Statin Therapy and Low-Density Lipoprotein Cholesterol Reduction after Acute Coronary Syndrome: Insights from the United Arab Emirates.

BACKGROUND AND AIMS: Attaining guideline-recommended low-density lipoprotein cholesterol (LDL-C) goals (<70 mg/dl or ≥ 50% reduction) with statin therapy remains suboptimal after an acute coronary syndrome (ACS). This study aimed to assess the level of lipid-lowering therapy (LLT) utilization and achievement of LDL-C targets after ACS hospitalization in the United Arab Emirates (UAE).
METHODS: A retrospective, observational, longitudinal database analysis of Emirati patients with ACS or stable coronary heart disease was evaluated from January 2015 to June 2018. Patients were divided based on whether or not they were treated with LLT at index hospitalization with ACS. LDL-C target level achievement was assessed according to the 2013 American College of Cardiology/American Heart Association and European Society of Cardiology/European Atherosclerosis Society guidelines.
RESULTS: A total of 3,066 patients (mean age 65.5 ± 14 years) met the inclusion criteria. Overall, 58.1% (n = 1782) of the patients in the cohort were on LLT during the ACS hospitalization. At discharge, the mean LDL-C level was 84.8 ± 39.0 mg/dl, and 28%, 21%, and 9% received high-, moderate-, and low-intensity statins, respectively. At 6 months (n = 2046; 66.7%), 27.7% and 16.7% achieved an LDL-C of <70 mg/dl and 70-100 mg/dl, respectively. The highest level of LDL-C reduction by 50% within 6 months was observed among patients using moderate-intensity statin (37.2%).
CONCLUSION: A large proportion of Emirati patients were not on LLT after ACS, and the rate of LDL-C target value attainment was extremely poor (27.7%). Optimal statin utilization by closely implementing the guidelines in the UAE is recommended. Copyright:

INTRODUCTION

Atherosclerotic cardiovascular disease (ASCVD) is a leading contributor to morbidity and mortality in both developing and developed countries.[12345] In the United Arab Emirates (UAE), cardiovascular disease (CVD) is the leading cause of death in Abu Dhabi, with 37.1% of fatalities.[6] Acute coronary syndrome (ACS) is a severe and life-threatening clinical manifestation of CVD. It is characterized by a sudden reduction in blood flow to the heart as a result of plaque rupture. Decreasing low-density lipoprotein cholesterol (LDL-C) with statins has been shown to reduce all-cause and CV-related mortality in patients with and without ASCVD.[78910] Previous studies reported that a 22% relative reduction in major CV events is achieved for each 1 mmol/L (38.7 mg/dl) reduction in LDL-C level.[111213]

The benefits of lowering LDL-C with statin therapy, particularly early after an ACS, have been established. Despite the benefits of statin therapy after an ACS event, attaining guideline-recommended LDL-C goals (<70 mg/dl or ≥50% reduction) is still suboptimal.[1415161718] Previous studies showed that less than one-third (28% women vs. 32% men) of the Arabian Gulf patients with ASCVD achieved their LDL-C targets.[16192021] However, little is known regarding the therapeutic management and achievement of guideline-recommended LDL-C goals in the UAE. The present study aimed to assess the real-world evidence of lipid-lowering therapy (LLT) utilization and achievement of LDL-C targets after ACS in the region of Abu Dhabi, UAE.

PATIENTS AND METHODS

A retrospective, observational, longitudinal database analysis of Emirati patients with ACS or with stable coronary heart disease (CHD) was conducted using data from the Cerner® electronic database. The Cerner database consisted of anonymized electronic medical records (EMRs) of patients treated under Abu Dhabi health services (SEHA) in the UAE from 49 health centers across the region of Abu Dhabi from January 1, 2015, to April 31, 2018.

Operational definitions

ACS was defined as an ST-segment elevation myocardial infarction or left bundle branch block myocardial infarction, a non-ST-segment-elevation myocardial infarction, or unstable angina

Stable CHD was defined as one or more of the following: coronary stenosis of >50% as assessed by cardiac computed tomography or coronary angiography, prior percutaneous coronary intervention or prior coronary artery bypass grafting, or history of ACS (>3 months from the index date)

Obesity was defined as the body mass index >30 kg/m2 according to the World Health Organization guidelines

Diabetes was defined as the current treatment for diabetes, a previous diagnosis of diabetes, or a fasting plasma glucose level of ≥126 mg/dl or glycated hemoglobin level of >6.5%

Hypertension was defined as the current treatment, as the previous diagnosis, or having blood pressure >140/90 mmHg

The lipid profile included measurement of serum levels of total cholesterol, high-density lipoprotein cholesterol(HDL-C), LDL-C, and triglycerides as per the local practice

LLT includes any category of statins, ezetimibe, fibrates, bile acid, and niacin

Patients on LLT treatment were considered if there was any evidence of medication coverage on or within 30 days or any recorded prescription of medication days supplied before the index hospitalization date (baseline)

Patients with no evidence for LLT over 30 days before the index date but used LLT for at least 90 days after ACS hospitalization were considered as “LLT treatment”

Patients with no evidence of a prescription for LLT on or during the 2 years before ACS hospitalization were considered as not on LLT treatment

LDL-C target level achievement was defined as <70 mg/dl, according to the 2013 American College of Cardiology/American Heart Association (ACC/AHA) and European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines.[12]

Inclusion criteria

The following inclusion criteria were used:

Adult Emirati patients discharged after an ACS event from January 2015 to April 2018

Patients were followed up at acute care centers, and ambulatory treatment of secondary prevention was considered

Patients treated with LLT at prior hospitalization and on admission for the ACS or at the time of the physician follow-up visit

Presence of ≥1 lipid profile in 2015 (the last LDL-C measurement in 2015 was considered the index date)

Evidence of at least one CV risk condition before the index hospitalization, for which statins would be recommended as per the 2013 ACC/AHA and ESC/EAS guidelines[12]

At least 3 months of follow-up from the index date with lipid parameters and LLT

Patients were identified using the International Classification of Diseases, Tenth Revision diagnosis, or procedure codes.

Data variables

Patient demographic data and clinical variables at discharge including age, gender, body mass index, and comorbidities such as hypertension, type 2 diabetes mellitus, chronic heart failure or chronic renal failure, prior myocardial infarction or angina, and chronic obstructive pulmonary disease were collected. Clinical parameters, lipid profile, and outcomes at 6 months of follow-up were collected. Patients with ACS who did not survive until discharge were excluded from the study.

Patients were divided into two subgroups based on whether or not they were treated with LLT at the baseline. The following mutually exclusive classes of LLT were considered based on the statin potency: high-, moderate-, and low-intensity statins.[1] The statins assessed were atorvastatin, rosuvastatin, simvastatin, and pravastatin. The CV health outcomes were assessed at weeks 12 and 24 after the index hospitalization. These outcomes included rehospitalization, recurrent myocardial infarction, percutaneous coronary intervention, coronary artery bypass grafting, and stroke. Any lipid profiles and LLT data available within the follow-up period were collected.

Ethical clearance

The study protocol was approved by the Abu Dhabi regional human ethics committees, and the research was performed in accordance with the Declaration of Helsinki. Patients’ informed consent was required for the retrospective study.

Statistical analysis

Categorical variables were presented as numbers and/or percentages and continuous variables as means and standard deviations. Demographic and clinical variables at baseline were initially compared between patients on LLT and those not on LLT using Chi-square or Mann–Whitney U-test. LDL-C target attainment was assessed using pre-ACS risk classification and also according to the time point (3 months and 6 months of follow-up). Lipid profiles and type of LLT used at the baseline and follow-up were assessed descriptively. Multivariate logistic regression analysis was performed to evaluate the odds ratio (OR) with 95% confidence interval (CI) to predict the patient factors associated with LDL-C goal attainment. P < 0.05 was considered statistically significant.

RESULTS

Patient characteristics

A total of 3066 Emirati adult patients were identified with documented ACS from January 2015 to June 2018. The mean (standard deviation) age of the patients with ACS was 65.5[14] years, and 64.4% were male [Table 1]. Overall, 58.1% (n = 1782) of the patients in the cohort were on LLT prior to index hospitalization with ACS, and these patients were younger compared with those not on LLT (P < 0.001). The majority of the patients not on LLT had hypertension (31.7% vs. 22.1%) or diabetes (31% vs. 22.7%). Thirty-six patients (1.2%) died during the follow-up period.

Table 1

Demographic and clinical characteristics of acute coronary syndrome cohort (n=3066)

	All patients	Patients on LLT (n=1782; 58.1%), n (%)	Patients not on LLT (n=1284; 41.8%), n (%)	P
Age (years), mean±SD	65.5±14	64.3±13.4	67.1±13.9	<0.001
Male	1976 (64.4)	1188 (38.7)	788 (25.7)	0.003
BMI	29.3±6.8	29.3±5.7	29.4±7.2	0.668
HbA1c	7.1±1.7	7.1±1.8	7.3±1.8	0.351
SBP	134.8±23.8	137.3±23.5	130.8±22.6	<0.001
DBP	73.8±14.5	76±14.4	71.8±13.9	0.001
Comorbidities
Heart rate	77.5±17.6	78.63±19	78±16.6	0.419
Hypertension	1653 (54)	680 (22.1)	973 (31.7)	0.368
Diabetes	1649 (53.7)	698 (22.7)	951 (31)	0.586
Heart failure	496 (16.1)	269 (8.77)	227 (7.4)	0.055
Chronic kidney disease	772 (23.5)	415 (13.5)	357 (11.6)	0.004
Prior angina	476 (15.5)	282 (9.2)	194 (6.3%)	0.589
COPD	76 (2.4)	40 (1.3%)	36 (1.1%)	0.326
Primary diagnosis				0.097
Acute coronary syndrome	2449 (79.8)	1449 (47.2)	1000 (32.6)	0.349
Lipid levels (mg/dl)
Total cholesterol	152.3±45.3	154.9±47.7	148.7±41.4	0.694
LDL-C	84.8±39.0	87.4±41.7	81.34±34.5	0.308
HDL-C	41.1±1.0	40.6±12.1	41.8±13.2	0.610
Triglycerides	58.1±34.4	58.9±36.6	56.9±30.9	0.319
Non-HDL-C	111.2±43.7	114.3±46.7	106.8±38.9	<0.001

P values reflect χ2 or Mann–Whitney-Wilcoxon test between values for treated and untreated patients. Statistically significant values are bolded. Data are presented as numbers and percentages and mean with standard deviations. ACS: Acute coronary syndrome, LLT: Lipid-lowering therapy, HbA1c: Glycated hemoglobin, SBP: Systolic blood pressure, DBP: Diastolic blood pressure, COPD: Chronic obstructive pulmonary disease, NSTEMI: Non-ST-elevated myocardial infarction, SD: Standard deviation, LDL-C: Low-density lipoprotein cholesterol, HDL-C: High-density lipoprotein cholesterol

Lipid profile

At discharge, the mean LDL-C level was 84.8 ± 39.0 mg/dl, with a total cholesterol of 152.3 ± 45.3 mg/dl [Table 1]. The LLT-treated patients had higher mean LDL-C level (87.4 ± 41.7 vs. 81.34 ± 34.5) and total cholesterol level (154.9 ± 47.7 vs. 148.7 ± 41.4) than the non-treated patients. In total, 58% of the patients were on LLT; 28%, 21%, and 9% received high-, moderate-, and low-intensity statins (9%), respectively [Figure 1a]. A large proportion of the patients (42%) did not have current evidence of any LLT, 32.8% had no written prescription of an LLT during the 2 years prior to the index hospitalization date, and 9.2% had a previous (but no current) LLT prescription. Among the patients using statin therapy, 41% were on atorvastatin; 15% were on simvastatin; and 2% were on rosuvastatin and pravastatin [Figure 1b].

Figure 1

(a) Lipid-lowering therapy treatment pattern. (b) Type of statins used in acute coronary syndrome patients

Low-density lipoprotein cholesterol changes after 3 months and 6 months

In the overall cohort, a higher proportion of patients with LDL-C <70 mg/dl (40.5%) or 71–100 mg/dl (31.8%) had prescribed high-intensity statins (19%) compared with the patients with LDL-C > 100 mg/dl [Table 2]. At 6 months (n = 2046; 66.7%), 27.7% and 16.7% of the patients with any LLT therapy achieved an LDL-C of <70 mg/dl and 70–100 mg/dl, respectively. In the ACS population, the highest level of LDL -C reduction by 50% within 6 months was observed among patients using moderate-intensity statin (37.2%) compared with high- and low-intensity statins (35.6% and 32.1%) [Figure 2]. Correspondingly, mean changes in lipid parameters between men and women at 3 months and 6 months are presented in Table 3. The mean reduction in LDL-C level in men was −2.4 mg/dl at 3 months and −7.1 mg/dl at 6 months. The mean reduction in LDL-C level in women was −3.3 mg/dl at 3 months and −5.2 mg/dl at 6 months.

Table 2

Low-density lipoprotein cholesterol changes after 3 months and 6 months of lipid-lowering therapy

	<70 mg/dl	71-100 mg/dl	101-159 mg/dl	151-190 mg/dl	>190 mg/dl
At discharge
High intensity	342 (11.2)	240 (7.8)	208 (6.8)	67 (2.2)	19 (0.6)
Moderate	261 (8.5)	195 (6.4)	134 (4.4)	35 (1.1)	12 (0.4)
Low	89 (2.9)	111 (3.6)	57 (1.9)	6 (0.2)	4 (0.1)
Not on LLT	551 (18)	429 (14)	240 (7.8)	57 (1.9)	7 (0.2)
After 3 months
High intensity	383 (12.5)	246 (8)	189 (6.2)	47 (1.5)	11 (0.4)
Moderate	272 (8.9)	205 (6.7)	126 (4.1)	29 (0.9)	5 (0.2)
Low	80 (2.6)	80 (2.6)	53 (1.7)	12 (0.4)	3 (0.1)
Not on LLT	394 (12.9)	394 (12.9)	253 (8.3)	52 (1.7)	13 (0.4)
At 6 months (n=2046)
High intensity	276 (13.5)	165 (8.1)	110 (5.4)	19 (0.9)	3 (0.1)
Moderate	210 (10.3)	125 (6.1)	63 (3.1)	20 (1)	1 (0.0)
Low	82 (4)	52 (2.5)	46 (2.2)	6 (0.3)	4 (0.2)
Not on LLT	415 (20.3)	243 (11.9)	172 (8.4)	25 (1.2)	7 (0.3)

LDL-C: Low-density lipoprotein cholesterol, LLT: Lipid-lowering therapy

Figure 2

Achievement of 50% reduction in low-density lipoprotein cholesterol level after 6 months in the acute coronary syndrome population

Table 3

Mean±standard deviation changes in lipid parameters

Mean changes	Baseline		Week 12		Week 24
	Male	Female	Male	Female	Male	Female
LDL-C (mg/dl)	85.2±40.1	84.3±36.8	82.8±38.2	81±37	78.1±34.8	79.1±36.4
HDL-C (mg/dl)	38.4±11.0	46±14	45.1±14.2	45.1±13.8	43.9±12.6	44.3±13.4
TC (mg/dl)	150.1±11	156±43.0	153.6±43.8	154.4±44.8	151±43	151.2±41
TG (mg/dl)	57±33.8	60±36.8	59.2±45.3	58.4±35.5	55.5±33	56.4±31
Non-HDL-C	111.6±45.3	110.3±40.9	110.5±46	109.4±47	107±44.8	106.9±43.1

LDL-C: Low-density lipoprotein cholesterol, HDL-C: High-density lipoprotein cholesterol, TC: Total cholesterol, TG: Triglyceride

Predictors of low-density lipoprotein cholesterol target attainment for patients treated with LLT

Several variables increased the likelihood of patients reaching an LDL-C level of < 70 mg/dl. Increasing age significantly increased the odds of achieving this level [Table 4]. In addition, hypertension (OR: 0.89; 95% CI: 0.754–1.050), diabetes (OR: 0.94; 95% CI: 0.810–1.090), and high-intensity statin (OR: 0.923; 95% CI: 0.749–1.136) were also associated with lower odds of LDL-C target value attainment but not statistically significant. On the other hand, being female (OR: 1.05; 95% CI: 0.90–1.22), obesity (OR: 1.00; 95% CI: 0.83–1.20), heart failure (OR: 1.04; 95% CI: 0.84–1.28), and moderate-intensity statin (OR: 1.28; 95% CI: 0.96–1.70) decreased the odds of achieving the LDL-C level of < 70 mg/dl.

Table 4

Predictors of achieving low-density lipoprotein cholesterol <70 mg/dl after 6 months of follow-up

	Reached LDL-C levels <70 mg/dl		OR (95% CI)	P
	Achieved (n=1243; 40.5%)	Not achieved (n=1823; 59.5%)
Gender
Male	809 (65.1)	1167 (64)	-	-
Female	434 (34.9)	656 (36)	1.048 (0.901-1.218)	0.544
BMI >30 (kg/m2)	310 (25)	489 (26.8)	1.001 (0.834-1.201)	0.994
Age
18-45	47 (3.8)	210 (11.5)	0.613 (0.393-0.956)	0.031
46-50	54 (4.3)	148 (8.1)	0.480 (0.321-0.719)	<0.001
51-55	89 (7.2)	191 (191)	0.327 (0.223-0.481)	<0.001
56-60	136 (10.9)	199 (10.9)	0.262 (0.189-0.364)	<0.001
>60	917 (73.8)	1075 (59)	-	-
Comorbidities
Hypertension	688 (55.3)	965 (52.9)	0.890 (0.754-1.050)	0.168
Diabetes	682 (54.9)	967 (53)	0.940 (0.810-1.090)	0.412
Heart failure	200 (16.1)	296 (16.2)	1.038 (0.840-1.282)	0.733
Chronic kidney disease	313 (25.2)	459 (25.2)	0.951 (0.776-1.165)	0.625
Prior angina	195 (15.7)	281 (15.4)	1.000 (0.818-1.222)	0.996
Statin intensity*
Not using statins	551 (44.3)	733 (40.2)	-	-
High-intensity statin	342 (27.5)	534 (29.3)	0.923 (0.749-1.136)	0.449
Moderate-intensity statin	261 (21)	376 (20.6)	1.281 (0.960-1.709)	0.092
Low-intensity statin	89 (7.2)	178 (9.8)	0.852 (0.715-1.015)	0.073

*Some patients are on statin + ezetimibe. Statistically significant values are bolded. OR: Odds ratio, CI: Confidence interval, LDL-C: Low-density lipoprotein cholesterol, BMI: Body mass index

DISCUSSION

The current study is the first to assess LLT utilization and achievement of LDL-C targets after ACS in real-world practice in Abu Dhabi using a large EMR database. We identified 3066 Emirati patients with ACS during the study period. The patients who had at least two lipid profiles within 180 days and those on/not on LLT were evaluated. The results of the study suggest two important findings. First, only 58.1% of the patients were treated with LLT. Second, only 27.7% of the patients on LLT therapy achieved a guideline-recommended LDL-C threshold.

Statin therapy has a significant role in secondary prevention by decreasing the burden of atherosclerotic plaque, the risk of adverse events, and revascularization in symptomatic patients with CAD. Compared with other studies, we observed a low percentage of Emirati patients who received LLT (58.1%) while being at high risk of CV events.[222324] Thus, it confirms that the use of statins in the UAE remains comparatively low despite the guideline recommendation worldwide. Further analysis showed that suboptimal dosing of statin prescription in secondary prevention and poor intensification of statin therapy were only moderate after ACS. In the present study, 28% of the patients received high-intensity statins and 30% received low-to-moderate-intensity statins. This result suggests a considerable discordance between the real-world practice and the guideline-recommended lipid targets in the UAE. Our results are similar to those observed in other studies[25262728] and confirm that statin treatment is an essential component for the secondary prevention of CVD.

Despite the recommendations of international guidelines for the use of high-intensity statins and the greater probability of goal achievement with increasing statin intensity, only 27.5% of the patients taking high-intensity statins achieved the LDL-C targets and 21% on moderate-intensity statins reached the very high-risk targets (70 mg/dl) in our study.

A study[29] that measured non-HDL-C levels in a Gulf population found that 73.3% had non-HDL-C levels <130 mg/dl (ESC/EAS high CV risk target: 3.3 mmol/l) and 48.6% had non-HDL-C levels <100 mg/dl (very high CV risk target: <2.6 mmol/l). Our study results are consistent with the evidence of the guideline-recommended goal achievement found in other studies.[14161922]

In the Dyslipidemia International Study II,[16] which evaluated LDL-C goal achievement in 18 countries, found that 19% and 37% of the patients with CHD and ACS treated with statins identified by the ESC/EAS guidelines achieved the <70 mg/dl LDL-C target at admission and follow-up, respectively. In the EUROASPIRE IV study, only 19.3% had an LDL-C level of <70 mg/dl despite the widespread use of LLT in this population.[30]

A study reported that a reduction of 39 mg/dl (1 mmol/dl) of LDL-C was associated with an approximate 23% reduction in CV events.[31] The results of our study suggest that many Emirati patients requiring LDL-C lowering are not receiving statin LLT. Therefore, closely implementing the guidelines in the UAE represents the best practice and would ultimately reduce the risk of CV-related events.

A multivariate regression analysis was performed to evaluate characteristics that may increase or decrease the likelihood of LDL-C target attainment in patients treated with LLT. Predictors for better LDL-C target attainment were younger age, comorbidities, and statin treatment intensity. A significant strong inverse correlation was found between age and attaining LDL-C target. With the increase in age, ACS patients were less likely to reach LDL-C level < 70 mg/dl in our study, in contrast to previous reports.[323334] Although the reason for this is not apparent, we did not reach any conclusion and suggested that additional studies are necessary to clarify these points specific to the Emirati population.

The use of combination therapy with statins and ezetimibe or proprotein convertase subtilisin/kexin type 9 inhibitors is an emerging therapeutic option that lowers LDL-C by 50%–70% and reduces CV events in patients with recent ACS to a greater degree than a statin alone.

Limitations

This study had several limitations that should be considered. This is a retrospective observational study; identifying the causes of low utilization of LLT and poor achievement of LDL-C target attainment in the UAE population is not possible. The cohort represents only the Emirati population treated under SEHA facilities in a general practice setting. Thus, caution should be taken when extrapolating the results to the general population.

Due to the retrospective nature of the study, some data were not available. Patients were selected based on the availability of lipid measurements, which might not be representative of the total UAE patients. The characteristics of medical conditions and risk factors were limited to EMR. Moreover, the population included only patients on some form of LLT, and the data were captured using prescription order in the CERNER database. Finally, the study did not include any evaluation of statin monotherapy versus statin with other LLTs. Despite these limitations, our results provided a useful overview of the current lipid management and LDL-C goal attainment in the UAE population.

CONCLUSION

A large proportion of Emirati patients were not on LLT after ACS, and the rate of LDL-C target value attainment was extremely poor. Optimal statin utilization by closely implementing the guidelines in the UAE is recommended so that patients could receive adequate LLT. Furthermore, not attaining the LDL-C goal despite statin therapy suggests that higher statin doses with proven non-statin treatments could improve lipid control and CVD outcomes. These findings suggest that there is a substantial opportunity to improve through optimization of intensity of statin therapy in the secondary prevention of ASCVD in the UAE.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.