Cardiology clinic visit increases likelihood of evidence‐based cholesterol prescribing in severe hypercholesterolemia

Patients with phenotypic severe hypercholesterolemia (SH), low‐density lipoprotein‐cholesterol (LDL‐c) ≥ 190 mg/dl, atherosclerotic cardiovascular disease (ASCVD) or adults 40–75 years with diabetes with risk factors or 10‐year ASCVD risk ≥20% benefit from maximally tolerated statin therapy. Rural patients have decreased access to specialty care, potentially limiting appropriate treatment.


| INTRODUCTION
Cardiovascular disease (CVD) is the leading cause of death in America and across the globe [1][2][3][4] and coronary artery disease is the most prevalent type of CVD. Nearly half (49%) of all Americans have one of the following risk factors for heart disease: elevated blood pressure, elevated low-density lipoprotein cholesterol (LDL-c), or smoking. 5 Elevated LDL-c, or severe hypercholesterolemia (SH), is defined as an LDL-c > 190 mg/dl. Patients with evidence of SH are at increased risk for atherosclerotic cardiovascular disease (ASCVD) and roughly 600 000 people in the United States manifest the phenotype. 6 The American Heart Association/American College of Cardiology (AHA/ACC) goals for 2019 focused on the primary prevention of CVD. One of the top 10 take-home messages for primary prevention of CVD in the 2018 guideline on cholesterol management recommends patients with primary SH be started on a maximally tolerated statin therapy without further risk stratification. 7 Despite the overwhelming evidence for statin therapy, there is still a large divide in patients who are eligible for and recommended by the national guidelines to be on a statin and those who are actually receiving statin therapy. [8][9][10][11] Patients presenting with evidence for SH along with other comorbidities, including diabetes, cigarette smoking, and hypertension, are at increased risk for CVD. 12 Management of these comorbidities could help reduce the risk for CVD in patients with a high LDL-c. 13 While patients with multiple comorbidities are more likely to be seen by a physician, this surprisingly has little impact on the likelihood of a patient receiving guideline-directed cholesterol management to reach their LDL-c goals. 14 Prior studies showed significant increase in statin adherence for patients with a higher number of lipids panels completed, and therefore more visits to their doctor's office. 15 One barrier to health equity (i.e., guideline-directed cholesterol management) within the Essentia Health (EH) population is service area. While about 20% of the United States population resides in rural area, very few specialty clinics exist within rural communities. 16  The impact of being seen by cardiology on the use of lipidlowering medication is not well-characterized. 9 We aimed to evaluate use of statins in SH patients in our predominantly rural population, based on prior visit with cardiology.

| METHODS
This is a cross-sectional study of patients who were in an electronic medical record-based SH registry defined by ever having an LDLc > 190 mg/dl between January 1, 2000-June 1, 2020 (n = 18 072) at EH. EH is an integrated healthcare delivery system with facilities in four states (Minnesota, Wisconsin, North Dakota, and Idaho) that integrates physician group practice, acute care delivery including primary, secondary, and tertiary care centers, critical access hospitals, long-term care facilities, hospice care, medical equipment, and ambulance services. EH services cover an area of approximately 55 000 sq. miles with over 1 million residents. Within this area, EH has 15 hospitals, 74 clinics, and 1700 physicians and credentialed practitioners with approximately 65% of the patients served living in rural areas.
The study was approved by the Institutional Review Board of Essentia Health. The need to obtain informed consent was waived for the collection, analysis and publication of the retrospectively obtained and anonymized data for this non-interventional study.
Patients were excluded if they were age <20 years (n = 38) or >75 years (n = 3133), due to inconsistency in the applicability of the evidence-based intervention suggested in the cholesterol guidelines 7 outside of that age range. Deceased patients were also excluded from analysis (n = 34; 0.19%; Figure 1). Patients were considered to have not been seen by cardiology if there was no documented clinic visit within the past 3 years. Majority of patients had been seen in primary care clinic in the past 5 years (98.8%). All visits were in person and not via telehealth during this study period.
Medications were pulled from the patient's active medication list.
Only atorvastatin 40 mg or 80 mg or rosuvastatin 20 mg or 40 mg were considered high-intensity statins. All other statin medications and doses were considered low-or moderate-intensity. Due to effectiveness in LDL lowering, patients prescribed a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor were grouped with the highintensity statin cohort, while patients prescribed Ezetimibe were combined with the low-to moderate-intensity statin group. Statin allergies were obtained from the patient's allergy list.
Baseline risk factors were obtained from the problem list using ICD-10 diagnoses, recent vitals, and laboratory results. Diabetes was defined as most recent glucose ≥126 mg/dl or A1c ≥ 6.5% or currently taking a glucose-lowering medication. Patients who did not Approximately 5% of the cohort had missing values for total cholesterol, HDL-c, and triglycerides (n = 794; 5.3%, n = 779; 5.2%, n = 792; 5.3%, respectively).
Categorical variables were expressed as absolute numbers and percentages and compared with chi-squared test. Continuous variables are expressed as means and SDs (median with 25th-75th F I G U R E 1 Flow chart of patient cohort from the electronic medical record-based severe hypercholesterolemia registry defined for patients who had ever had an LDL-c ≥ 190 mg/dl between January 1, 2000 and June 1, 2020 (n = 18 072) percentile interquartile range for non-normally distributed variables) and were compared using a t-test where appropriate. Univariate and multivariate logistic regression models with 95% confidence intervals (CI) were calculated adjusting for age, sex, history of ASCVD, hypertension, obesity, and diabetes. A p-value of <.05 was considered statistically significant. All statistical analyses were performed with STATA 16.0 (College Station, TX).

| RESULTS
We identified 14 867 patients within the EH system with evidence for SH that did not meet exclusion criteria (58.7% female, mean age 59.7 + 10.3 years). Of these patients, 1795 (12.1%) had been seen by cardiology within the past 3 years, whereas 13 072 (87.9%) did not have a recent cardiology visit. Severe hypercholesterolemia patients who had been seen by cardiology had a higher prevalence of hypertension, diabetes mellitus, and coronary artery disease, compared with SH patients who had not been seen by cardiology ( System that showed a higher percentage of patients with ASCVD who saw cardiology had been prescribed high-intensity statins. 9 We found less than half of all patients with diabetes were on a highintensity statin and just over 63% of hypertension patients were receiving any intensity of statin therapy. This is slightly better than a previous study of a German diabetes registry which showed that of 51 640 SH patients with type 2 diabetes, 25.5% were prescribed a statin. 14  inhibitors. [24][25][26][27][28] Moreover, risk discussions should remind physicians to increase statin intensity as necessary for patients with a history of SH. Other options for assisting in the discrepancy between eligibility for and use of high-intensity statins may include use of computer prompts based on diagnoses and increased use of support staff like pharmacists and nurses to educate patients about the importance of lowering their LDL-c to goal through the use of lipid-lowering medications.

| LIMITATIONS
EH is a large accountable care organization in a rural area of the Midwest and besides a higher Native American population, is largely Caucasian and may not reflect demographics in all regions. The cardiology clinic is staffed with physicians as well as advanced practice providers.
Any LDL-c > 190 mg/dl defined SH and the authors were unable to exclude erroneous labs or elevated LDL-c due to secondary etiologies.
Data on medication prescriptions was used but adherence was not tracked in this retrospective study. Very few patients had genetic testing or detailed clinical examination to confirm Familial Hypercholesterolemia. Details of statin allergy or intolerance were not available.
Another limitation includes not excluding patients with the common secondary causes of hyperlipidemia, such as thyroid-related disease, certain medications, and nephrotic syndrome. Prior studies suggest that this is likely only 1-2% of this population. 20

| CONCLUSIONS
Being seen by cardiology is associated with increased statin prescriptions in phenotypic SH. Better access to specialty care may improve cholesterol management. Due to the largely rural EH service area, overcoming barriers for patients to be seen by specialty practice like cardiology, future telehealth or virtual visits may provide better access to cardiology and therefore improve the guideline-directed use of lipid-lowering medications in this population.