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Prospective evaluation of lipid management following acute coronary syndrome in non‐Western countries

Abstract Background Half the global burden of cardiovascular disease (CVD) is concentrated in the Asia‐Pacific (APAC) region. Hypothesis Suboptimal control of low‐density lipoprotein cholesterol (LDL‐C) may play a large role in the burden of CVD in APAC and non‐Western countries. Methods The Acute Coronary Syndrome Management (ACOSYM) registry is a multinational, multicenter, prospective observational registry designed to evaluate LDL‐C control in patients within 6 months after hospitalization following an acute coronary syndrome (ACS) event across nine countries. Results Overall, 1581 patients were enrolled, of whom 1567 patients met the eligibility criteria; 80.3% of the eligible patients were men, 46.1% had ST‐elevation myocardial infarction, and 39.5% had non‐ST‐elevation myocardial infarction. Most (1245; 79.5%) patients were discharged on a high‐intensity statin. During the follow‐up, only 992 (63.3%) patients had at least one LDL‐C measurement; of these, 52.9% had persistently elevated LDL‐C (>70 mg/dl). The patients not discharged on a high‐dose statin were more likely (OR 3.2; 95% CI 2.1–4.8) to have an LDL‐C above the 70 mg/dl LDL‐C target compared with those who were discharged on a high‐dose statin. Conclusion Our real‐world registry found that a third or more of post‐ACS patients did not have a repeat LDL‐C follow‐up measurement. In those with an LDL‐C follow‐up measurement, more than half (52.9%) were not achieving a <70 mg/dl LDL‐C goal, despite a greater uptake of high‐intensity statin therapy than has been observed in recent evidence. This demonstrates the opportunity to improve post‐ACS lipid management in global community practice.


| INTRODUCTION
Cardiovascular disease (CVD) remains a major cause of death globally, resulting in 17.8 million deaths worldwide in 2017. 1 It is estimated that approximately half of the global burden of CVD is concentrated in the Asia-Pacific (APAC) region. 2 In developing countries, agespecific cardiovascular mortality rates have not decreased to the same extent as mortality rates in high-income countries. 3 Lipid-lowering therapies (LLT), including statins, are a cornerstone of secondary prevention. [3][4][5] The 2018 American guidelines recommend uptitration of LLT if low-density lipoprotein cholesterol (LDL-C) remains over 70 mg/dl, while the 2019 European guidelines use an LDL-C goal of <55 mg/dl as a class IA recommendation in secondary prevention, and an LDL-C of <40 mg/dl as a class IIb/B goal. [5][6][7] In patients not reaching their target LDL-C concentration on maximally tolerated statin therapy, both guidelines recommend adding ezetimibe and, in some subgroups, proprotein convertase subtilisin/kexin type 9 inhibitors. 8,9 Recent data have suggested that LDL-C target attainment in certain countries in Asia, Eastern Europe, and the Middle East is suboptimal, with limited information on the treatment success and characteristics of high-risk CVD patients. 10,11 The guidelines for target LDL-C in these countries vary but generally align with either the US or European guidelines. 12,13 The objective of this registry was to describe LDL-C levels follow-  After the baseline visit, registry-specific follow-up visits were scheduled at 3 and 6 months (Table S1) and could be conducted via phone or in person by the study coordinator, clinic nurse, or site investigator. In Saudi Arabia and Russia, all visits were conducted by physicians as per local laws. Patients who did not have a routinely scheduled in-person visit could be followed up via telephone visit by the investigator. Patient data collected at baseline included demographics, ACS details (including treatment prior to hospitalization due to ACS and after ACS), medical history, physical examination, laboratory measurements, and treatment patterns. Patient data recorded at subsequent visits (at 3 months, 6 months, or during an unscheduled visit) included a physical examination, and documentation of any laboratory measurements and medication changes since the prior study visit. As this was an observational registry, no study-specific labs were mandated and only those collected as part of routine clinical care were captured.
The registry began on December 12, 2017 and was completed on October 10, 2019. All patients were followed for 6 months. Enrollment was completed on March 31, 2019.
Two analysis periods were defined in this registry: the baseline period was defined as up to 14 days from the ACS admission, including the day of ACS admission, and the follow-up period as the period starting on the 15th day after ACS admission ( Figure 1). Patients within the primary objective population had at least one LDL-C value measured during the follow-up period. The first LDL-C measurement on the day of admission or within 14 days of admission was considered as the "baseline" value. All LDL-C levels measured over the follow-up period were collected and considered as follow-up value, but the last one available was used for target achievement assessment. The primary objective of the registry was to describe the proportion of post-ACS patients reaching the four LDL-C targets within 6 months: <130, <100, <70, and <50 mg/dl. For descriptive purposes, the following cutoffs were used to describe categories of LDL-C achievement: ≥160 mg/dl, ≥130 to <160 mg/dl, ≥100 to <130 mg/dl, ≥70 to <100 mg/dl, ≥50 to <70 mg/dl, and <50 mg/dl. Data on statin use was collected prior to ACS admission and at the time of discharge. High-intensity statin therapy was defined as the daily dose expected to lower LDL-C by >50% (atorvastatin ≥40 mg, rosuvastatin ≥20 mg). Moderate-intensity statin therapy was defined as the daily dose expected to lower LDL-C by 30% to <50% (atorvastatin 10 to <40 mg, rosuvastatin 5 to <20 mg, simvastatin ≥20 mg, pravastatin ≥40 mg, lovastatin 40 mg, fluvastatin XL 80 mg, fluvastatin 40 mg twice daily [bid], pitavastatin ≥2 mg), and all other statin doses were considered low-intensity. 14

| Statistical analysis
The number and percentages of patients who reached specific LDL-C ranges and a two-sided 95% confidence interval (CI) were calculated.
When sample sizes were small, the Clopper-Pearson algorithm was used for computation of the 95% CI and is based on exact binomial distribution.
Categorical variables were summarized as the number and percentage of patients in each category. Continuous variables were described using mean and SD. The count of missing observations was provided.
A logistic regression model 15 was used to describe the association between non-achievement of LDL-C <70 mg/dl and potential associated factors including demographic characteristics, lipid profile, medical history, treatments at discharge, and disease characteristics.
At first, univariate models were run on all potential associated factors (Table S2). Then, a multivariable model, based on all factors statistically significant at univariate step with p < 0.20, was implemented using a stepwise selection procedure with an entry threshold of p < 0.20 and a stay threshold of p < 0.10. Odds ratio (OR), 95% CI and corresponding p values were provided for univariate models and for each of the factors retained in the final step of the stepwise selection procedure.  and Hong Kong (n = 68). Overall, 80.3% (n = 1258) of patients were male. The mean (SD) age at baseline was 59.9 (11.6) ( Table 1).

| Overview of ethical standards
From the eligible population, 992 (63.3%) patients had at least one LDL-C value measured more than 14 days following ACS admission (primary objective population) ( Figure S2). The characteristics of those with an LDL-C measurement >14 days post-ACS were in general similar to the overall eligible population (Table 1) Table S3). The mean (SD) LDL-C value at the target achievement assessment was 77.0 (32.03) mg/dl. Following multivariable analysis, the likelihood of nonachievement of target LDL-C <70 mg/dl increased as the baseline LDL-C level increased (Table 2).
In addition to this, there was a higher likelihood of not achieving LDL-C targets in patients with no statin use or low/moderate statin potency at discharge compared with high-intensity statin at discharge (<70 mg/dl target: OR 3.2; 95% CI 2.1-4.8) (Table 2, Figure 3).
In the primary objective population (n = 992), 32.1% were on a statin prior to their ACS admission, of whom 39.3% were on a highintensity statin. At discharge, nearly all patients (96.4%) were on a statin, with information on statin intensity available for 970 patients in the primary objective population. Of these, 80.0% (n = 776) were on a high-intensity statin.
Within this population, 99.1% of patients that achieved an LDL-C of <70 mg/dl were on statins at hospital discharge, while 98.9% of patients that achieved the lower LDL-C goal of <50 mg/dl were on statins at hospital discharge. Within the primary objective population, 80.0% (n = 776) were on high-intensity statins (Table 1, Figure S4).
F I G U R E 1 Registry design and data collection. *ACS defined as any group with clinical symptoms compatible with STEMI, NSTEMI, and hospitalization with discharge diagnosis of unstable angina. BL LDL-C is the closest LDL-C value measured within 14 days of ACS admission. The LDL-C target achievement assessment was the last available value during follow-up, at least 14 days after ACS admission. Registry duration for each patient enrolled was 6 months, with patient data collected over three visits: baseline (Visit 1), 3 months (Visit 2), and 6 months (Visit 3), including additional unscheduled visits. ACS, acute coronary syndrome; BL, baseline; LDL-C, low-density lipoprotein cholesterol; NSTEMI, non-ST-elevation myocardial infarction; STEMI, ST-elevation myocardial infarction T A B L E 1 Key baseline characteristics in those patients with an LDL-C value measured more than 14 days following ACS admission (n = 992) and those without this measurement (n = 575)   (Table S4).

| DISCUSSION
The results from this prospective registry on lipid management in post-ACS patients from non-US, non-Western European countries demonstrate that a large proportion of this population is not achieving the LDL-C goal of <70 mg/dl, as recommended by most lipid management guidelines. 5,7,13 More than half (52.9%) of participants in the primary objective population did not achieve this target and almost 20% of these had an LDL-C value >100 mg/dl. An even greater number of patients (81.4%) failed to reach the more aggressive European recommendation for high-risk patients of a target LDL-C level of <50 mg/dl. 6 The low rate of LDL-C goal achievement is in line with previous data in non-Western European patients, suggesting that very-high-risk patients do not attain target goals to the same extent as moderate/  high-intensity statin therapy in the ACOSYM registry. 10 Importantly, in multivariable analysis, the only factors associated with achievement of LDL-C goal were a low LDL-C level at baseline and the use of highintensity statin at discharge. High-intensity statins may lower LDL-C by more than 50% and thus improve cardiovascular outcomes in patients with prior ACS. 5 Improving and maintaining high uptake of high-intensity statins at discharge will be critical to improving lipid control in high-risk ACS patients.

| Limitations
During this registry, it was difficult to determine from the data whether an increase or decrease in LDL-C over time was due to treat-  on high-intensity statins; however, even in patients receiving highintensity statins, only around half achieved LDL-C <70 mg/dl.
Although the benefit and use of high-intensity statins post-ACS is well supported by evidence from clinical research and international guidelines, the current results show that this therapeutic strategy is not completely adopted and optimized in real-world clinical practice in the studied countries and is still not efficacious enough in many patients to allow them to achieve LDL-C targets.

ACKNOWLEDGMENTS
The authors would like to thank the registry participants, registry staff,

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request and with permission from Sanofi. F I G U R E 3 LDL-C target achievement assessment in patients by statin intensity at discharge. LDL-C, low-density lipoprotein cholesterol