Hypercholesterolemia Treatment Patterns and Low-Density Lipoprotein Cholesterol Monitoring in Patients with a Diagnosis of Atherosclerosis in Clinical Practice

Article Outline

• Abstract
• Methods
• Results
  • Prevalence of Atherosclerosis
  • Hypercholesterolemia Treatment Patterns
  • Lipid Monitoring and LDL Cholesterol Distribution
  • Postdiagnosis LDL Cholesterol Levels
  • Hypercholesterolemia Treatment Effectiveness: Subgroup Analysis Findings
• Summary and discussion
• Pearls for clinical guidance
• Author disclosures
• Acknowledgments
• Supplementary data
• Supplementary data
• References
• Copyright

Abstract 

Little is known about the lipid profiles and associated treatment patterns of patients in whom atherosclerosis is diagnosed. This investigation assessed and described the low-density lipoprotein (LDL) cholesterol levels and treatment patterns for hypercholesterolemia in patients with atherosclerosis who were treated in routine clinical practice. This retrospective database study used a random sample (1 million patients) from a national outpatient electronic medical record database (GE Medical Systems, Milwaukee, WI) and included patients with a diagnostic code for atherosclerosis (International Classification of Diseases [ICD]-9 code of 440.xx or 414.x or 437.x) between January 2004 and March 2006. Use of hypercholesterolemia medications at the time ICD codes for atherosclerosis were recorded and thereafter was documented. Patient demographics, comorbid conditions, baseline LDL cholesterol (closest value within 6 months of the diagnosis date), and follow-up LDL cholesterol (after diagnosis) were also documented. A total of 10,637 eligible patients had an ICD diagnostic code for atherosclerosis. Most patients (61.3%) were not taking any dyslipidemia medication at the time of and after atherosclerosis diagnosis. A total of 3% were prescribed therapy with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) before the time of atherosclerosis diagnosis, and 25% were prescribed a statin after diagnosis. Approximately 62% of patients with atherosclerosis did not have a baseline LDL cholesterol estimate. Of patients with LDL cholesterol recorded at diagnosis (n = 4,067), 24% had LDL cholesterol ≥130 mg/dL (1 mg/dL = 0.02586 mmol/L), 53% had LDL cholesterol ≥100 mg/dL, and 87% had LDL cholesterol ≥70 mg/dL. Among patients with LDL cholesterol ≥100 mg/dL at diagnosis, 57% were not prescribed statin treatment after diagnosis. Of those with baseline and postdiagnosis LDL cholesterol values (n = 1,395), 49% had baseline LDL cholesterol ≥100 mg/dL. Among patients on statin or any other hypercholesterolemia therapy after diagnosis who had baseline and follow-up LDL cholesterol values (n = 682), 87% had baseline LDL cholesterol ≥70 mg/dL and 51% had baseline LDL cholesterol ≥100 mg/dL, whereas 82% had postdiagnosis LDL cholesterol ≥70 mg/dL and 43% had postdiagnosis LDL cholesterol ≥100 mg/dL. The results from this study, which was conducted in a routine clinical practice setting, indicate the opportunities and the need for better monitoring and management of lipid levels in patients with atherosclerosis.

Keywords: Atherosclerosis, Hypercholesterolemia, Statin

Atherosclerosis is a chronic, progressive disease that is characterized by continuous accumulation of plaque within the arterial wall, which is accelerated by risk factors such as hypercholesterolemia. Systemic atherosclerosis of coronary artery disease, cerebrovascular disease, and peripheral arterial disease accounts for approximately 50% of morbidity and mortality rates in the population aged ≥50 years.¹ In the United States alone, cardiovascular disease (CVD) is responsible for >1 million deaths each year,² and it generates almost $130 billion in medical costs and lost productivity annually.³ People with symptomatic atherosclerosis are at increased risk for subsequent ischemic events, including acute myocardial infarction, stroke, and other vascular events.⁴, ⁵

One of the major risk factors for clinical atherosclerosis is hypercholesterolemia.⁶ Numerous epidemiologic studies and clinical trials have provided an in-depth understanding of the biological role of lipoproteins in the pathogenesis of atherosclerosis.⁷ The importance of reducing cholesterol levels for the prevention of cardiovascular disease has been well recognized by US and European guidelines.⁸, ⁹, ¹⁰ New evidence of the varying levels of beneficial impact of high-intensity statin therapy on atherosclerosis has been reported in recent clinical trials.¹¹, ¹², ¹³

The impact of long-term morbidity and the economic consequences of this disease emphasize the importance of optimizing current therapies in clinical practice. Little is known about the lipid profiles and associated treatment patterns of patients given a diagnosis of atherosclerosis who are treated in clinical practice. Information is needed regarding patterns of screening and treatment for hypercholesterolemia among patients with atherosclerosis. The present study determined the prevalence of diagnosed atherosclerosis in the community and characterized those patients who were being treated in the primary care setting. This investigation also assessed low-density lipoprotein (LDL) cholesterol levels and treatment patterns for hypercholesterolemia among patients diagnosed with atherosclerosis who were treated in the usual care setting rather than in a controlled clinical trial setting. A glossary of the terms used in this article is included in Table 1.

Table 1. Glossary of terms

CVD = cardiovascular disease; HDL = high-density lipoprotein; ICD-9 = International Classification of Diseases, 9th revision; IVUS = intravascular ultrasound; LDL = low-density lipoprotein; TG = triglyceride; WHO = World Health Organization.

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Methods 

This retrospective database study used a national outpatient electronic medical records (charts) database (GE Medical Systems [GEMS], Milwaukee, WI) of patients with a diagnosis of atherosclerosis who were treated in community-based physician practices. The GEMS database included >3 million patients from >60 large to mid-sized physician practices, including approximately 3,000 physicians (85% primary care) who were geographically dispersed across the United States. The electronic medical record (EMR) includes only the medical care and treatment provided within the physician's office and does not capture care provided outside the office. A random sample of 1 million patients was selected from the database, and the following inclusion criteria were applied: (1) a diagnosis of atherosclerosis (coronary or cerebral; International Classification of Diseases [ICD]-9 code of 440.x, 414.x, or 437.x [Table 2]) between January 2004 and March 2006; (2) no diagnosis of atherosclerosis (ICD-9 code of 440.x, 414.x, or 437.x) in the 12 months before the first atherosclerosis diagnosis given in the period just described; and (3) patient age ≥18 years. All eligible patients were required to have been in the EMR database for ≥12 months before their index date (date of diagnosis).

Table 2. Atherosclerosis International Classification of Diseases (ICD)-9 codes used to identify eligible patients and the number of patients with each code^⁎

So that lipid monitoring and treatment patterns could be studied, LDL cholesterol measures were selected on the basis of the date of diagnosis of atherosclerosis. The database did not record whether the lipid sample was collected in a fasting state. Baseline LDL cholesterol was defined as the LDL cholesterol measure closest to (but up to 6 months before) the date of diagnosis. Postdiagnosis LDL cholesterol was defined as the LDL cholesterol measure reported after the diagnosis date and within 12 months of diagnosis. Current therapy with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) was defined as receiving ≥1 prescription within the 4 months before atherosclerosis was diagnosed. Postdiagnosis statin therapy was defined as receiving ≥1 prescription in the 12 months after diagnosis. Hypercholesterolemia treatment included a prescription for a statin, fibric acid, a bile acid sequestrant, niacin, or ezetimibe.

The pattern of hypercholesterolemia prescribing, statin therapy alone or any hypercholesterolemia treatment, was reported. The distributions of LDL cholesterol levels at the time of diagnosis and after diagnosis were computed for the total sample, as well as for those prescribed hypercholesterolemia therapy. Categorical variables were described with the use of frequencies, and continuous variables were reported as means with standard deviations (SDs). Analyses were performed with SAS software, version 9.1 (SAS Institute Inc., Cary, NC).

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Results 

Prevalence of Atherosclerosis 

Of 1 million patients randomly sampled from the GEMS database, 49,218 had ≥1 encounter with a diagnosis of atherosclerosis between January 1996 and July 2005 (9.5 years). In all, 10,637 patients were given a new diagnosis of coronary or cerebral atherosclerosis between January 2004 and March 2006 (2.25 years). A total of 4,067 (38.2%) eligible patients who were given a diagnosis of atherosclerosis (based on ICD codes) had a baseline LDL cholesterol value recorded in the database. Patients diagnosed with atherosclerosis were older, with a mean age of 66 years (Table 3). Most patients were men (54%), 46% had hypertension, and 28% had diabetes mellitus. Approximately 85% of patients were given an ICD code for coronary atherosclerosis, and 5% were given a code for cerebral atherosclerosis. Patients with a baseline LDL cholesterol value were similar to the total population of patients with atherosclerosis (Table 3).

Table 3. Characteristics of patients with a diagnosis of atherosclerosis between January 2004 and March 2006

Characteristics	Total Atherosclerosis Population (N = 10,637)	Patients with Atherosclerosis with Baseline LDL cholesterol (n = 4,067)
Age (yr), mean ± SD	65.9±11.4	69.0±11.4
Male (%)	54	59
Smoker (%)	8	8
Hypertension (%)	46	41
Diabetes mellitus (%)	28	27
Coronary atherosclerosis (%)	85	85
Cerebral atherosclerosis (%)	5	6

LDL = low-density lipoprotein.

Hypercholesterolemia Treatment Patterns 

Among all eligible patients in whom atherosclerosis was diagnosed (n = 10,637), 61% were not currently receiving any hypercholesterolemia therapy at the time of diagnosis or within the 12 months after diagnosis (Figure 1). A similarly high proportion (56%) of patients with recorded baseline LDL cholesterol were not currently receiving hypercholesterolemia therapy within 4 months before and 12 months after their diagnosis. Fewer than 5% of patients were currently receiving hypercholesterolemia therapy at the time of diagnosis but not after diagnosis, and 25% began hypercholesterolemia treatment after their condition had been diagnosed (Figure 1). A similar pattern of limited therapy was observed when only statin therapy prescriptions were tabulated. Of all eligible patients in whom atherosclerosis was diagnosed (n = 10,637), 64% were not currently receiving any statin therapy at the time of diagnosis or within the first 12 months after diagnosis; 24% of patients began statin treatment after atherosclerosis diagnosis.

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• Figure 1. 

  Hypercholesterolemia therapy patterns in patients with International Classification of Diseases (ICD) code for atherosclerosis. LDL-C = low-density lipoprotein cholesterol.

Lipid Monitoring and LDL Cholesterol Distribution 

Most patients (62%) with a diagnosis of atherosclerosis did not have an LDL cholesterol measurement taken around (up to 6 months before) the time of their diagnosis. For those with LDL cholesterol measurements, mean (± SD) LDL cholesterol at the time of diagnosis was 108.9 ± 41.4 mg/dL, and mean total cholesterol was 182.5 ± 43.8 mg/dL (1 mg/dL = 0.02586 mmol/L). Mean high-density lipoprotein (HDL) cholesterol for patients with diagnosed atherosclerosis was 49.1 ± 15.3 mg/dL, and mean triglycerides (TGs) were 147.9 ± 110.3 mg/dL (1 mg/dL = 0.01129 mmol/L). The proportion of patients with LDL cholesterol <100 mg/dL at baseline was 46.8%, and 12.7% of patients had LDL cholesterol <70 mg/dL (Figure 2).

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• Figure 2. 

  Distribution of low-density lipoprotein cholesterol (LDL-C) at the time of diagnosis for patients with an International Classification of Diseases (ICD) code for atherosclerosis and a baseline LDL-C measurement (n = 4,067).

Patients with diagnosed atherosclerosis whose baseline LDL cholesterol was <100 mg/dL had hypercholesterolemia treatment patterns that were similar to those of patients whose baseline LDL cholesterol was ≥100 mg/dL (Figure 3). Only 15% of patients with baseline LDL cholesterol ≥100 mg/dL were currently receiving hypercholesterolemia therapy both at diagnosis and within the 12 months after diagnosis. Statin therapy utilization was similarly low, with 63% of patients with baseline LDL cholesterol <100 mg/dL and 57% of patients with LDL cholesterol ≥100 mg/dL not currently receiving a statin at the time of diagnosis or after diagnosis. A similar proportion of patients began statin therapy after diagnosis (21% for those with LDL cholesterol <100 mg/dL and 24% for those with LDL cholesterol ≥100 mg/dL). A total of 13% of patients with baseline LDL cholesterol <100 mg/dL and 14.5% of those with baseline LDL cholesterol ≥100 mg/dL were on statin therapy at diagnosis and after diagnosis.

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• Figure 3. 

  Hypercholesterolemia therapy (fibric acid, bile acid sequestrant, niacin, statin, ezetimibe, or combination therapy) patterns stratified by baseline low-density lipoprotein cholesterol (LDL-C) in patients given a diagnosis of atherosclerosis.

Treatment patterns based on the optional LDL cholesterol goal of <70 mg/dL for intensive management of hypercholesterolemia were similar for those with a baseline LDL cholesterol <70 mg/dL, a baseline LDL cholesterol ≥70 mg/dL, and LDL cholesterol <100 mg/dL. Overall, 58% of patients with baseline LDL cholesterol <70 mg/dL were not currently receiving hypercholesterolemia therapy at the time of diagnosis or after diagnosis compared with 55% of patients with baseline LDL cholesterol ≥70 mg/dL. Only 15% of patients with baseline LDL cholesterol ≥70 mg/dL were currently receiving hypercholesterolemia therapy both at diagnosis and within 12 months after diagnosis. A total of 63% of patients with baseline LDL cholesterol <70 mg/dL and 59% of patients with LDL cholesterol ≥70 mg/dL were not currently receiving a statin at the time of diagnosis or after diagnosis. Only 14% of patients with baseline LDL cholesterol ≥70 mg/dL were currently receiving a statin at diagnosis and within 12 months after diagnosis.

Postdiagnosis LDL Cholesterol Levels 

Of the 4,067 patients with a baseline LDL cholesterol measure, 1,395 (34.3%) had an LDL cholesterol measure after diagnosis. Of patients with baseline and postdiagnosis LDL cholesterol values, 682 (48.9%) were prescribed hypercholesterolemia therapy; 622 (44.6%) were prescribed a statin only. Among patients on hypercholesterolemia therapy, LDL cholesterol levels in the 12 months after diagnosis of atherosclerosis were similar to levels at the time of diagnosis (Figure 4). A similar pattern was observed for patients on statin therapy only; 50.8% of patients had baseline LDL cholesterol ≥100 mg/dL, and 42.2% had postdiagnosis LDL cholesterol ≥100 mg/dL. Of patients with baseline LDL cholesterol ≥100 mg/dL who were prescribed hypercholesterolemia therapy after diagnosis, 63.7% still had a postdiagnosis LDL cholesterol ≥100 mg/dL.

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• Figure 4. 

  Distribution of baseline and postdiagnosis low-density lipoprotein cholesterol (LDL-C) values for patients given a diagnosis of atherosclerosis (International Classification of Diseases [ICD] code) and prescribed hypercholesterolemia therapy (fibric acid, bile acid sequestrant, niacin, statin, ezetimibe, or combination therapy).

Hypercholesterolemia Treatment Effectiveness: Subgroup Analysis Findings 

In a subgroup analysis, patients from the random sample of 1 million patients in whom atherosclerosis was diagnosed were combined with patients with a new diagnosis of atherosclerosis who had been selected from all patients in the entire GEMS database who were prescribed any statin. Only those statin users who began statin therapy after the time of diagnosis were included in the combined sample. The final combined sample of patients with a new atherosclerosis diagnosis was restricted to those who had baseline and postdiagnosis LDL cholesterol measures. Thus, the 1,395 patients diagnosed with atherosclerosis with baseline and postdiagnosis LDL cholesterol measures from the random patient sample were combined with 2,714 patients with a new diagnosis of atherosclerosis among all statin therapy users in the GEMS database, to ascertain the effectiveness of hypercholesterolemia therapy. For this subgroup analysis, a post–therapy initiation LDL cholesterol measure was defined as the LDL cholesterol value that occurred after the statin therapy start date. A total of 4,109 patients had been given a diagnosis of atherosclerosis and had baseline and post–statin initiation LDL cholesterol measures. Mean (± SD) baseline LDL cholesterol was 108.2 ± 42.9 mg/dL, and mean post-statin LDL cholesterol was 90.2 ± 29.1 mg/dL; mean percent LDL cholesterol reduction was 10.3%. Average LDL cholesterol reduction was greater among patients with baseline LDL cholesterol ≥100 mg/dL (24.4%).

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Summary and discussion 

Patients in whom atherosclerosis was diagnosed on the basis of ICD diagnostic codes were not optimally treated at the time these codes were first recorded in this large electronic medical record database, nor within the following 12 months. Most patients did not have their lipid profiles recorded during the 6 months before ICD codes for atherosclerosis were first recorded. Also, only one-third of patients with a baseline LDL cholesterol level had follow-up lipid profiles within 12 months after the diagnosis of atherosclerosis was recorded. More than 60% of patients were not currently receiving hypercholesterolemia treatment at diagnosis or after diagnosis, regardless of their baseline LDL cholesterol levels. These low rates of treatment were observed even when most patients had LDL cholesterol ≥100 mg/dL at the time of diagnosis. Hypercholesterolemia and statin-only therapy patterns were remarkably similar for patients with baseline LDL cholesterol ≥100 mg/dL and for those with LDL cholesterol <100 mg/dL. Furthermore, among patients receiving hypercholesterolemia therapy, postdiagnosis LDL cholesterol levels did not reflect optimal lipid control.

These findings from routine clinical practice highlight the need for more aggressive management of at-risk patients who have been given a diagnosis of atherosclerosis. Emphasis should be placed on routine lipid monitoring and hypercholesterolemia treatment as mainstays of the therapeutic approach for patients with atherosclerosis. Consistent with current study findings, earlier studies reported undertreatment and suboptimal LDL cholesterol goal attainment rates.¹⁴, ¹⁵ A multicenter survey, the Lipid Treatment Assessment Project (L-TAP), was conducted to assess treatment patterns and LDL cholesterol goal achievement among patients with hypercholesterolemia,¹⁴ rather than in those given a diagnosis of atherosclerosis, as was done in this study. L-TAP findings indicate that overall, only 38% of patients and 18% of those with coronary heart disease (CHD) attained National Cholesterol Education Program (NCEP)-specified LDL cholesterol target levels, and many patients treated with lipid-lowering therapy did not achieve LDL cholesterol target levels.¹⁴ The NCEP Evaluation Project Utilizing Novel E-technology (NEPTUNE) II, the first survey to assess treatment success under NCEP Adult Treatment Panel (ATP) III guidelines in 2003, showed higher frequencies of LDL cholesterol goal achievement than were seen in L-TAP, but patients with non-CHD clinical atherosclerosis still exhibited low goal success rates (40% achieved goal).¹⁵ NEPTUNE II also highlighted the large proportion of patients who would be classified as at very high risk in the updated ATP III report; only 18% had LDL cholesterol <70 mg/dL—the target for the very-high-risk category. The present study adds to these findings of suboptimal LDL cholesterol goal attainment rates and provides more current information (from 2004 to 2006) and LDL cholesterol levels during the period of updated ATP III guidelines, which recommended aggressive lipid management for high-risk and very-high-risk patients.¹⁶ The percentage of patients with a diagnosis of atherosclerosis who were not receiving any dyslipidemia therapy was surprisingly high in our study; this finding requires further investigation.

The NCEP ATP III guidelines state that atherosclerosis is a CHD condition/CHD risk equivalent condition that renders the patient at high risk for CVD.⁸ Therefore, it is recommended that these high-risk patients should be treated with statin therapy to reduce their LDL cholesterol to <100 mg/dL. Updates to the ATP III guidelines recommend that more aggressive target levels of LDL cholesterol <70 mg/dL should be achieved in very-high-risk patients.¹⁶ Closer attention to these recommendations may be needed for patients who are not at desired LDL cholesterol levels. Increased awareness among clinicians may be needed regarding the importance of lipid monitoring and the treatment of elevated cholesterol among patients with atherosclerosis, along with the NCEP ATP III guideline standards. Clinical trials have demonstrated the effects of statin therapy on the progression of atherosclerosis.¹¹, ¹², ¹³, ¹⁷, ¹⁸ These findings from clinical trials need to be translated and disseminated to clinicians who are treating patients with atherosclerosis who live in the community.

This study has several limitations. First, it could not be ascertained whether all prescriptions were captured within the GEMS database; failure to capture any prescriptions may affect percentage estimates of patients receiving specific therapies before or after atherosclerosis was diagnosed. The GEMS database captures only outpatient care provided within the physician's office and does not capture medical care and treatment provided outside the physician's office. No attempt was made to obtain data outside of the EMR. Thus, we were not able to study the occurrence of cardiovascular events such as acute myocardial infarction, stroke, or angioplasty, because these data were not captured in the database. Patients included in this study were required to have an ICD-9 diagnosis of atherosclerosis. This provides insight into which patients are given a diagnosis and are assigned coding for atherosclerosis by healthcare professionals. Although ICD-9 codes for atherosclerosis were available, data on imaging tests and test results were not available and therefore were not included in the inclusion criteria or identification of patients with atherosclerosis for this study purpose. Patients in whom atherosclerosis had not been diagnosed (lack of recorded ICD-9 codes for atherosclerosis) could not be included in this study. Also, atherosclerosis often is advanced before symptoms appear and the diagnosis is made.¹⁹ The severity of atherosclerosis was unknown in this study because data on diagnostic tests or inpatient cardiovascular events were not available.

Furthermore, pharmacy data included in the study comprised the prescription ordered by the physician and not the drug claim indicating that the prescription had been filled and dispensed. Thus, statin/other lipid medication usage may have been overestimated in the study if patients did not fill their hypercholesterolemia prescriptions. However, if we had overestimated the number of patients using hypercholesterolemia drugs, the gap in care demonstrated here would be even larger. With these limitations, the prevalence rate estimated in this study refers to patients with an ICD code of atherosclerosis and is not a US population–based representative estimate of prevalence. Additional research should seek to incorporate both inpatient and outpatient data to better characterize patients with atherosclerosis.

CVD is the leading source of morbidity, disability, and mortality in Western countries, and atherosclerosis is the main underlying pathology.¹⁹ Results from this study, in which real-world clinical practice data were used, indicate a deficit in the optimal management of hypercholesterolemia in patients with atherosclerosis and the need for increased awareness of the importance of monitoring and treating lipids in patients with atherosclerosis. Improvement in evaluation and control of hypercholesterolemia is needed, particularly in this high-risk segment of the population. Also, a more aggressive therapeutic approach may be needed to further reduce LDL cholesterol levels in patients with atherosclerosis. The study findings highlight opportunities for clinicians to better manage hypercholesterolemia in individual patients with atherosclerosis.

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Pearls for clinical guidance 

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Author disclosures 

The authors who contributed to this article have disclosed the following industry relationships:

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Acknowledgments 

We thank Dolores Matthews of Scientific Connexions, Newtown, Pennsylvania, who provided editorial assistance funded by AstraZeneca Pharmaceuticals LP.

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Supplementary data 

Supplementary material cited in this article is available online.

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Supplementary data 

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References 

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