Lipid goal attainment in post‐acute coronary syndrome patients in China: Results from the 6‐month real‐world dyslipidemia international study II

Abstract Background Dyslipidemia International Study II (DYSIS II)‐China was conducted to determine the low‐density lipoprotein cholesterol (LDL‐C) goal (<1.8 mmol/L) attainment rate in patients with post‐acute coronary syndrome (ACS). Hypothesis Compliance with treatment guideline recommendations improves the LDL‐C goal attainment rate in post‐ACS patients. Methods This multicenter prospective observational study conducted at 28 tertiary hospitals determined the LDL‐C goal attainment rates at admission and 6‐month follow‐up in patients on lipid‐lowering treatment (LLT) for ≥3 months and those not on LLT (LLT‐naive or off LLT for ≥3 months) at admission. Predictors of goal attainment at 6 months were identified using multivariate logistic regression. Results The LDL‐C goal attainment rate at admission in 1102/1103 enrolled patients was 17.1%; it was 41.2% among 752 patients with available lipid results at 6 months. The distance to goal was 0.7 mmol/L at 6 months. Statin monotherapy was the most prescribed LLT. Only 7.7% of patients were receiving statin + ezetimibe and 8.4% of patients were receiving an atorvastatin‐equivalent dose of ≥40 mg/day at 6 months. Being male (odds ratio [OR] 1.7, 95% confidence interval [CI] 1.1–2.6) and undergoing percutaneous coronary intervention during index hospitalization (OR 1.5, 95% CI 1.1 to 2.1) were the independent predictors for LDL‐C goal attainment. Conclusions This real‐world DYSIS II study in China reports a low LDL‐C goal attainment rate in post‐ACS patients even after 6 months of LLT. Lack of intensification of statin therapy and underutilization of combinations suggest gaps between real‐world treatment practices and guideline recommendations.


| INTRODUCTION
Ischemic heart disease (IHD) is one of the leading causes of death in China. 1 Acute coronary syndrome (ACS) is an acute manifestation of IHD and includes ST elevation myocardial infarction (STEMI), non-ST elevation myocardial infarction (NSTEMI), and unstable angina (UA). 2 The introduction of percutaneous coronary intervention (PCI), as well as advanced antithrombotic and antiplatelet treatments, has led to a significant improvement in outcomes in patients presenting with ACS. 3 However, patients surviving ACS episodes remain at high-risk for recurrent atherothrombotic events. 4,5 The GRACE registry reported 6-month postdischarge death rates of 4.8%, 6.2%, and 3.6% for patients with STEMI, NSTEMI, and UA, respectively. 6 These mortality rates mandate the need for a rigorous and persistent monitoring with optimum long-term medical management of patients' post-ACS to improve their survival. Elevated low-density lipoprotein cholesterol (LDL-C) level is a major risk factor for the development and recurrence of ACS. 7 Lipid-lowering therapy (LLT) has been identified as a positive predictor of LDL-C goal attainment. 8,9 Statin-based LLT reduces the risk of subsequent cardiovascular (CV) events such as cause-specific mortality, and major vascular events in patients with stable coronary heart disease (CHD) or ACS. 10 Intensive LLT in ACS survivors has demonstrated improved long-term clinical outcomes in PROVE-IT 11 and IMPROVE-IT 12 studies.
The 2016 Chinese guidelines for the management of dyslipidemia in adults adopted the 2011 European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) guidelines, 13 recommending intensive lipid control with an LDL-C goal <1.8 mmol/L (<70 mg/dl) for patients with very high-risk CHD (atherosclerotic CV disease, including ACS). For people who cannot achieve this target level, a reduction in LDL-C level by at least 50% is recommended. The guidelines recommend the use of medium-intensity statins for the initial treatment of patients who present with ACS, with optimal dosetitration to achieve target lipid levels. A combination of statins with other LLT is recommended for patients who do not achieve lipid goals. 14 In 2019, ESC/EAS lowered the LDL-C goal to <1.4 mmol/L (<55 mg/dl) with an LDL-C reduction of ≥50% from baseline in very high-risk patients for secondary prevention. In case of nonachievement of the goal in 4-6 weeks, the highest tolerated statin dose and ezetimibe is recommended; a PCSK9 inhibitor is also recommended to be added. 15 There is a lack of evidence to understand the gaps between guideline recommendations and real-world long-term treatment practices for secondary prevention (post-ACS), necessitating to determine the LDL-C goal attainment rates in China. A recent cross-sectional study from a region of China based on electronic medical records from 2001 to 2018 reports a low LDL-C goal attainment (LDL-C < 1.8 mmol/L) rate of 33.8% in patients having a recent episode of ACS. 16 ESC/EAS also suggest evidence generation regarding attainment of recommended LDL-C goals among very high-risk patients in real-world practice. Thus we conducted a realworld observational dyslipidemia international study II (DYSIS II) study to assess LDL-C goal attainment in a prospective manner in a large pool of patients across multiple centers representing patients with ACS in China. We report on patterns of LLT, and LDL-C goal attainment at baseline (ACS) and at 6 months post-ACS in China. be 96 patients with an assumption of a lower one-sided precision at 6% for an estimated LDL-C goal attainment rate of 21% in the smallest subgroup of 'nonstatin users' of the study population at a 6-month follow-up. Considering approximately 10% of patients to be 'nonstatin users' in the total study population and a dropout rate of 15%, the sample size for the overall study was calculated to be 1130. Data on reason(s) for study discontinuation were also recorded during follow-up visits. The LDL-C goal of <1.8 mmol/L was considered as the cut-off for lipid control. 14 At admission, patients were categorized according to their lifetime estimated CV risk at pre-event as having very high-risk, high-risk, medium, and low risk. 14

| Statistics analysis
Point estimates (percentage) for goal attainment rate were calculated with a corresponding two-sided 95% CI at baseline (admission) and the 6-month follow-up visit by Wilson score method for all patients, LLT patients, and non-LLT patients. The differences in the point estimates (percentage) were compared between the groups using Chi-square and Wald asymptotic method for a binomial proportion.
A multivariate logistic regression model was constructed for identifying the predictors of LDL-C goal attainment.

| Patient disposition
Of the 1154 patients screened, 1103 patients were enrolled. Of the enrolled patients, those receiving some dose of LLT within 3 months of enrolment (n = 29) could not be categorized in the LLT or non-LLT group; therefore, they were only included in the all patients group. Of the remaining patients, 216 were enrolled in the LLT group and 858 in the non-LLT group. A total of 192 patients from the LLT group and 703 from the non-LLT group returned for 6-month clinic visits (median follow-up duration: 6.3 months, interquartile range 1.1) and completed study assessments. In all, 907 patients completed the study including patients who could not be categorized as LLT or non-LLT. Figure 1 describes the patient disposition.

| Baseline demographics and clinical profile
The mean age of the study population was 61.7 ± 11.3 years; about 75.0% of the patients were men. Overall, UA (53.2%) was more prevalent followed by STEMI (29.7%) and NSTEMI (17.0%).  Table 1).
As per pre-admission risk assessment, an overall 43.9% (483/1101) of patients were categorized as very high-CV risk. The majority of the LLT patients (82.9%) were at very high-risk before admission, whereas the non-LLT patients were evenly distributed among four risk levels, very high (33.0%), high (34.5%), medium (14.1%), and low (18.3%) ( Table 1). Non-LLT group: LLT-naive or off LLT for ≥3 months. *All enrolled patients also include 29 patients who had taken some dose of LLT during the 3 months prior to enrolment but could not be categorized in LLT or non-LLT groups as per protocol-specified definitions (36.0%, p = 0.137) ( Figure 2B). The mean LDL-C level at 6-month follow-up for all ACS patients was 2.1 ± 0.8 mmol/L, while for LLT and non-LLT groups, the levels were 2.2 ± 0.8 mmol/L and 2.1 ± 0.8 mmol/L, respectively. In overall patients who could not attain the LDL-C goal, the mean distance to LDL-C goal reduced from 1.1 ± 0.8 mmol/L at baseline to 0.7 ± 0.7 mmol/L at 6-month follow-up. The distance to LDL-C goal in the non-LLT group reduced from 1.2 ± 0.99 mmol/L at baseline to 0.7 ± 0.7 mmol/L at 6-month follow-up (Figure 2(C)).  F I G U R E 2 LDL-C goal attainment rates and distance to LDL-C Goal. LDL-C, low-density lipoprotein cholesterol; LLT, lipid-lowering therapy.  A cross-sectional DYSIS-China study, which reported a much higher LDL-C goal attainment rate of 61.5%, had a less stringent LDL-C goal cut-off (<2.0 mmol/L) and included non-ACS patients. 24 The 6-month LDL-C goal attainment rates observed in our study are marginally higher than the rates observed for secondary prevention cohorts of the DYSIS-China study (33.1%) 25  patients. [27][28][29] Though local clinical practice is governed by the regional guidelines, in this case, we found gaps between practice and the latest ESC/EAS guidelines recommending an LDL-C reduction of ≥50% from baseline, an LDL-C goal of <1.4 mmol/L (<55 mg/dl), monitoring at 4-6 weeks, and prescribing the highest tolerated statin dose or combinations for secondary prevention in very high-risk patients. 15 Thus, rigorous follow-ups for close monitoring carry immense value.

| Lipid-lowering therapy
The possible reasons behind this practice gap may be specific to Asian countries. Even though the efficacy of high-intensity statins in secondary prevention of adverse CV outcomes is established, a recent study in Chinese patients reported a low LDL-C goal attainment rate of 36.2% in ACS patients treated with intensive statin therapy. 30 CHILLAS study found that for ACS patients with a relatively low baseline LDL-C level receiving optimized current medication and interventional therapy, LDL-C reduction by 6.4% achieved by double-dose statins did not bring significant clinical effectiveness. 31 Moreover, a recent real-world study in Singapore found that initiation of low-, medium-, and high-intensity statins resulted in a lowering of LDL-C by similar proportions of 21.6%, 28.9%, and 25.2%, respectively, in the primary care. 32 These results may stem the belief that Asian population may respond better to low-to-moderate dose statins.
The patient and physician related factors for lower LDL-C goal attainment in a community based study in the US and CEPHEUS II study for secondary prevention were suboptimal adherence, a lower rate of high-intensity statin prescriptions, dissatisfaction with the treatment, physicians not setting the lipid goals, and guideline nonconcordance. 33

| Limitations
The study enrolled patients from tertiary hospitals; hence, the applicability of results to general clinical practice may be limited. In this study, the lipid profile was measured within 24 hours of hospital admission.
The LDL-C goal attainment rates at admission (i.e., at ACS occurrence) may not reflect the chronic LDL-C levels observed in routine clinical practice in China as LDL-C decreases during the first day post-ACS and hence should be interpreted cautiously. Adherence to LLT, an important predictor, was not systematically explored in this study.
Secondly, LDL-C goal attainment was not explored as per monotherapy and combination therapy because the number of patients receiving combination therapy was very small. Around 80.0% of patients returned for follow-up at 6 months; those who were lost to follow-up may have been less compliant with their LLT, which remains unexplored. Moreover, a 6-month follow-up may not be sufficient to provide information and estimates about the long-term lipid management in patients with ACS.

| CONCLUSIONS
This real-world study in China reports a low LDL-C goal attainment rate in patients at ACS occurrence and 6 months after discharge.
The majority of the study patients were on LLT at discharge and