Guideline-directed low-density lipoprotein management in high-risk ischemic stroke or transient ischemic attack admissions in China from 2015 to 2019

Introduction

Stroke is a leading cause of death and disability globally, accounting for almost 5% of all disability-adjusted life-years and 10% of all deaths worldwide (1). China has the highest incidence and lifetime risk of stroke among all countries, and the burden is still increasing (2,3). Lowering low-density lipoprotein cholesterol (LDL-C) levels is an essential measure of stroke prevention (4), as evidence from clinical trials have shown that the LDL-C-lowering therapies can reduce the risk of major vascular events (5,6). Scientific associations including the American Heart Association, American Stroke Association, American College of Cardiology, National Lipid Association, Chinese Stroke Association, European Society of Cardiology and European Atherosclerosis Society have established guidelines to reflect the importance of risk factor assessment and management, and most guidelines focus on LDL-C as the primary therapeutic target with LDL-C goals of <2.6, <1.8, or <1.4 mmol/L depending on the risk level of the population (7-12).

Despite the well-established efficacy of lipid-lowering therapy, limited data are available on guideline attainment among high-risk stroke/TIA patients, such as those with a history of cerebrovascular diseases (CeVD; stroke and TIA) and cardiovascular diseases [CVD; coronary heart disease (CHD) and myocardial infarction (MI)]. Using data from the Chinese Stroke Center Alliance (CSCA), we aimed to evaluate the proportion and determinants of patients admitted with stroke/TIA meeting LDL-C guidelines, and conduct subgroup analyses among patients with different levels of risk based on their history of CeVDs and CVDs.

We present the following article in accordance with the STROBE reporting checklist (available at https://dx.doi.org/10.21037/atm-21-1467).

Methods

Study cohort

The CSCA is a national, hospital-based, multicenter, voluntary, multifaceted intervention and continuous quality improvement initiative. This program is made available to all Chinese secondary and tertiary hospitals. Details of the CSCA Program have been published previously (13).In brief, patients were enrolled if they had a primary diagnosis of stroke/TIA and were then confirmed by brain CT or MRI. Hospitals were instructed to record data of patient demographics, medical history, medications before admission, diagnostic tests, treatment, and in-hospital outcomes. Data were collected via a web-based patient data collection and management tool, which subsequently checks for data quality to ensure that the reported data are complete and internally consistent.

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the ethics board of Beijing Tiantan Hospital (approval number: KY2018-061-02), and individual consent for this retrospective analysis was waived.

Study population

We evaluated all patients with acute ischemic stroke or TIA enrolled in the CSCA project from August 1, 2015, to July 31, 2019 for potential inclusion in our analysis. Patients with missing data on low-density lipoprotein and other relevant clinical information were excluded. We classified patients into the following groups: (I) patients with preexisting stroke/TIA (group CeVD); (II) patients with preexisting CHD/MI (group CVD); (III) patients with concomitant preexisting CVD and CeVD; and (IV) patients with no documented history of CeVD or CVD.

Management measures

The 2016 Chinese guidelines for the management of dyslipidemia in adults (11) and Chinese Stroke Association guidelines for clinical management of cerebrovascular disorders (12) recommended the same target LDL-C (<2.6 mmol/L) for patients with ischemic stroke or TIA and comorbid atherosclerosis. A lower target (<1.8 mmol/L) was recommended for high-risk patients to achieve maximal benefit. The latest guidelines for dyslipidemia management issued by the European Society of Cardiology and European Atherosclerosis Society recommended an LDL-C goal of <1.4 mmol/L for very high-risk patients (9). In this study, we first assessed the attainment of the recommended level LDL-C <2.6 mmol/L for the general stroke/TIA patient population and LDL-C <1.8 mmol/L for high-risk patients at admission. In addition, we assessed the attainment of LDL-C <1.4 mmol/L at admission and prescription of cholesterol-lowering agents at discharge.

Statistical analysis

Patients’ baseline characteristics were described using frequencies and percentages for categorical variables and means and standard deviations (SD) for continuous variables. Due to the large sample size, we did not provide P values when comparing baseline characteristics across groups. Pearson chi-squared tests were used to test differences across the four patient groups for outcome measures. Temporal trends in meeting LDL-C targets were assessed using the Cochran Armitage trend test. Multivariable logistic regression models were performed to determine the independent predictors of meeting LDL-C targets, using the generalized estimating equations approach to account for within-hospital clustering. Covariates in the multivariable analysis included patient age, sex, medical history (hypertension, diabetes, dyslipidemia, atrial fibrillation, heart failure, PVD, smoking, drinking or stroke/TIA), medication history (antiplatelets, anticoagulants, antihypertensives, antihyperglycemics, or antihyperlipidemics) and hospital characteristics (hospital grade and geographical region). Medical history was self-reported disease prior to the index hospitalization, and medication history was defined as self-reported medication used from the index hospitalization up to 6 months ago.

SAS version 9.4 (SAS Institute, Cary, NC, USA) was used for all analyses. The macro %ggBaseline was used to generate statistical tables (14). A value of P<0.05 was considered statistically significant.

Results

A total of 903,158 patients presenting with an acute stroke/TIA were initially enrolled. After excluding patients with missing data on low-density lipoprotein and other relevant clinical information, 858,509 patients were enrolled in the study (Figure 1). Of 858,509 patients with acute ischemic stroke or TIA, 251,176 (29.3%) had preexisting CeVD, 44,158 (5.1%) had preexisting CVD, 33,070 (3.9%) had both, and 530,105 (61.7%) had neither. Overall, the mean age (SD) was 66.0 (12.0) years, and 324,402 (37.8%) were women. A total of 62,094 (7.2%) of patients were TIA, whereas the remaining 796,415 (92.8%) were stroke (Table 1). The mean (SD) LDL-C was 2.76 (1.35), 2.70 (1.17), 2.70 (1.31), 2.85 (1.19) mmol/L in patients in group CeVD, CVD, both CeVD and CVD, neither CeVD nor CVD, respectively (Figure 2).

Figure 1 Study flow chart. TIA, transient ischemic attack; CSCA: the Chinese Stroke Association Alliance; CHD/MI, coronary heart disease or myocardial infarction; CeVD, cerebrovascular disease; CVD, cardiovascular disease; LDL-C, low-density lipoprotein cholesterol.

Table 1 Baseline characteristics of patients with stroke or TIA by risk-groups
Full table

Figure 2 Box-plot representing low-density lipoprotein cholesterol (LDL-C) values on admission for each disease group. CeVD, cerebrovascular disease; CVD, cardiovascular disease; and LDL-C, low-density lipoprotein cholesterol.

Characteristics

Compared with other groups, especially with patients without a history of CeVD/CVD, patients with preexisting CeVD and CVD were older, more likely to have a history of hypertension, diabetes mellitus, dyslipidemia, atrial fibrillation, heart failure or peripheral vascular disorder, and were more likely to have a medication history of antiplatelets, anticoagulants, antihypertensives, antihyperglycemics, or antihyperlipidemics (Table 1).

Management measures

Overall, 46.3% (n=397,596) met the target for LDL-C <2.6 mmol/L, 14.9% (n=128,177) for LDL-C <1.8 mmol/Land 6.4% (n=55,275) for LDL-C <1.4 mmol/L. Although 33.1% (n=83,112) of patients with preexisting CeVD were receiving antihyperlipidemics at admission, only 49.7% (n=124,927) met the LDL-C <2.6 mmol/L target, 17.9% (n=45,008) met the LDL-C <1.8 mmol/L target, and 7.9% (n=19,932) met the LDL-C <1.4 mmol/L target. Similarly, 17.6% (n=7,779) patients with preexisting CVD who were receiving antihyperlipidemics at admission, only 50.3% (n=22,193), 17.4% (n=7,676) and 7.6% (n=3,349) met the LDL-C <2.6 mmol/L, LDL-C <1.8 mmol/L and the LDL-C <1.4 mmol/L targets, respectively. Among patients with preexisting concomitant CeVD and CVD, the proportion that met the LDL-C <2.6 mmol/L, LDL-C <1.8 mmol/L and LDL-C <1.4 mmol/L targets were 52.5%, 20.7% and 9.2%, respectively. Notably, nearly 90% of patients, overall and in each group, were discharged on statins after their index hospitalization (Table 2).

Table 2 Attainment of guideline LDL-C targets by patient disease group
Full table

Temporal trends

We assessed the temporal trends in the proportion of patients meeting the LDL-C target from 2015 to 2019. Small increases over time were observed in the proportion that met the LDL-C <1.8 mmol/L target among patients with preexisting CeVD (relative increase by 11.5%, from 17.4% to 19.4%), among patients with preexisting CVD (relative increase by 27.7%, from 17.3% to 22.1%), and among patients with preexisting concomitant CeVD and CVD (relative increase by 12.3%, from 21.9% to 24.6%), but not in patients without a medical history of CeVD or CVD (Figure 3 and Table 3).

Figure 3 Temporal trend of attainment of LDL-C targets in CSCA program. (A) Trend of admission LDL-C <2.6 mmol/L from 2015 to 2019 for each disease group; (B) trend of admission LDL-C <1.8 mmol/L from 2015 to 2019 for each disease group; (C) trend of admission LDL-C <1.4 mmol/L from 2015 to 2019 for each disease group; (D) trend of discharge on statins from 2015 to 2019 for each disease group. CeVD, cerebrovascular disease; CVD, cardiovascular disease; LDL-C, low-density lipoprotein cholesterol.

Table 3 Temporal trends of attainment of guideline LDL-C targets among different risk groups
Full table

Factor associated with meeting LDL-C targets

Multivariable analysis using generalized estimating equations to account for within-hospital clustering showed that younger age, being female, having a history of hypertension or dyslipidemia, current smoking or drinking, and being admitted to hospitals located in eastern China were associated with lower odds of meeting the LDL-C goals. Atrial fibrillation, heart failure, and concomitant CeVD or CVD were associated with higher odds of achieving of LDL-C goals (Table 4).

Table 4 Factors associated with meeting different levels of LDL-C targets
Full table

Discussion

In this study of more than 850,000 patients with an acute ischemic stroke or TIA who were enrolled in CSCA, we evaluated attainment of guideline-recommended LDL-C targets in four different groups: patients with previous CeVD, CVD, both, and neither. We found that the attainment rates of guideline LDL-C targets in patients with stroke or TIA remain low. Overall, high-risk patients with concomitant preexisting CeVD and CVD were more likely to attain the LDL-C targets compared to other groups. We also identified independent factors associated with attainment to the LDL-C guidelines among high-risk patients, and found that younger age, being female, having a history of hypertension or dyslipidemia, currently smoking or drinking, and being admitted to hospitals located in eastern China were associated with lower odds of attaining the recommended LDL-C targets.

Large epidemiologic studies have shown that dyslipidemia is associated with an increased risk of unfavorable outcomes, and lower LDL-C levels are associated with lower rates of major coronary events (5,15-17).In accordance with these findings, most guidelines recommend lowering LDL-C to 2.6, 1.8 or 1.4 mmol/L, or alternatively to achieve ≥50% LDL-C reduction from baseline. Our study provides an assessment of the efficacy of real-world clinical practice on guideline-based cholesterol management in high-risk ischemic stroke patients with concomitant preexisting CeVD or CVD. We observed significant gaps between recommendations from evidence-based medicine and data from real-world clinical practice.

In our study, significant gaps were found between guideline recommendations and real-world clinical practice. Previous studies also reported significant gaps between evidence-based medicine and real-world clinical practice (18-21). For example, in DYSIS II, only 29.4% of the patients attained the LDL-C target of <1.8 mmol/L (22). In the French cohort from DYSIS II, 67.7% and 28.4% of the CHD patients attained the LDL-C targets of <2.6 and <1.8 mmol/L, respectively (23). The attainment rates to the recommended LDL-C targets in the CSCA program was lower than those in the Get-With-The-Guidelines-Stroke Registry several years ago with 51.3% for <2.6 mmol/L and 19.8% for <1.8 mmol/L (18). Encouragingly, however, temporal trend analysis showed there is an increasing trend for the attainment rates of LDL-C <2.6 mmol/L, LDL-C <1.8 mmol/L, LDL-C <1.4 mmol/L and prescription of cholesterol-lowering agents at discharge, though the increase was only marginal. One possible reason was that high-level evidence to support these guideline recommendations were not available until the release of results from the Treat Stroke to Target trial in 2020 (6).

Our study also showed that patients with history of CeVD or CVD were more likely to meet the LDL-C level recommended by the guidelines than other groups, indicating that patients with more vascular risk factors might pay more attention to their health management. Additionally, we found that patients with no history of CeVD or CVD had the lowest attainment rates. This suggests that clinicians should not overlook lipid management for low-risk populations. Consistent with previous studies (22,24-26), our results showed that patients who are younger, female, have a history of hypertension or dyslipidemia, or are currently smoking or drinking had lower odds of attaining recommended LDL-C targets. More attention should be paid to these groups to improve their lipid management.

In Preexisting CeVD group, a higher proportion of anticoagulants use than that of atrial fibrillation were observed in our study. One possible reason is that self-reported medical history of atrial fibrillation was under-reported. Another possible reason is, except for stroke patients with atrial fibrillation, stroke patients with other cardio-embolic reason (e.g., valvular heart disease, deep vein thrombosis, etc.) are recommend taking anticoagulants in clinical practice. The proportions of antihyperlipidemics use were higher than those of dyslipidemia in all groups. Two possible reasons may account for it. First, self-reported medical history of dyslipidemia was under-reported. Second, with the recognition ASCVD (atherosclerotic cardiovascular disease), patients with history of stroke/TIA or CHD/MI would be recommend taking statins for prevention of stroke recurrence, according to the Chinese Stroke Association guidelines (27).

Our study has several limitations. First, participation in CSCA was voluntary and this study did not have an elaborately designed sampling frame. The participating hospitals were more likely to be larger teaching hospitals with a strong interest in stroke care improvement. However, the large sample size and similar profile of patient characteristics to other registries may help improve the robustness and generalizability of our findings. Second, LDL-C measurements were not performed in a central core laboratory. However, this reflects real-world practice where physicians initiate or titrate therapy based on available test results. Third, the database does not contain information on prestroke cholesterol drug class or dose, and therefore we could not assess LDL-C reduction relative to baseline values. Finally, we were not able to assess post-discharge lipid-lower drugs adherence and persistence or clinical outcomes since no follow-up data were collected.

Conclusions

The proportion of patients with stroke/TIA who meet the guideline targets for LDL-C are suboptimal for the overall population and for high-risk subgroups. At the time of admission, only 1 in 6 of stroke/TIA patients met the target for LDL-C <1.8 mmol/L, and less than half met the target for LDL-C <2.6 mmol/L. Although high-risk patients with concomitant preexisting stroke/TIA and CHD/MI were more likely to attain LDL-C targets, levels are still relatively low and may require intervention to improve management.

Acknowledgments

We thank all participating hospitals, physicians and nurses, and the Chinese Stroke Center Alliance Steering Committee members.

Funding: This work was supported by grants from the Ministry of Science and Technology of the People’s Republic of China (National Key R&D Program of China, 2017YFC1310901, 2016YFC0901002, 2017YFC1307905, 2015BAI12B00), Beijing Talents Project (2018A13, 2018000021223ZK03), CAMS Innovation Fund for Medical Sciences (2019-I2M-5-029), Beijing Municipal Committee of Science and Technology (Z201100005620010), and Beijing Natural Science Foundation (Z200016).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://dx.doi.org/10.21037/atm-21-1467

Data Sharing Statement: Available at https://dx.doi.org/10.21037/atm-21-1467

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/atm-21-1467). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the ethics board of Beijing Tiantan Hospital (approval number: KY2018-061-02), and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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