Trends in low-density lipoprotein cholesterol goal achievement and changes in lipid-lowering therapy after incident atherosclerotic cardiovascular disease: Danish cohort study

Annette Kjær Ersbøll; Marie Skov Kristensen; Mads Nybo; Simone Møller Hede; Kristian Handberg Mikkelsen; Gunnar Gislason; Mogens Lytken Larsen; Anders Green

doi:10.1371/journal.pone.0286376

. 2023 May 31;18(5):e0286376. doi: 10.1371/journal.pone.0286376

Trends in low-density lipoprotein cholesterol goal achievement and changes in lipid-lowering therapy after incident atherosclerotic cardiovascular disease: Danish cohort study

Annette Kjær Ersbøll ^1,^*, Marie Skov Kristensen ¹, Mads Nybo ², Simone Møller Hede ³, Kristian Handberg Mikkelsen ⁴, Gunnar Gislason ^1,^5,^6,⁷, Mogens Lytken Larsen ⁸, Anders Green ^3,⁹

Editor: Fares Alahdab¹⁰

¹National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark

²Department of Clinical Biochemistry, Odense University Hospital, Odense, Denmark

³Institute of Applied Economics and Health Research, Copenhagen, Denmark

⁴Sanofi-Aventis Denmark A/S, Copenhagen, Denmark

⁵Department of Cardiology, The Cardiovascular Research Centre, Copenhagen University Hospital Herlev and Gentofte, Gentofte, Denmark

⁶Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen, Denmark

⁷The Danish Heart Foundation, Copenhagen, Denmark

⁸Department of Cardiology, Aalborg University, Aalborg, Denmark

⁹Steno Diabetes Center Odense, Odense University Hospital and University of Southern Denmark, Odense, Denmark

¹⁰Houston Methodist Academic Institute, UNITED STATES

Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: When this study was performed, KH Mikkelsen was an employee of Sanofi Aventis Denmark A/S A Green and SM Hede were associated with ApHER that received funding from Sanofi Aventis Denmark A/S during the conduct of the study, and they declare no other relationships or activities outside the submitted work GG declare that he has received funding from Bristol Myers Squibb, Bayer, Boehringer Ingelheim and Pfizer outside the submitted work. Page 2 All other authors declare no conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

^✉

* E-mail: ake@sdu.dk

Roles

Annette Kjær Ersbøll: Conceptualization, Data curation, Formal analysis, Project administration, Validation, Writing – original draft, Writing – review & editing

Marie Skov Kristensen: Conceptualization, Data curation, Writing – review & editing

Mads Nybo: Conceptualization, Validation, Writing – review & editing

Simone Møller Hede: Writing – review & editing

Kristian Handberg Mikkelsen: Conceptualization, Writing – review & editing

Gunnar Gislason: Conceptualization, Writing – review & editing

Mogens Lytken Larsen: Conceptualization, Writing – review & editing

Anders Green: Conceptualization, Validation, Writing – review & editing

Fares Alahdab: Editor

PMCID: PMC10231813 PMID: 37256879

Abstract

Background

We aimed to investigate trends in low-density lipoprotein cholesterol (LDL-C) goal achievement (LDL-C<1.8 mmol/L, equivalent to 70 mg/dL), initiation of lipid-lowering therapy (LLT) and changes in LLT intensity in individuals with atherosclerotic cardiovascular disease (ASCVD) at very high risk of recurrent cardiovascular disease.

Methods

A cohort study design was used including individuals with incident ASCVD and LDL-C≥1.8 mmol/L in 2010–2015. Data were obtained from national, population-based registers (patient, prescription, income, and laboratory).

Results

We included 11,997 individuals. Acute myocardial infarction, ischemic stroke and stable angina pectoris accounted for 79.6% of the qualifying ASCVD events. At inclusion, 37.2% were in LLT. Mean LDL-C before or during ASCVD hospitalization was 3.1 mmol/L (120 mg/dL). LDL-C goal achievement increased within the first two years after inclusion from 40.5% to 50.6%. LLT initiation within the first 90 days increased from 48.6% to 56.0%. Initiation of intensive LLT increased from 9.6% to 32.8%. The largest change in LLT intensity was seen in the period 180 days before to 90 days after discharge with 2.2% in 2010 to 12.1% in 2015.

Conclusion

LDL-C goal achievement within the first 2 years after inclusion increased from 40.5% in 2010 to 50.6% in 2015. LLT initiation within the first year after inclusion increased, especially for intensive LLT, although only one third initiated intensive LLT in 2015. Despite trends show improvements in LDL-C goal achievement, 49.4% of individuals at very high risk of a CV event did not achieve the LDL-C goal within 2 years after ASCVD hospitalization.

Introduction

Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of death with ischemic heart disease and stroke accounting for 27% of deaths worldwide [1–3]. Furthermore, previous ASCVD increases the risk of recurrent cardiovascular (CV) events [4, 5].

Several lines of evidence together strongly suggest that low-density lipoprotein cholesterol (LDL-C) is causal in the development of ASCVD [6]. Therefore, the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines recommended LDL-C goals<1.8 mmol/L (equivalent to 70 mg/dL) in individuals with established CV disease [7]. The 2019 revised guidelines recommend an even lower treatment goal as LDL-C<1.4 mmol/L (55 mg/dL) for individuals at very high risk or with ASCVD [8].

Effective lipid-lowering therapy (LLT) is widely available with statins being the cornerstone. Treatment efficacy is well established [9], but the statin dose is important to effectively reduce the LDL-C level and thereby the risk of ASCVD and CV events. New drugs for managing dyslipidemia have recently emerged, such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors [10, 11].

A considerable proportion of individuals with ASCVD do not achieve LDL-C<1.8 mmol/L (70 mg/dL) [12–19]. Furthermore, many individuals with an elevated LDL-C do not receive LLT doses according to guidelines [18, 20–22].

LDL-C goal achievement and LLT intensity in high-risk CV populations have improved over the last decades [23–27]. However, these studies were either performed using cross-sectional data, other high-risk populations than ASCVD, small sample sizes, limited recent data or short times series.

The aim of the study was to investigate LDL-C goal achievement and changes in LLT intensity in a population with an incident ASCVD diagnosed in 2010 to 2015 and LDL-C≥1.8 mmol/L (70 mg/dL) before or during ASCVD hospitalization.

Specifically, we examined 1) if the proportion of individuals achieving LDL-C<1.8 mmol/L (70 mg/dL) within the first two years after diagnosis increased during the study period, 2) if the proportion of individuals initiating LLT or initiating intensive LLT before or within the first year after diagnosis increased during the study period, and 3) if the proportion of individuals initiating LLT or changing towards more intensive LLT within the first year after diagnosis increased during the study period.

Materials and method

Study design and population

This population-based cohort study included individuals with a first-ever incident diagnosis of ASCVD in the study period 2010–2015. Index date was defined as date of hospitalization with a qualifying ASCVD diagnosis. ASCVD included acute myocardial infarction (AMI), ischemic stroke (IS), unstable angina pectoris (UA) together with a procedure of coronary angiography (CAG), stable angina pectoris (SA) together with a procedure of CAG or computerized tomography coronary angiography (CT-CAG), and peripheral artery disease (PAD). Furthermore, a procedure of coronary artery bypass grafting (CABG), and a procedure of percutaneous coronary intervention (PCI) qualified for ASCVD regardless of discharge diagnoses connected with the procedure. We used primary diagnoses or primary procedures recorded at a hospital except for AMI and stroke where also secondary diagnoses were included (S1 Table in S1 File for ICD-8/10 and procedure codes). In case of two or more ASCVD events at the same date, we coded ASCVD in the following order: AMI, IS, UA, SA, PAD, CABG, and PCI.

Inclusion and exclusion criteria

To be included in the study, individuals should be residents of Funen Island, Denmark, at index date. The population in the Region of Southern Denmark including Funen is a representative sample of the entire Danish population [28] regarding demographic and socioeconomic characteristics, healthcare utilization, and use of medication. Furthermore, individuals should have at least one LDL-C measurement up to 18 months before index date or during ASCVD hospitalization (i.e., index date to date of discharge).

We excluded individuals with an ASCVD diagnosis in the period 1977–2009 to ascertain truly first-ever ASCVD cases. Individuals were also excluded if the unique personal identification number was invalid, if the address was outside the Funen municipality at date of the ASCVD diagnosis, or if they died during the ASCVD hospitalization. Finally, individuals were excluded if the LDL-C measurement during ASCVD hospitalization was <1.8 mmol/L (70 mg/dL) or no LDL-C measurements were available during or before ASCVD hospitalization.

Data sources

We used national, population-based registers including the Danish National Patient Register [29], the Danish National Prescription Register [30], the Danish income registers [31] and the Laboratory databases at Odense University Hospital [32]. Individual-level linkage of data from the registers and the database was possible due to the unique personal identification number assigned to all individuals at birth or immigration and registered in the Danish Civil Registration System [33].

Low-density lipoprotein cholesterol (LDL-C)

The collection of blood samples, laboratory analyses and database storage have been described previously [20]. Briefly, blood samples collected by the general practitioner or at hospital wards were analyzed at hospital-based laboratories at Funen, Denmark. The test results were stored in a laboratory information system (BCC) administrated by Odense University Hospital. The lipid measurements included LDL-C, high-density lipoprotein cholesterol (HDL-C), total cholesterol and triglycerides. LDL-C is given as mmol/L and can be converted to mg/dL by multiplying with 38.6. LDL-C goal achievement was defined as LDL-C<1.8 mmol/L in periods after hospital admission (1–180 days, 181–356 days, 366–730 days).

Lipid-lowering therapy (LLT)

Type and intensity of LLT were defined based on prescription redemptions (S1 Table in S1 File for ATC codes) as described previously [20]. Briefly, type of LLT was defined as statins, ezetimibe, other non-statins, and combination therapies. Intensity of LLT was categorized as: no LLT, moderate LLT and intensive LLT [5, 7, 26, 34]. We defined intensive LLT by having 1) a minimum of two prescription redemptions of one combinational drug; 2) a minimum of two prescription redemptions of statins (80 mg Simvastatin, 40–80 mg Atorvastatin or 20–40 mg Rosuvastatin); 3) a minimum of two prescription redemptions of statins (all doses and types) and one ezetimibe prescription redemption; or 4) a minimum of two prescription redemptions of statins (all doses and types) and one other non-statin prescription redemption (i.e. not ezetimibe). We defined moderate LLT intensity as having LLT prescription redemption not included in the definition of intensive LLT. Initiation of LLT therapy was defined as having a prescription redemption of the above-described drugs before hospital admission (180 days before admission) and in periods after admission (admission-90 days after discharge, 91–180 days after discharge, 181–365 days after discharge). Initiation of LLT therapy later than 90 days after discharge was included to capture potentially late initiations, although clinical guidelines recommend initiation of individuals at very high risk or with ASCVD.

Follow-up and censoring

Individuals were followed for a maximum of two years with censoring at the end of the study period (2 years after discharge), at death, or if they moved out of Funen, whichever came first.

Baseline characteristics

Sociodemographic characteristics included were age (30–39, 40–49, 50–59, 60–69, 70–79, ≥80), gender, cohabitation (yes, no), ethnicity (ethnic Danes, emigrants or descendants from Western or Non-western countries), and income (quartiles). The clinical variables included were ASCVD event at index date (AMI, IS, UA+CAG, SA+CAG/CT-CAG, PAD, CABG, PCI), comorbidity (diabetes and chronic kidney disease), LLT (statins, ezetimibe, other non-statins, combination therapy, no treatment), LLT intensity (intensive, moderate, no) and lipid measurements (LDL-C, HDL-C, total cholesterol, triglycerides) (S1 Table in S1 File for ICD-8, ICD-10, procedure, and ATC codes).

Statistical analysis

We used basic descriptive statistics to present baseline characteristics of the study population, the development in LDL-C goal achievement, development in initiation of LLT therapy, and changes in LLT therapy during the study period.

We used a logistic regression model to test if the proportion of individuals achieving LDL-C goal increased during the study period. Goal achievement was a binary outcome. Similarly, we used a logistic regression model to test if a larger proportion of individuals initiated (or continued) LLT therapy after index date. LLT prescription redemption was a binary outcome. In both analyses, year of hospitalization due to the qualifying ASCVD event was included as a continuous variable to test for trend. Linearity between year of ASCVD event and log(odds) of each of the binary outcomes was evaluated visually by the parameters estimates of year as a categorical variable versus calendar year.

All analyses were performed with SAS 9.4. A 5% significance level was applied.

Supplementary analyses

In the first supplementary analysis, the treatment goal for LDL-C for individuals at very high risk or with ASCVD was reduced to 1.4 mmol/L (55 mg/mL) as recommended in the 2019 revised guidelines [8]. The descriptive analysis of development of LDL-C goal achievement in the study period was repeated with LDL-C treatment goal at 1.4 mmol/L.

The second supplementary analysis examined sociodemographic and clinical characteristics associated with initiation of LLT therapy (moderate or intensive) between admission and 90 days after discharge among individuals with no LLT therapy before admission using a logistic regression model. LLT initiation was a binary outcome. In this analysis, lipid measurements (LDL-C, HDL-C, total cholesterol (TC) and triglycerides) were included as categorical variables in three categories (lowest 25%, middle 50%, and highest 25%).

A third supplementary analysis of trends in initiation of LLT therapy was performed stratified by type of qualifying event of ASCVD (AMI and IS versus remaining diagnoses and/or procedures). This was performed to evaluate if initiation of LLT therapy varied depending on the severity of the ASCVD event.

Results

We identified a total of 39,608 individuals with a first-ever diagnosis of ASCVD in the period 1.1.1977–31.12.2015 among residents of Funen Island, Denmark. We excluded 22,647 individuals with ASCVD before the study period (before 1.1.2010), resulting in a total of 16,961 individuals with incident ASCVD in the study period 2010–2015. Among individuals who survived to discharge (15,396), 10% lack LDL-C measurements before and/or during hospitalization (S2 Table in S1 File). After exclusions for various reasons (Fig 1 and S2 Table in S1 File), the final study population comprised 11,997 individuals who were discharged alive and with an LDL-C≥1.8 mmol/L (70 mg/dL) before or during ASCVD hospitalization.

Fig 1 — CPR, unique personal identification number.

Baseline characteristics

The study population was characterized by a mean age of 68.2 years, 59.7% males, 56.0% cohabitants, and 94.5% ethnic Danes (Table 1).

Table 1. Sociodemographic and clinical baseline characteristics of individuals (N = 11,997) at date of the incident atherosclerotic cardiovascular disease (ASCVD population) stratified by low-density lipoprotein cholesterol (LDL-C) ≥1.8 mmol/L (70 mg/dL) either during or before ASCVD hospitalization given by number and percentage (N, %) if nothing else is indicated.

Percentages are given by rows, except for Total where percentages are given within the column.

	LDL-C ≥ 1.8 mmol/L (equivalent to 70 mg/dL)
	During or before ASCVD (index) hospitalization
	Total	During	Before
	N = 11,997	6537 (54.5%)	5460 (45.5%)
Qualifying ASCVD event at index date
AMI	2949 (24.6%)	2375 (80.5%)	574 (19.5%)
IS	4159 (34.7%)	3019 (72.6%)	1140 (27.4%)
UA+CAG	330 (2.8%)	171 (51.8%)	159 (48.2%)
SA+CAG/CT-CAG	2431 (20.3%)	418 (17.2%)	2013 (82.8%)
PAD	1524 (12.7%)	291 (19.1%)	1233 (80.9%)
CABG	221 (1.8%)	114 (51.6%)	107 (48.4%)
PCI	383 (3.2%)	149 (38.9%)	234 (61.1%)
Calendar year of qualifying ASCVD event
2010	2114 (17.6%)	1064 (50.3%)	1050 (49.7%)
2011	2142 (17.9%)	1107 (51.7%)	1035 (48.3%)
2012	2099 (17.5%)	1033 (49.2%)	1066 (50.8%)
2013	1935 (16.1%)	982 (50.8%)	953 (49.2%)
2014	1840 (15.3%)	1141 (62.0%)	699 (38.0%)
2015	1867 (15.6%)	1210 (64.8%)	657 (35.2%)
Age (years), mean (SD)	68.2 (13.0)	67.5 (13.7)	70.0 (12.1)
Age group (years)
<40	187 (1.6%)	143 (76.5%)	44 (23.5%)
40–49	833 (6.9%)	545 (65.4%)	288 (34.6%)
50–59	1968 (16.4%)	1131 (57.5%)	837 (42.5%)
60–69	3241 (27.0%)	1694 (52.3%)	1547 (47.7%)
70–79	3315 (27.6%)	1658 (50.0%)	1657 (50.0%)
≥80	2453 (20.5%)	1366 (55.7%)	1087 (44.3%)
Gender
Male	7157 (59.7%)	3970 (55.5%)	3187 (44.5%)
Female	4840 (40.3%)	2567 (53.0%)	2273 (47.0%)
Cohabitation
Yes	6715 (56.0%)	3626 (54.0%)	3089 (46.0%)
No	5282 (44.0%)	2911 (55.1%)	2371 (44.9%)
Ethnicity
Denmark	11,333 (94.5%)	6175 (54.5%)	5158 (45.5%)
Western	378 (3.2%)	204 (54.0%)	174 (46.0%)
Non-western	286 (2.4%)	158 (55.2%)	128 (44.8%)
Comorbidity
Diabetes mellitus	1775 (14.8%)	809 (45.6%)	966 (54.4%)
Chronic kidney disease	439 (3.7%)	193 (44.0%)	246 (56.0%)
Socioeconomic position (quartiles based on income) ^a
Q₁ (lowest 25%)	2973 (24.8%)	1614 (54.3%)	1359 (45.7%)
Q₂	2970 (24.8%)	1615 (54.4%)	1355 (45.6%)
Q₃	2949 (24.6%)	1573 (53.3%)	1376 (46.7%)
Q₄ (highest 25%)	3105 (25.9%)	1735 (55.9%)	1370 (44.1%)
Lipid lowering therapy within 180 days before ASCVD hospitalization ^b
Statins	4313 (36.0%)	1534 (35.6%)	2779 (64.4%)
Ezetimibe	74 (0.6%)	30 (40.5%)	44 (59.5%)
Other non-statins	49 (0.4%)	21 (42.9%)	28 (57.1%)
Combination therapies	28 (0.2%)	11 (39.3%)	17 (60.7%)
No treatment	7533 (62.8%)	4941 (65.6%)	2592 (34.4%)
Intensity of lipid lowering therapy within 180 days before ASCVD hospitalization
No LLT	7533 (62.8%)	4941 (65.6%)	2592 (34.4%)
Moderate LLT^c	4114 (34.3%)	1467 (35.7%)	2647 (64.3%)
Intensive LLT^d	350 (2.9%)	129 (36.9%)	221 (63.1%)
Lipid measurements within 18 months before ASCVD hospitalization^e, N (%), mean (SD)
LDL-C	9721 (81.0%),	4261 (43.8%),	5460 (56.2%),
LDL-C	3.09 (0.96)	3.19 (1.01)	3.01 (0.91)
HDL-C	9719 (81.0%),	4262 (43.9%),	5457 (56.1%),
HDL-C	1.36 (0.42)	1.36 (0.42)	1.36 (0.43)
Total cholesterol	9766 (81.4%),	4306 (44.1%),	5460 (55.9%),
Total cholesterol	5.21 (1.14)	5.31 (1.17)	5.13 (1.12)
Triglycerides	9723 (81.0%),	4263 (43.8%),	5460 (56.2%),
Triglycerides	1.75 (1.16)	1.76 (1.14)	1.75 (1.18)

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ASCVD: Atherosclerotic cardiovascular disease; AMI: Acute Myocardial Infarction; UA: Unstable angina pectoris; CAG: Coronary angiography; SA: Stable angina pectoris; PCI: Percutaneous coronary intervention; CABG: Coronary artery bypass grafting; PAD: Peripheral artery disease; IS: Ischemic stroke.

^a Socioeconomic position is derived as quartiles based on income. Quartiles are estimated for combinations of sex (male, female) and age (age<65 years, age≥65 years), for each year, separately.

^b The latest prescription of LLT redeemed is identified up to 180 days prior index date.

^c Persons who are treated with LLT, but who are not eligible for the group of “intensive treatment” or “no LLT” treatment.

^d Intensive LLT including statins with ezetimibe. To identify LLT intensity, prescription redemptions of LLT are identified up to 180 days prior index date.

^e The latest available lipid measurement is identified up to 18 months prior to index date.

AMI, IS, and SA-CAG/CT-CAG accounted together for 79.6% of the qualifying ASCVD events. A history of diabetes and chronic kidney disease at index date was observed among 14.8% and 3.7% of the study population, respectively. In total, 4464 individuals (37.2%) had redeemed at least one LLT prescription up to 180 days before ASCVD hospitalization, of which 350 (7.8%) had redeemed prescriptions of intensive LLT. Mean LDL-C during or before ASCVD hospitalization was 3.1 mmol/L (120 mg/dL). The mean HDL-C, total cholesterol and triglycerides were 1.4 mmol/L, 5.2 mmol/L and 1.8 mmol/L, respectively.

Stratified by time of LDL-C measurement (before or during ASCVD hospitalization) only minor differences were seen, except for the distribution of the qualifying ASCVD event. Among individuals with AMI and IS being the qualifying ASCVD event, 80.5% and 72.6% had an LDL-C measurement during ASCVD hospitalization, while only 17.2% and 19.1% of the individuals with SA+CAG/CT-CAG and PAD as the qualifying events had an LDL-C measurement during ASCVD hospitalization.

Development in LDL-C goal achievement (LDL-C<1.8 mmol/L)

The proportion of individuals who achieved LDL-C<1.8 mmol/L (70 mg/dL) during the first 730 days after ASCVD hospitalization increased from 40.5% in 2010 to 50.6% in 2015 (p<0.001) (Fig 2 and S3 Table in S1 File). Stratified by days after ASCVD hospitalization, the proportion of individuals who achieved LDL-C<1.8 mmol/L (70 mg/dL) within 180 days after ASCVD hospitalization increased from 13.1% in 2010 to 23.3% in 2015 (p<0.001). A small increase was also seen in the period 181–365 days after ASCVD hospitalization (5.9% in 2010 to 9.0% in 2015). No significant difference was seen in the period 366–735 days after ASCVD hospitalization.

Development in initiating LLT and initiating intensive LLT

The proportion of individuals in LLT (i.e., at least one LLT prescription redemption) before index date did not change during the study period (19.2–22.3% in LLT, p = 0.36) (Fig 3A and S4 Table in S1 File). The proportion of individuals who initiated LLT within the first 90 days after index date increased from 48.6% in 2010 to 56.0% in 2015 (p<0.001). No differences were seen in the proportion of individuals who initiated LLT 91–180 days (2.2% to 4.4% initiated LLT, p = 0.063) or 181–365 days after index date (2.0% to 3.1% initiated LLT, p = 0.78). Overall, 33.3% to 39.4% did not initiate LLT within 365 days after index date.

The proportion of individuals in intensive LLT before index date increased from 2.4% in 2010 to 3.6% in 2015 (p<0.001) (Fig 3B and S4 Table in S1 File). The proportion of individuals who initiated intensive LLT within the first 90 days after index date increased from 2.2% in 2010 to 12.6% in 2015 (p<0.001). Within 91–180 days and 181–365 days after index date, the proportion of individuals who initiated intensive LLT increased from 0.9% in 2010 to 3.6% in 2015 (p<0.001) and from 4.3% in 2010 to 17.3% in 2015 (p<0.001).

Development in changing treatment towards more intensive LLT

The largest change in LLT intensity was seen among individuals who changed from none or moderate LLT to intensive LLT (Fig 4A–4C and S5 Table in S1 File). In the period 180 days before index date to 90 days after discharge, the proportion of individuals who changed to intensive LLT increased from 2.2% among individuals with index date in 2010 to 12.1% among individuals with index date in 2015 (p<0.001). In the period 181–365 days after discharge, the proportion of individuals who changed to intensive LLT increased from 6.7% among individuals with index date in 2010 to 24.4% among individuals with index date in 2015 (p<0.001). The proportion of individuals with no changes in LLT intensity decreased during the study period in all three periods. In the period 180 days before index date to 90 days after discharge, the proportion of individuals with no changes in LLT intensity decreased from 49.0% among individuals with index date in 2010 to 42.0% among individuals with index date in 2015 (p<0.001). In the period 181–365 days after discharge, the proportion of individuals with no changes in LLT intensity decreased significantly from 71.8% among individuals with index date in 2010 to 58.0% among individuals with index date in 2015 (p<0.001).

Supplementary analyses

In the first supplementary analysis, the treatment goal for LDL-C for individuals at very high risk or with ASCVD was reduced to 1.4 mmol/L (55 mg/mL) as recommended in the 2019 revised guidelines [8]. Only 23.8–29.3% of the individuals achieved the goal within 730 days. It is further seen that LDL-C goal achievement within the first 180 days increased from 4.9% in 2010 to 9.4% in 2015 (S6 Table in S1 File).

In the second supplementary analysis, sociodemographic and clinical characteristics associated with initiation of LLT therapy (moderate or intensive) among individuals with no LLT therapy before admission was examined. Odds for initiation of LLT was highest for individuals with AMI or IS as the qualifying ASCVD event at index date (AMI: OR = 10.84 (95% CI: 9.41; 12.48); IS: OR = 8.77 (95% CI: 7.65; 10.05)), younger age (<40 years: OR = 3.95 (95% CI: 2.48; 6.28); 40–49 years: OR = 2.85 (95% CI: 2.38; 3.41); 50–59 years: OR = 1.51 (95% CI: 1.34; 1.71)), without comorbidity (not diabetes: OR = 3.12 (95% CI: 2.75; 3.53); not CKD: OR = 2.29 (95% CI: 1.78; 2.94)) and no LDL-C measurements before admission (OR = 13.17 (95% CI: 11.18; 15.51)) (S7 Table in S1 File). Odds for initiation of LLT was high for individuals with a moderate to high LDL-C measurement (LDL-C at 2.4–3.8: OR = 6.99 (95% CI: 6.13; 7.96) and LDL-C>3.8: OR = 18.38 (95% CI: 15.73; 21.46)), and with a moderate to high total cholesterol, TC (TC at 4.4–59: OR = 4.14 (95% CI: 3.69; 4.65) and TC>5.9: OR = 9.75 (95% CI: 8.50; 11.18)).

The third supplementary analysis examined trends in initiation of LLT therapy stratified by type of ASCVD event (AMI and IS versus remaining diagnoses and/or procedures). A remarkably higher proportion of individuals with AMI or IS initiated LLT therapy between admission and 90 days after discharge compared with the remaining ASCVD diagnoses (S8 Table in S1 File). Among individuals with AMI or IS, the proportion initiating LLT between admission and 90 days after discharge increased during the study period from 67.4% to 74.6%. Among individuals with other ASCVD diagnoses or procedures (SA, UA, PAD, CABG, PCI), the proportion initiating LLT between admission and 90 days after discharge also increased during the study period, however, from 23.1% to 25.0%.

Discussion

The main findings of the study are an overall improvement in LDL-C goal achievement and an increased LLT initiation for individuals with index date in 2010–2015.

LDL-C goal achievement (i.e., LDL-C<1.8 mmol/L (70 mg/dL)) within the first two years after ASCVD hospitalization increased and the largest increase was seen 1–180 days after ASCVD discharge. However, despite an improvement in LDL-C goal achievement, a large proportion of individuals did not reach the goal within 730 days after index date. In relation to the revised guidelines with treatment goal at 1.4 mmol/L, less than 10% achieved the goal within 180 days, and less than 30% within 730 days among individuals with index date in 2015.

An increase in LLT initiation during the first year after ASCVD hospitalization was seen. The largest increase was seen in initiation of intensive LLT during the study period. However, only a minor increase was seen in initiation of any LLT in the study period. No improvement in LLT initiation was seen in the period before index date. Characteristics associated with a high odds for initiation of LLT (moderate or intensive) from admission to 90 days after discharge included type of ASCVD event (AMI and IS), younger age, no comorbidities, and no LDL-C measurements before index date. In the study period, LLT initiation increased to 75% among individuals with AMI and IS, while only 25% of individuals with other ASCVD diagnoses in 2015 initiated LLT.

Some improvement was also seen in the development towards more intensive LLT within the first year after ASCVD hospitalization. An increase in individuals changing to more intensive LLT was seen in the period from before an ASCVD event to 90 days after the event, and in the period 181 to 365 day after an ASCVD event.

Comparison with other studies

Our findings are in line with previous studies showing an increased proportion of individuals with LDL-C goal achievement and LLT initiation in populations at very high risk of CV events [23–27].

Rodriguez et al. examined trends in LDL-C goal achievement and use of high-potency statins in an American population with an ASCVD diagnosis and at least one LDL-C measurement in 2004–2012 [26]. The monthly percentage of individuals achieving LDL-C<1.8 mmol/L (70 mg/dL) increased from 11.1% to 27.3% and the percentage of individuals with LLT increased from 61.4% to 70.5%. We found similarly an increased LDL-C goal achievement within the first 6 months and similar treatments patterns.

Lamprecht et al. examined trends in lipid management in a population of individuals in Colorado, USA with acute or chronic ASCVD in the period 2007–2016 [24]. The proportion of individuals achieving LDL-C goal <1.8 mmol/L (70 mg/dL) increased from 39% to 54%. This is similar to the findings in the present study. The proportion of individuals receiving LLT was stable at approximately 87% in the study in Colorado, which is a larger proportion than seen in the present study.

Fox et al. examined LDL-C goal achievement in Germans with ASCVD and at least one LDL-C measurement and in statin (moderate or intensive) therapy at inclusion in 2012–2014 [27]. The proportion of individuals achieving LDL-C goal <1.8 mmol/L (70 mg/dL) during 1-year follow-up was 19.5%. Only a limited number of individuals changed LLT during the study period. In the present study, we found a 1-year LDL-C goal achievement increasing from 18.6%to 31.8%.

Tattersall et al. and Wongsalap et al. also studied trends in LDL-C goal achievement [23, 25]. However, these studies focused on a high-risk population in 1999–2008 and a population of individuals with acute coronary disease in 2013–2017, respectively. These studies also found some improvements during the study periods.

Strengths

This population-based cohort study has several strengths including a large, representative sample of individuals with incident ASCVD at very high risk of a CV event. This limits the impact of selection bias [35], increased the precision of the parameter estimates, and ensures a high level of completeness and validity [29, 30, 33]. The data sources used in the present study (i.e., laboratory database, prescription, and patient registers) are reliable and validated with a high degree of completeness and validity [29, 30, 32]. This strengthened the validity of the study and the findings. Furthermore, we followed a cohort of individuals at individual-level up to two years after index date which enabled us to establish temporal relationships between ASCVD hospitalization, LLT initiation and LDL-C goal achievement. This is preferable compared to previous studies using repeated cross-sectional studies [23, 25]. Finally, appropriate statistical analyses were applied which also strengthened the validity of the study and the findings.

Limitations

The study also has some limitations. The health registers do not contain data that might explain the patterns identified. Thus, we had no information on reasons for a suboptimal LLT. We had no information of health behavior (such as diet and physical activity) which may influence LLT initiation and LDL-C goal achievement. However, we included information about income in the second supplementary analysis of sociodemographic and clinical characteristics associated with LLT initiation. Income (as a measure of socioeconomic status) and health behavior are to some extent correlated. The available prescription data regarding LLT are based on prescription redemption but without data on actual issuing a prescription. Data include information on date and amount of drug prescribed, but do not inform on the specific dosage to be used by the individual user. Neither do we have information about the actual consumption of drugs. Furthermore, 10% of the individuals with an incident ASCVD were excluded due to the lack of LDL-C measurements either before or during ASCVD hospitalization. In addition to individuals excluded due to the different exclusion criteria, we excluded individuals with a missing or invalid personal identification number. However, it concerned a limited number of individuals (N = 59) and is considered not to have any impact on the results. Another limitation is inclusion of lipid measurements only from a single laboratory in Denmark. Including all laboratories in Denmark would have strengthened the study and increased the generalizability of the findings. However, utilizing data from a single laboratory could also be an advantage regarding homogeneity and comparability. Finally, by identifying individuals with LLT initiation, we only used information of first prescription redemption, and longitudinal medication adherence was not tracked.

Implications

Our findings have clinical and public health implications. The ESC/EAS guidelines [8] consider individuals with the ASCVD diagnoses included in the present study to be at a very high CV risk. Furthermore, the guidelines recommend individuals at very high risk of a CV event to initiate LLT to reduce LDL-C (<1.4 mmol/L according to the 2019 guidelines). The findings in the present study indicate a need to focus on clinical practice of individuals with ASCVD to limit the risk of further CV events and mortality. A much larger proportion of individuals with UA, SA, PAD, or coronary revascularization (e.g., PCI and CABG) should initiate LLT. A focus is also needed on individuals at older age and individuals with comorbidities (CKD, DM) where only a low proportion of individuals initiates LLT.

It is recommended to replicate the study with other and larger populations to examine the generalizability of the findings. Furthermore, it is recommended to repeat the study to monitor the development and evaluate improvement in LLT initiation and LDL-C goal achievement in the ASCVD population in order to limit the risk of a CV event.

Conclusion

In a large population-based cohort study of LDL-C goal achievement and LLT initiation in individuals with incident ASCVD, the proportion achieving LDL-C<1.8 mmol/L (70 mg/dL) within the first 2 years after index date increased from 40.5% in 2010 to 50.6% in 2015. With the revised treatment goal of 1.4 mmol/L, less than 10% of the individuals with ASCVD achieved the goal with 180 days, and less than 25% within 730 days after index date. The proportion of individuals initiating LLT within the year after index date increased, especially for intensive LLT initiation, although only one third were initiating intensive LLT in 2015. Among individuals with AMI or IS, 75% initiated LLT with 90 days after index, whereas individuals with other ASCVD diagnoses or coronary revascularization only 25% initiated LLT within 90 days. Although trends show an improvement in LDL-C goal achievement, 49.4% of the individuals at very high risk of a CV event did not achieve the LDL-C goal within 2 years after ASCVD hospitalization.

Supporting information

S1 File

(PDF)

Click here for additional data file.^{(280.8KB, pdf)}

Acknowledgments

We would like to acknowledge Jan Helldén from the Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, for his contribution to extraction of laboratory data.

Ethics approval and consent to participate

The study was approved by the Danish Data Protection Agency (record number 2015-41-4130) and the Danish Health and Medicines Authority.

According to Danish law, register-based studies can be performed without consent from the subjects if the data processing takes place with the only purpose of performing statistical or scientific studies of significant public health concerns and where the processing is required to perform these studies. Before data collection, data management, and data analyses, approval was obtained from the relevant national data agencies required. The Act on Processing of Personal Data (Act No. 429 of 31 May 2000 with amendments) is the legal foundation for analyses of register-based data in Denmark [36].

Data Availability

Data cannot be shared because of data privacy regulations by Statistics Denmark. The datasets generated and analyzed during the current study are not available. The researchers have access to data at servers at Statistics Denmark. According to the regulations at Statistics Denmark, it is not allowed to extract data from the servers at Statistics Denmark. Therefore, data are not available. The Act on Processing of Personal Data is describing the regulations regarding use of individual-level data for research in Denmark. According to this Act, individual level data from Statistics Denmark are not delivered to any external firm, institution, or person. Instead, datasets and linkages between datasets are stored at Statistics Denmark. Researchers employed at specific authorised environments can establish remote online access to these datasets stored at Statistics Denmark. The researcher gets online access to the datasets. Although the researchers may get access to rather detailed individual level data, they are only allowed to publish statistical analyses and results at an aggregate level where no single person or enterprise may be identified. For security reasons, only researchers employed at authorised research institutions can get access to individual level data at Statistics Denmark. And only permanent research institutions with a responsible leader and several researchers can be authorised.

Funding Statement

This work was supported by Sanofi Aventis Denmark A/S (www.sanofi.dk) and Applied Economics and Health Research (ApHER) (appliedeconomics.dk). The paper is based on data originating from a study conducted for Applied Economics and Health Research (ApHER) as an independent research institute and funded by Sanofi Aventis Denmark A/S. The sponsor (Sanofi) was involved in the conceptualization and the final review and editing of the manuscript.

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PLoS One. doi: 10.1371/journal.pone.0286376.r001

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22 Feb 2022

PONE-D-21-35228Trends in low-density lipoprotein cholesterol goal achievement and changes in lipid-lowering therapy after incident atherosclerotic cardiovascular disease: Danish cohort study.PLOS ONE

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Reviewer #1: The authors presented data to investigate trends in LDL-C goal achievement, initiation of lipid-lowering therapy and changes in LLT intensity in a population with atherosclerotic cardiovascular disease. The topic is of interest.

The authors found that an increased proportion achieved LDL-C goal within the first 2 years after index date.

General comments:

1) While the paper is within the word limit, I feel that readability would be enhanced by being more succinct and shortening the word count.

Detailed comments:

2) Please describe the inclusion and exclusion criteria more in detail.

3) The authors consider LDL-C assays up to 18 months before the event. They do not believe this is a very large time frame for an assessment of the lipid profile? Please specify.

4) What definition of PAD did they use?

5) Dosing timepoints were different for different patients. This is an important limitation. Don't the authors think they should mention it?

6) The authors mention "other non-statins" several times. What therapies are they referring to? What is meant by "combination therapies"? Isn't ezetimibe already in combination with statins? Please specify this point.

7) The results seem to run counter to international data showing reduced adherence with respect to statin intake manifested by poor target attainment. How do the authors explain this difference?

8) There are errors in the calculation of some percentages in Table 1. Please recheck the section "Lipid lowering therapy within 180 days before ASCVD hospitalalization" and the " Intensity of lipid lowering therapy within 180 days before ASCVD hospitalization " section.

9) The authors should at least mention new therapeutic strategies that allow the ambitious new targets to be reached. Reference is made to PCSK9 inhibitors and their effects on adherence and quality of life.

(doi: 10.1056/NEJMoa1801174; 10.1056/NEJMoa1615664; 10.1016/j.phrs.2019.03.021; 10.1177/2047487319839179; 10.2459/JCM.0000000000000611)

Reviewer #2: The study analyses the proportions of high cardiovascular risk patients achieving the recommended therapeutic target for LDL-C after starting lipid-lowering therapy (LLT) following an acute cardiovascular event in a large population sample from Funen Island in Denmark.

The manuscript is overall well written and the statistical analysis is properly conducted. In addition, the study includes a very large population sample, which render the main findings of the analysis of potential clinical relevance.

Some methodological aspects, however, remain unclear to me and should be better defined. I have some comments and suggestions to propose:

#1. It would be very useful for the readers to have also the converted units (mg/dl), eventually between parentheses, for each value reported within the text. This would render the manuscript more easy to follow for those who are less confident with international units.

#2. In the abstract, instead of reporting the proportions of patients who started LLT or intensive LLT or the proportions of patients who changed LLT intensity, it would be better to have the answers to the following questions: 1) which was the proportion of patients achieving the predefined LDL-C targets for those who started LLT within 90 -180 days?; 2) which was the proportion of patients achieving the LDL-C targets for those who started intensive LLT?; 3) how many patients who changed LLT intensity had their LLT up-titrated and how many had their LLT down-titrated? There were any difference between these two groups in terms of achievement of the predefined LDL-C targets?

#3. Some recent studies can be added to support the statement reported on page 5, lines 86-88, that a large proportions of high risk individuals do not achieve the recommended therapeutic targets for LDL-C and other lipid parameters in the real world practice. For example, the following references should be added: Cardiovasc Diabetol. 2021 Jul 16;20(1):144. doi: 10.1186/s12933-021-01338-y. + Atherosclerosis 2019 Jun;285:40-48. doi: 10.1016/j.atherosclerosis.2019.03.017 + Clin Cardiol. 2021 Nov;44(11):1575-1585. doi: 10.1002/clc.23725.

#4. Which were the main reasons for not starting LLT (or intensive LLT)? On page 10, lines 206-207, it is stated that proportion of individuals who initiated LLT within the first 90 days after index (event) increased from 48.6 to 56.0%; in other words, about half of the study population did not receive any LLT therapy after acute cardiovascular events. Which were the main reasons for these missed prescriptions in very high risk individuals?

#5. In line with the previous comment, it is not clear to me why not all patients with acute cardiovascular event did not have any LLT prescribed at hospital discharge and why they should start LLT after 90-180 days or later on. Please clarify which were the clinical indications, since they are not in line with recommendations from current international guidelines.

#6. In line with comment #2, in the conclusive remarks more emphasis should be devoted to the proportions of patients achieving the recommended therapeutic targets after hospitalization for acute cardiovascular events, rather than on absolute proportions of patients starting LLT or changing LLT intensity. Given the fact that very low proportions of patients at high cardiovascular risk were treated for high cholesterol levels before the index event, it would be easy to expect a trend toward increase in LLT prescriptions after hospitalizations, mostly in the recent years.

**********

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Reviewer #1: No

Reviewer #2: No

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PLoS One. 2023 May 31;18(5):e0286376. doi: 10.1371/journal.pone.0286376.r002

Author response to Decision Letter 0

21 Jun 2022

Thank you for comments and suggestions for revision of the manuscript.

We have addresses all comments and revised the manuscript accordingly. I point-to-point revision note is uploaded with the revised manuscript with a detailed description of the changes we have made in the revised manuscript and explanations and responses to the reviewers

Attachment

Submitted filename: RevisionNote.docx

Click here for additional data file.^{(35.9KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0286376.r003

Decision Letter 1

Fares Alahdab

4 Nov 2022

PONE-D-21-35228R1Trends in low-density lipoprotein cholesterol goal achievement and changes in lipid-lowering therapy after incident atherosclerotic cardiovascular disease: Danish cohort study.PLOS ONE

Dear Dr. Ersbøll,

Thank you for resubmitting your work. We are interested in reviewing a revised version of your manuscript after addressing the comments and concerns from the reviewers below.

Please submit your revised manuscript by Dec 19 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Fares Alahdab

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: (No Response)

Reviewer #3: (No Response)

Reviewer #4: All comments have been addressed

Reviewer #5: (No Response)

Reviewer #6: All comments have been addressed

Reviewer #7: All comments have been addressed

Reviewer #8: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #2: Yes

Reviewer #3: Partly

Reviewer #4: (No Response)

Reviewer #5: Yes

Reviewer #6: Yes

Reviewer #7: Yes

Reviewer #8: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

Reviewer #3: No

Reviewer #4: (No Response)

Reviewer #5: Yes

Reviewer #6: Yes

Reviewer #7: Yes

Reviewer #8: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #2: Yes

Reviewer #3: (No Response)

Reviewer #4: (No Response)

Reviewer #5: Yes

Reviewer #6: No

Reviewer #7: Yes

Reviewer #8: No

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: (No Response)

Reviewer #5: Yes

Reviewer #6: Yes

Reviewer #7: Yes

Reviewer #8: Yes

**********

6. Review Comments to the Author

Reviewer #2: Authors addressed some of the comments proposed and modified the manuscript accordingly. Please consider specific responses to the remaining issues:

Reviewer #3: While the revised paper showed the modest changes of lipid treatment during a period time in the past, three are still some issues remained to be clarified including those suggested in the previous review.

1. Since only one population is evaluated, it is not known if this is a usual condition or region-specific condition. It is well known that many factors including the budget administration, medicare system, national/regional treatment guidelines, the specialty of the doctors for patient care, and so on may significantly impact on the real world lipid treatment. The above information and data analysis may be required to improve the background, the understanding and the potential implication of the current findings.

2. It seems all types of the patients including acute coronary syndrome, stable symptomatic CAD, and silent CAD were enrolled according to the definition of incident atherosclerotic cardiovascular disease in the current study. However, it is well known that the indication for lipid-lowering treatment especially the use of stratin could be quite different in case of acute coronary syndrome vs. stable CAD in clinical practice according to the contemporary guideline. It is critical to divide the patients according to acute coronary syndrome, stable symptomatic CAD, and silent CAD by their clinical presentation to see if there is difference in lipid lowering treatment as indicated. Hopefully such analysis may answer the questions of the reviewers and improve the understandings on the current data.

3. As mentioned by the authors, there are significant portion of the patients still without (adequate) lipid lowering treatment in the current observations. It is very important to the potential implication of the current findings. Some additional analysis may be required to see if there is difference in the patient characteristics (age, gender, and some on), disease patterns, living areas, medical resources, economic status, the specialty of the in charge doctors, and so on between patients with and those without (adequate) lipid lowering treatment. It should be helpful to improve the future lipid control in such patients.

4. Further discussion to explain and interpret at the current findings is indicated, which may be possible if the above-mentioned data and statistical analysis are available.

Reviewer #4: The authors have considered the reviewers’ suggestion and improved the paper accordingly. I’ve no further comments on it.

Reviewer #5: My major concern is that the 2019 revised guidelines recommend an even lower treatment goal (as LDL-C< 54 mg/dL) for individuals at very high risk. Thus, the results of the study may appear obsolete from this point of view. Obviously, they describe a trend that is independent from target values, but it could be very interesting to have some data on the initial and final proportion of individuals reaching this more ambitious target in this population, at least in form of supplementary table. Besides, this should be indicated as a major limitation of the study.

A procedure of coronary of angiography (CAG) is not an equivalent of ASCVD. Namely, no coronary plaques could be demonstrated. So, the inclusion of these subjects should be also indicated as a study limitation.

Minor concerns:

According to the most recent guidelines, your population should be considered at very high risk and not at high risk. This should be specified.

Definition of CKD should be specified.

In table 1, the indicated percent for total single ASCVD is relative to type of ASCVD, whereas that during or before hospitalization is relative to the proportion between these periods. This may be confounding and may be specified with a note or in the table legend. The same is valid for the other variables (calendar year, age group, and so on).

I think that the note on lipid measurements within 18 months before ASCVD hospitalization is e and not a; besides, notes b, c and e are indicated in the legend but not in the main text of the table.

In the methods, you affirm to exclude patients with a previous event in the period 197-2009; this should be clearly specified in the study flow-chart.

Discussion is clear but very synthetic; I think it may be enlarged focusing on the many study results.

Reviewer #6: This paper reports data obtained in the years 2010 to 2015. In these years, the target for LDL-C in high-risk patients, who are included into this study, was set at 1.8 mmol/L. As the authors indicate in their introduction, this target has been reduced to 1.4 mmol/L in the 2019 guideline. In the latter guidelines, an even lower target was recommended for patients who suffered from several ASCVD events within two years. This aspect has not been taken into consideration in this manuscript. Authors looked at first-ever ASCVD cases only. Lipoprotein(a) was not mentioned at all.

Data of this manuscript essentially only describe the treatment with statins and ezetimibe. The reviewer did not see numbers for the use of fibrates, bile acid sequestrants or nicotinic acid. LLT was categorized by intensity groups which have been defined by the number of prescription redemptions. Individuals were followed for a maximum of two years with censoring at the end of the study period.

The major finding of this study is that the proportion of individuals who achieved LDL-C<1.8 mmol/L (70 mg/dL) during the first 730 days after ASCVD hospitalization increased from 40.5% in 2010 to 50.6% in 2015. But unfortunately, as discussed by the authors in their responses to the comments of the previous two reviewers, no reason for this increase can be described. This is also discussed in the chapter on limitations of the study.

The scientific significance of the data given for different time periods (e g 181 – 365 days) is rather minimal.

It is astonishing to read the 10 % of the individuals with an incident ASCVD were excluded due to the lack of LDL-C measurements either before or during hospitalization.

The figures are difficult to read – color is needed to differentiate the curves.

Reviewer #7: The authors correctly responded to the reviewers' comments and corrected the errors. The manuscript has improved readability and the message is now sharper in focus and clearer.

Reviewer #8: Appreciate all of your corrections. The paper reads well. The big question ,of course, is why weren’t a higher proportion of patients able to reach a guideline recommended goal of LDL-C <1.8 mmol/L (70 mg/dl) within 2 years of a diagnosis of incident ASCVD. Hope that’s a source of further inquiry

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

Reviewer #3: No

Reviewer #4: Yes: Arrigo F.G Cicero

Reviewer #5: No

Reviewer #6: No

Reviewer #7: Yes: Lluís Masana

Reviewer #8: No

**********

PLoS One. 2023 May 31;18(5):e0286376. doi: 10.1371/journal.pone.0286376.r004

Author response to Decision Letter 1

3 Apr 2023

Dear Editor and Reviewers

Thank you very much for reviewing the manuscript, your comments and suggestions. We have addressed all comments and suggestions and revised the manuscript accordingly. We have described all changes in the document: "Revision note" included in the submission.

Attachment

Submitted filename: RevisionNoteR2.docx

Click here for additional data file.^{(33.7KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0286376.r005

Decision Letter 2

Fares Alahdab

17 Apr 2023

PONE-D-21-35228R2Trends in low-density lipoprotein cholesterol goal achievement and changes in lipid-lowering therapy after incident atherosclerotic cardiovascular disease: Danish cohort study.PLOS ONE

Dear Dr. Ersbøll,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Thank you for submitting your paper to our journal. We appreciate the effort and time you have invested in your research. After a thorough review, we believe your study has merit and potential to contribute to the field. We would like to move forward toward acceptance after one (hopefully last) round of minor edits. Below you will find a few comments raised regarding the strengths and weaknesses of the paper. We understand many of the weaknesses raised require substantial work to improve this manuscript, which makes it more suitable for future work. But we would like that you make sure those weaknesses are addressed in the current manuscript (if possible), and expressed explicitly in the Limitations section (if unable to remedy).

In order to help you improve the quality of your manuscript, we have provided detailed feedback and suggestions. We kindly ask you to consider these comments and critiques carefully as you revise your paper. Addressing these points will not only strengthen the methodology and discussion but also enhance the overall clarity, organization, and significance of your study.

Once you have made the necessary revisions, please resubmit your manuscript for further review. We look forward to receiving your revised paper and evaluating its potential for publication in our journal.

Thank you for considering our feedback, and we hope to receive your revised manuscript soon.

Please submit your revised manuscript by Jun 01 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Fares Alahdab, MD, MSc

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: (No Response)

Reviewer #2: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: (No Response)

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: (No Response)

Reviewer #2: No

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: (No Response)

Reviewer #2: Yes

**********

6. Review Comments to the Author

Reviewer #1: The authors have satisfactorily responded to the problems which I raised in my previous review.

The supplementary analyses clearly improved the quality of the manuscript.

The nature of this study based on prescription redemptions limits possible interpretations with respect to reasons for this low rate of achievement of target values for LDL-C. Physicians attitude towards the initiation of LLT cannot be evaluated in this way, but it may have had a major impact on the performance of LLT in a given patient.

Data have been gathered about 10 years ago – since that time new developments of drugs were made, ASCVD is now more in the focus of the medical community.

Reviewer #2: This is a study that examined trends in lipid-lowering therapy (LLT) and low-density lipoprotein cholesterol (LDL-C) goal achievement among individuals with incident atherosclerotic cardiovascular disease (ASCVD) in Funen Island, Denmark, between 2010 and 2015. The study found an overall improvement in LDL-C goal achievement and an increased initiation of LLT during the first year after ASCVD hospitalization, particularly in the initiation of intensive LLT. However, a large proportion of individuals did not achieve the LDL-C goal within 730 days after index date, and less than 30% of individuals achieved the revised LDL-C goal of 1.4 mmol/L within that same timeframe. The study also identified characteristics associated with higher odds for LLT initiation, including type of ASCVD event, younger age, no comorbidities, and no LDL-C measurements before index date. The study's findings were generally consistent with previous studies that examined trends in LDL-C goal achievement and LLT initiation in populations at high risk of cardiovascular events.

Study Design: The study utilized a retrospective cohort design which is appropriate for investigating the relationship between exposure and outcome in large populations. The study design enabled the researchers to establish temporal relationships between LDL-C goal achievement and LLT initiation, and ASCVD hospitalization.

Data Sources: The study utilized several sources of data including the Danish National Patient Register, the Danish National Prescription Registry, and the Danish Civil Registration System. These are reliable and validated sources of data, and their use strengthens the validity of the study.

Study Population: The study population was individuals with incident ASCVD on Funen Island, Denmark. The sample size was large (n=11,997), and the sample was representative of the general Danish population. However, the study may not be generalizable to populations outside Denmark.

Exposure and Outcome Measures: The study utilized LDL-C measurements as the primary exposure and LLT prescription redemption as a secondary exposure. The outcome measures were LDL-C goal achievement and LLT initiation. The use of these measures is consistent with current guidelines and strengthens the validity of the study.

Statistical Analysis: The statistical analysis was rigorous and appropriate. The researchers utilized multivariable logistic regression models to determine the odds of achieving LDL-C goal and initiating LLT. They also utilized Kaplan-Meier curves to determine the time to LDL-C goal achievement and LLT initiation. These methods were appropriate and strengthened the validity of the study.

Strengths: The authors describe a few legitimate strengths in their paper, here are a few more.

1. Large sample size: The study had a large sample size, which increased the precision of the estimates.

2. Use of reliable data sources: The study utilized reliable and validated data sources which strengthened the validity of the study.

3. Appropriate statistical analysis: The statistical analysis was rigorous and appropriate, which strengthened the validity of the study.

4. Temporal relationships: The study design enabled the researchers to establish temporal relationships between LDL-C goal achievement, LLT initiation, and ASCVD hospitalization.

Weaknesses: The authors describe a few legitimate limitations in their paper, here are a few more.

1. Limited generalizability: The study was conducted on Funen Island, Denmark, which may limit the generalizability of the findings to other populations.

2. Exclusion criteria: The study excluded individuals with missing data which may have resulted in a selection bias. But there is no better alternative that the authors could easily do at this point, so this was the appropriate approach to follow.

3. Limited information on lifestyle factors: The study did not include information on lifestyle factors such as diet and exercise which may have influenced LDL-C goal achievement and LLT initiation.

4. No adjustment for confounding by indication: The study did not adjust for confounding by indication, which may have influenced the estimates.

Ways for the authors to improve their paper: (mostly in future work)

1. The authors could include information on lifestyle factors such as diet and exercise to determine their influence on LDL-C goal achievement and LLT initiation.

2. The authors could adjust for confounding by indication to increase the validity of the estimates.

3. The authors could conduct the study on a larger and more diverse population to increase the generalizability of the findings.

4. The authors could consider using other measures of exposure such as total cholesterol or HDL-C to determine their influence on LDL-C goal achievement and LLT initiation.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Arrigo Francesco Giuseppe Cicero

Reviewer #2: No

**********

PLoS One. 2023 May 31;18(5):e0286376. doi: 10.1371/journal.pone.0286376.r006

Author response to Decision Letter 2

14 May 2023

A revision note has been uploaded with a point-to-point response to all comments from the reviewers including a description of changes introduced in the manuscript and supplementary material.

Attachment

Submitted filename: RevisionNoteR3.docx

Click here for additional data file.^{(25.9KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0286376.r007

Decision Letter 3

Fares Alahdab

16 May 2023

Trends in low-density lipoprotein cholesterol goal achievement and changes in lipid-lowering therapy after incident atherosclerotic cardiovascular disease: Danish cohort study.

PONE-D-21-35228R3

Dear Dr. Ersbøll,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Fares Alahdab, MD, MSc

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

PLoS One. doi: 10.1371/journal.pone.0286376.r008

Acceptance letter

Fares Alahdab

18 May 2023

PONE-D-21-35228R3

Trends in low-density lipoprotein cholesterol goal achievement and changes in lipid-lowering therapy after incident atherosclerotic cardiovascular disease: Danish cohort study.

Dear Dr. Ersbøll:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Fares Alahdab

Academic Editor

PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 File

(PDF)

Click here for additional data file.^{(280.8KB, pdf)}

Attachment

Submitted filename: RevisionNote.docx

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Attachment

Submitted filename: RevisionNoteR2.docx

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Data Availability Statement

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PERMALINK

Trends in low-density lipoprotein cholesterol goal achievement and changes in lipid-lowering therapy after incident atherosclerotic cardiovascular disease: Danish cohort study

Annette Kjær Ersbøll

Marie Skov Kristensen

Mads Nybo

Simone Møller Hede

Kristian Handberg Mikkelsen

Gunnar Gislason

Mogens Lytken Larsen

Anders Green

Roles

Abstract

Background

Methods

Results

Conclusion

Introduction

Materials and method

Study design and population

Inclusion and exclusion criteria

Data sources

Low-density lipoprotein cholesterol (LDL-C)

Lipid-lowering therapy (LLT)

Follow-up and censoring

Baseline characteristics

Statistical analysis

Supplementary analyses

Results

Baseline characteristics

Development in LDL-C goal achievement (LDL-C<1.8 mmol/L)

Development in initiating LLT and initiating intensive LLT

Fig 3.

Development in changing treatment towards more intensive LLT

Fig 4.

Supplementary analyses

Discussion

Comparison with other studies

Strengths

Limitations

Implications

Conclusion

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Arturo Cesaro

Roles

Author response to Decision Letter 0

Decision Letter 1

Fares Alahdab

Roles

Author response to Decision Letter 1

Decision Letter 2

Fares Alahdab

Roles

Author response to Decision Letter 2

Decision Letter 3

Fares Alahdab

Roles

Acceptance letter

Fares Alahdab

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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