
Hypertension	13 (65.0)	61 (63.5)	0.902
Familial hypercholesterolemia	3 (15.0)	7 (7.3)	0.264
Hemodialysis	0 (0)	2 (2.1)	0.515
eGFR (mL/min/1.73 m2)	77.5±25.3	71.8±19.3	0.350
Total cholesterol (mg/dL)	218.0 [198.0–261.0]	215.0 [194.0–234.0]	0.286
Triglycerides (mg/dL)	87.0 [33.0–156.0]	95.5 [64.0–168.0]	0.409
HDL-C (mg/dL)	42.0 [33.0–51.0]	46.5 [39.0–55.0]	0.186
LDL-C (mg/dL)	155.0 [137.0–188.0]	139.0 [126.0–156.0]	0.020
Medication for dyslipidemia
Statin	–	–
Ezetimibe	–	–
EPA	0 (0)	2 (2.1)	0.515

Data are presented as n (%), mean (SD), or median [IQR]. Abbreviations as in Table 1.

Table 4.

Multivariable Analysis

	Crude OR	95% CI	P value	Adjusted OR	95% CI	P value
Age ≥75 years	1.095	0.38–3.15	0.86	1.238	0.38–3.97	0.72
Sex, male	0.735	0.25–2.13	0.57	0.947	0.25–3.52	0.93
BMI >25 kg/m2	1.043	0.39–2.73	0.93	0.890	0.30–2.62	0.83
Smoking	0.911	0.34–2.40	0.85	1.273	0.38–4.26	0.69
LDL-C ≥146 mg/dL	3.387	1.23–9.29	0.018	4.411	1.46–13.2	0.018

Abbreviations as in Tables 1,2.

Furthermore, the analysis was conducted with the target LDL-C level set at <55 mg/dL. In the ILLT group, the rate of achieving the LDL-C target at the initial outpatient visit had decreased by 44.2%. ROC curve analysis showed that the cutoff value of baseline LDL-C levels to predict unachieved LDL-C levels <55 mg/dL at the first outpatient visit was 142 mg/dL (AUC=0.72; Supplementary Figure 2).

Discussion

This study demonstrated that ILLT with high-dose statins and ezetimibe significantly increased the rate of LDL-C target attainment at the initial outpatient visit and reduced the incidence of MACE during the subsequent 3-year observation period compared with conventional protocol in patients with ACS. The study also revealed that several patients failed to achieve their LDL-C target despite the ILLT protocol. In patients not taking statins on admission, LDL-C ≥146 mg/dL was an independent predictor of failure to achieve the LDL-C goal of <70 mg/dL.

In this study, the achievement rate of the LDL-C target of <70 mg/dL in the ILLT group was 71.8%, which is higher than in a previous study of an aggressive lipid-lowering protocol in patients with ACS.^13,17 In the CT group, patients were prescribed the maximum tolerated doses of statin and ezetimibe, whereas the initial statin dose, timing of dose-up, and addition of ezetimibe were left to the discretion of the physician. Although adherence to the ILLT protocol was not perfect, the initial dose of statins and timing of dose increases were predetermined by the ILLT protocol, which may have contributed to a higher LDL-C target attainment rate. Consistent with our findings, dual therapy with high-dose statins and ezetimibe was reported to be non-inferior in composite outcomes compared with high-dose statin monotherapy,⁹ and also demonstrated a reduction in coronary plaque volume.¹⁸

In several cases, even with adherence to the ILLT protocol, the LDL-C goal was not achieved. One approach to achieve this goal is the addition of a PCSK9 inhibitor. Musumeci et al. reported that in patients with LDL-C levels >140 mg/dL at high risk for cardiovascular events, including ACS, the addition of a PCSK9 inhibitor at discharge, in addition to dual therapy, enabled 91% of patients to achieve their LDL-C goal (LDL-C <55 mg/dL).¹⁹ If the LDL-C target level is <55 mg/dL, according to the US and European guidelines,⁴ the introduction of a PCSK9 inhibitor may become more crucial. A previous study found no significant difference in LDL-C levels between the initial outpatient visit and 1 year later,²⁰ suggesting that LDL-C levels tend to decrease at the initial outpatient visit. Therefore, it may be useful to introduce a PCSK9 inhibitor as early as possible in patients who are expected to have difficulty achieving their LDL goals with dual therapy. We previously reported that early initiation of evolocumab, a PCSK9 inhibitor, in addition to statins, resulted in a 100% achievement rate of LDL-C <70 mg/dL by 4–6 weeks after primary PCI in patients with ACS.²¹ However, in Japan, PCSK9 inhibitors are used for secondary prevention in only 36% of cases, of which only 19% are used after ACS.²²

According to the results of this study, patients with baseline LDL-C levels ≥146 mg/dL may be candidates for treatment with PCSK9 inhibitors in addition to dual therapy. In such cases, early initiation of a PCSK9 inhibitor alongside dual therapy should be considered.

This study determined the cutoff value of LDL-C on admission for predicting non-achievement of the LDL-C target to be 146 mg/dL. However, implementation of this value in clinical practice requires caution, because a previous study showed that LDL-C level at admission decreases by approximately 30% in ACS patients compared with basal concentrations.²³ Hence, the cutoff value determined in this study is only applicable to the acute phase of ACS patients and not to patients with stable coronary artery disease.

Study Limitations

This study has several limitations. First, there was a patient selection bias as the study excluded patients whose LDL-C levels could not be measured on admission and patients whose LDL-C levels could not be measured at the initial outpatient visit. Second, the sample size was small. Third, the attending physicians verified whether oral medication was administered correctly. Therefore, we cannot exclude the possibility that patients stopped taking their medications for some reason. Fourth, the maximum statin dose in Japan is lower than that in other countries, and therefore these results cannot be directly applied to patients in other countries. Fifth, this was a single-center trial and included a comparison of different enrollment periods, which could contain unanticipated confounding factors. To address this issue, a multicenter, prospective randomized study is required to validate our findings.

Conclusions

Implementation of the ILLT protocol using statins and ezetimibe proved effective in reaching the target LDL-C level and improving outcomes in patients with ACS. In patients not receiving statins on admission, an LDL-C level ≥146 mg/dL was identified as an independent predictor of failure to achieve the LDL-C goal with dual therapy. Further studies are required to explore the utilization of PCSK9 inhibitors to enhance the achievement rate for treatment of ACS.

Acknowledgments

The authors thank Editage (www.editage.jp) for English language editing.

Sources of Funding

This research received no external funding.

Disclosures

The authors declare that there are no conflicts of interest.

IRB Information

This study was approved by the Ethics Committee of Kagawa Prefectural Central Hospital (Approval no. 1192).

Data Availability

The deidentified participant data will not be shared.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circrep.CR-24-0071

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