A Tale of Two Approaches.

OBJECTIVES: To summarize and assess the literature on the performances of methods beyond the Friedewald formula (FF) used in routine practice to determine low-density lipoprotein cholesterol (LDL-C). METHODS: A literature review was performed by searching the PubMed database. Many peer-reviewed articles were assessed. RESULTS: The examined methods included direct homogeneous LDL-C assays, the FF, mathematical equations derived from the FF, the Martin-Hopkins equation (MHE), and the Sampson equation. Direct homogeneous assays perform inconsistently across manufacturers and disease status, whereas most FF-derived methods exhibit variable levels of performance across populations. The MHE consistently outperforms the FF but cannot be applied in the setting of severe hypertriglyceridemia. The Sampson equation shows promise against both the FF and MHE, especially in severe hypertriglyceridemia, but data are still limited on its validation in various settings, including disease and therapeutic states. CONCLUSIONS: There is still no consensus on a universal best method to estimate LDL-C in routine practice. Further studies are needed to assess the performance of the Sampson equation.

Proportion of High-Risk/Very High-Risk Patients in Europe with Low-Density Lipoprotein Cholesterol at Target According to European Guidelines: A Systematic Review.

OBJECTIVE: Assess achievement of low-density lipoprotein cholesterol (LDL-C) targets in European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines. DESIGN: Systematic literature review. DATA SOURCES: Medline, EMBASE, Cumulated Index to Nursing and Allied Health Literature. ELIGIBILITY CRITERIA: Observational studies reporting LDL-C levels/target attainment, measured between 1 August 2006 to 31 August 2017, in European adults with established cardiovascular disease (CVD), diabetes with target organ damage, familial hypercholesterolaemia (FH) or 10-year risk of fatal CVD ≥ 5% (assessed by Systematic Coronary Risk Evaluation [SCORE]). DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted relevant studies and assessed study quality using the Risk of Bias for Non-Randomised Studies-Interventions (ROBINS-I) tool. Primary outcome was the proportion of patients achieving LDL-C targets in the 2011/2016 ESC/EAS guidelines. Where available, patient characteristics were presented as means weighted by sample size. The proportions of patients achieving LDL-C targets in the 5 years before and after publication of the 2011 guidelines were compared using a chi-square test. RESULTS: Across 81 eligible studies (303,534 patients), achievement of LDL-C < 1.8 mmol/L was poor among patients with established CVD (16%; range 9-56%) and at very high risk of CVD (SCORE ≥ 10% [18%; 14-25%]). In individuals with FH, SCORE 5-10%, or diabetes and target organ damage, LDL-C < 2.5 mmol/L was achieved by 15% (9-22%), 46% (21-55%) and 13% (6-34%), respectively. Comparing the 5 years before/after publication of the 2011 guidelines, target achievement increased significantly over time but remained suboptimal (LDL-C < 1.8, 22% versus 15%; LDL-C < 2.5, 68% versus 61%; both p < 0.001; established CVD group only). CONCLUSIONS: These data show suboptimal LDL-C control among European patients at high risk of CVD. Those at greatest overall risk (clinically established CVD or at least a 10% 10-year risk of fatal CVD) had the lowest achievement of 2011/2016 EAS/ESC LDL-C targets. With lower LDL-C targets advocated in 2019 ESC/EAS guidelines, this unmet need will increase. PROTOCOL REGISTRATION: PROSPERO registration number; CRD77844.

Adherence to statins and LDL-cholesterol goal attainment.

OBJECTIVES: To examine the relationship between low-density lipoprotein cholesterol (LDL-C) goal attainment and adherence to statin medications in patients with coronary artery disease (CAD). STUDY DESIGN: Cross-sectional study of CAD patients 18 years of age or older in an integrated healthcare system. METHODS: Patients dispensed 2 or more statin prescriptions between May 2009 and May 2010, were identified. Medication possession ratio (MPR) was calculated to estimate adherence. The LDL-C value closest to May 27, 2010, was used to determine goal. Adherence and LDL-C goal were defined as 80% or greater MPR and less than 100 mg/dL or less than 70 mg/dL, respectively. Electronic medical records were used to identify patient demographics and clinical information. Logistic regression was used to estimate the effect of these factors on goal attainment. RESULTS: A total of 67,100 CAD patients were identified. Overall, 85.8% had LDL-C less than 100 mg/dL, 32.4% had LDL less than 70 mg/dL, and 79.8% were adherent to their statin medication. Over 65% of patients not at LDL-C goal less than 100 mg/dL were adherent. Among patients with LDL-C less than 100 mg/dL, 17.9% were not adherent. Increasing medication adherence was associated with improved LDL-C levels. Adherence to statins, male sex, Asian and Hispanic race/ethnicity, a higher number of concurrent prescriptions, higher Charlson Comorbidity Index, and hypertension were associated with LDL-C goal attainment. CONCLUSIONS: Incorporating LDL-C levels and medication adherence at the point of care allows providers to focus interventions to address either adherence challenges or the need for medication titration in an effort to improve LDL-C goal attainment and ultimately reduce morbidity and mortality.

Impact of interpretative commenting on lipid profiles in people at high risk of familial hypercholesterolaemia.

BACKGROUND: Familial hypercholesterolaemia (FH) is an autosomal dominant condition characterised by increased low density lipoprotein cholesterol (LDL-c), xanthomata and premature cardiovascular disease. However, it is currently underdiagnosed and undertreated in Australasia. We sought to investigate whether interpretative commenting on lipid profiles could improve FH detection and treatment. METHODS: A case-historical control study of individuals with serum LDL-c concentrations ≥6.5 mmol/L; 96 cases receiving an interpretative comment suggesting FH compared with 100 controls not receiving a comment. RESULTS: Serum LDL-c was repeated in 63 (66%) cases and 70 (70%) controls within 12 months. LDL-c decreased in 59 (94%) cases and in 61 (87%) controls. In individuals with a repeat LDL-c, a mean LDL-c reduction of 2.3 mmol/L (32%; p<0.0001) was demonstrated in controls, compared with 3.0 mmol/L (42%; p<0.0001) in cases; significantly greater than that of controls (p<0.005). Interpretative comments suggesting specialist review were associated with a higher referral rate compared with controls (11.5% vs 1%, p<0.05). CONCLUSION: Interpretative commenting was associated with a significant additional LDL-c reduction and increased specialist referrals compared with controls. However, only a minority of individuals received a specialist referral. Interpretative commenting may play an important role in the detection and management of FH.

Optimal range of triglyceride values to estimate serum low density lipoprotein cholesterol concentration in Korean adults: the Korea National Health and Nutrition Examination Survey, 2009.

The aims of this study were to investigate the validity of Friedewald's formula and to propose a range of triglyceride values over which the formula can be used without significant error. This was a cross-sectional analysis of 1,929 subjects (946 males and 983 females) aged 20 yr and older using data of the Korea National Health and Nutrition Examination Survey in 2009. Estimated total number was considered to be 10,633,655 (5,846,384 males and 4,787,271 females). Calculated and directly-measured low density lipoprotein cholesterol (LDL-C) values were highly correlated (r = 0.96); however, significant differences were observed between the directly-measured and calculated LDL-C concentrations. Subjects in the underestimated group (10.5%) had higher dysmetabolic profiles than those in the overestimated group (11.4%). Although serum triglyceride level showed the greatest independent association with differences between the calculated and directly-measured LDL-C concentrations, no statistically significant differences were noted when triglyceride concentration was between 36 and 298 mg/dL (93.2%). In conclusion, Friedewald's formula accurately estimates directly-measured serum LDL-C concentration in Korean adults. However, the formula can be applied to subjects with serum triglyceride concentrations from 36 to 298 mg/dL without significant error.

What combination therapy with a statin, if any, would you recommend?

The latest recommended goals for blood lipid levels may require multiple lipid drugs. Lower doses in combination may render more efficacy and safety than highest doses of single agents. Except for isolated hypoalphalipoproteinemia (a low level of high-density lipoprotein cholesterol), therapies will start with a statin. All marketed statins are acceptable. The choice may be based on dose- efficacy and patient's tolerability. High-potency statins (eg, atorvastatin, simvastatin, or rosuvastatin) are often chosen. Currently, generic statins, such as simvastatin, lovastatin, pravastatin, and fluvastatin, offer cost benefits. The choice of added agent depends on the "residual lipoprotein abnormalities" after statin therapy, efficacy, compliance issues, and cost. Approved "combined" preparations improve cost and compliance. To further lower low-density lipoprotein cholesterol, ezetimibe is a safe, efficacious choice, pending resolution of a controversial trial's results. Colesevelam is moderately effective and the best tolerated bile acids sequestrant. In combined dyslipidemias, extended-release niacin is the best tolerated niacin preparation; other quality-controlled immediate-release preparations have similar safety and efficacy but produce more flushing of the skin. Niacin or fenofibrate is effective in normalizing high-density lipoprotein and triglyceride levels persisting after statin therapy. Agents approved by the US Food and Drug Administration and the latest guidelines of the National Cholesterol Education Program, American Heart Association/American College of Cardiology provide choices and indications of drug combinations.

Ten-year evaluation of homogeneous low-density lipoprotein cholesterol methods developed by Japanese manufacturers. Application of the Centers for Disease Control and Prevention/Cholesterol Reference Method Laboratory Network lipid standardization protocol.

AIM: The risk index for atherosclerotic cardiovascular diseases in the Japanese metabolic syndrome-focused health checkup program was changed from total cholesterol (TC) to low-density lipoprotein cholesterol (LDL-C). We discuss the validity of this change with respect to standardization. METHODS: The beta-quantification procedure of the Centers for Disease Control and Prevention (CDC) uses the LDL-C reference value as a target. Clinical laboratories and commercial manufacturers use homogeneous LDL-C methods for standardization. (A) For clinical laboratories, LDL-C in 648 samples requested from 108 hospitals was analyzed. (B) Manufacturers participated in the CDC/Cholesterol Reference Method Laboratory Network LDL-C standardization protocol. The standardization was conducted with a performance follow-up for the 10-year period from 1998 to 2008 at 2-year intervals, 6 times. RESULTS: (A) In clinical laboratories, acceptable LDL-C levels within ±4% of the CDC's criteria remained 70.4%, 456 of 648 subjects. Negative maximum bias deviating from the LDL-C target value was -35.8%, -52.5 mg/dL, and positive maximum bias was +24.5%, +32.3 mg/dL. (B) For manufacturers, the standardization achievement rate of the analytical reagent/instrument/calibrator system in the last four standardizations from 2002 to 2008 remained on average 66.6%, far lower than the level required. CONCLUSIONS: The standardization achievement rate of homogeneous LDL-C methods was much low-er than that of TC. TC should still be used as a risk index for atherosclerotic cardiovascular diseases. The standardization achievement rate of homogeneous LDL-C should be maintained at 100%, at least using samples with normal lipoprotein profiles. The accuracy and specificity of LDL-C should be further improved before practical and clinical use.

Serum oxidized-LDL is associated with diabetes duration independent of maintaining optimized levels of LDL-cholesterol.

Oxidized low-density lipoprotein (ox-LDL) plays a key role in the progression of atherosclerosis and diabetes complications. The aim of this study was first, to evaluate the association between ox-LDL and diabetes duration, and second, to examine serum level of ox-LDL in patients with prolonged diabetes and a desirable LDL-cholesterol level. A total of 36 type-2 diabetic patients with a diabetes duration of more than 5 years, 36 newly diagnosed diabetic patients, and 36 age-, sex- and BMI-matched healthy participants were recruited. Healthy participants and newly diagnosed patients were not receiving any treatment. All patients with prolonged diabetes had desirable LDL-cholesterol levels (<100 mg/dL), according to the adult treatment panel-III guidelines. While LDL-cholesterol was significantly lower in patients with diabetes duration >5 years, in comparison to newly diagnosed patients (P < 0.01), ox-LDL was significantly higher in patients with prolonged diabetes (P < 0.001). The ox-LDL-to-LDL ratio was dramatically higher in patients with diabetes duration >5 years in comparison to newly diagnosed patients and healthy participants (P < 0.001). Ox-LDL was significantly associated with diabetes duration (r = 0.519, P = 0.001). In multivariate analysis, this association remained significant (beta = 0.501, P = 0.003) after adjustment for potential confounders. In conclusion, this study showed that the serum ox-LDL level increases with the length of diabetes, even though the patients' LDL-cholesterol level is maintained at a desirable level. Our findings highlight that possibly more attention should be focused on markers of oxidative stress in the management of lipids in diabetic patients.

Undertreatment of hypercholesterolemia.

Abstract Recent guidelines recommend strict goals for low-density lipoprotein cholesterol (LDL-C) (1.8-2.6 mmol/L; 70-100 mg/dL). However, these goals are not always met and many primary and secondary prevention patients are not optimally controlled. Both the under-prescription of lipid-lowering medication and lack of adherence to prescribed medications could account for this situation. In this issue of the journal, two studies evaluated the under-treatment of hypercholesterolemia in European countries, as well as patient/physician characteristics that are related to poor control of LDL-C. This editorial considers the implications of these findings. While we have come far in recent years in terms of treating hypercholesterolemia, we still have considerable room for improvement and progress towards evidence-based clinical practice.

Prevalence and extent of dyslipidemia and recommended lipid levels in US adults with and without cardiovascular comorbidities: the National Health and Nutrition Examination Survey 2003-2004.

BACKGROUND: Despite improvements in low-density lipoprotein cholesterol (LDL-C) levels, recent national data are limited regarding the proportion of adults at recommended lipid levels according to the presence of cardiovascular disease (CVD) and related comorbidities. We evaluated the proportion of US adults with and without these conditions at (and distance to) recommended levels of LDL-C, non-high-density lipoprotein cholesterol (non-HDL-C), HDL-C, and triglycerides. METHODS: We analyzed data from adults aged > or =20 who had fasted for 8 or more hours (n = 2,883, weighted to a US population of 128.5 million) in the National Health and Nutrition Examination Survey 2003-2004, a nationally representative cross-sectional survey. The number of adults at National Cholesterol Education Program recommended levels for LDL-C, non-HDL-C, HDL-C, triglycerides, and combined lipids, stratified by sex, age group, ethnicity, and the presence of CVD comorbidities was determined. RESULTS: Although 85% to 89% of persons without CVD or related comorbidities were at recommended levels for LDL-C, non-HDL-C, HDL-C, and triglycerides, only 36% to 37% of those with CVD or related comorbidities were at recommended levels for LDL-C and non-HDL-C, and only 17% were at recommended levels for all lipids. Treated persons compared with those untreated had significantly lower LDL-C (112.3 vs 156.7 mg/dL, P < .001) and non-HDL-C levels (145.9 vs 188.7 mg/dL, P < .001), but similar HDL-C (52.0 vs 50.1 mg/dL, P = .09) and triglyceride (160.1 vs 148.7 mg/dL, P = .20) levels. CONCLUSIONS: Despite improved LDL-C levels, many adults, especially with CVD or related comorbidities, are not at recommended levels for all lipids. Improved treatment efforts to target the spectrum of dyslipidemia are needed.

A national study on lipid management.

BACKGROUND: Hyperlipidemia remains a major cause of morbidity in Western countries. The objective of this study was to document the percentage of adults who underwent periodical LDL measurement, and the percentage of patients with diabetes and post-angioplasty who were treated to goal. METHODS: Using a national database, data were obtained on the percentage of adults who had an LDL performed and the percentage of adults with an LDL at pre-specified levels. We also assessed the attainment of target LDL levels in diabetic and post-angioplasty patients. Data were also collected from patients with an acute coronary syndrome (ACS) admitted to seven hospitals within a 5 year period (2000-2004). RESULTS: Primary prevention: In 2005, 64.6% of the total population of 754,910 aged 35-44 had at least one record of LDL cholesterol measurement documented. This figure was 79.6% in the 717,617 adults aged 45-54. Secondary prevention: Of 253,233 diabetics in 2005, 220,023 (86.9%) have undergone at least one annual LDL measurement. The percentage of patients on statin therapy 3 and 12 months after an ACS admission increased significantly during the years 2000-2004 and reached 87%. Of the 42,292 patients who underwent PTCA during 2005, 34,346 (81.2%) have purchased at least 3 prescriptions of statins during 2005, 35,261 (83.4%) have performed at least one LDL measurement and 57.8% attained an LDL level of <100 mg/dl. CONCLUSIONS: We have shown an improvement in primary and secondary preventions of CV disease as documented by LDL measured and attainment of treatment goals, but further efforts are needed.

Utility of currently recommended pediatric dyslipidemia classifications in predicting dyslipidemia in adulthood: evidence from the Childhood Determinants of Adult Health (CDAH) study, Cardiovascular Risk in Young Finns Study, and Bogalusa Heart Study.

BACKGROUND: New age- and sex-specific lipoprotein cut points developed from National Health and Nutrition Examination Survey (NHANES) data are considered to be a more accurate classification of a high-risk lipoprotein level in adolescents compared with existing cut points established by the National Cholesterol Education Program (NCEP). The aim of this study was to determine which of the NHANES or NCEP adolescent lipoprotein classifications was most effective for predicting abnormal levels in adulthood. METHODS AND RESULTS: Adolescent and adult measures of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides were collected in 365 Australian, 1185 Finnish, and 273 US subjects participating in 3 population-based prospective cohort studies. Lipoprotein variables in adolescence were classified according to NCEP and NHANES cut points and compared for their ability to predict abnormal levels in adulthood. With the use of diagnostic performance statistics (sensitivity, specificity, positive predictive value, negative predictive value, area under receiver operating characteristic curve) in pooled and cohort-stratified data, the NHANES cut points (compared with NCEP cut points) were more strongly predictive of low high-density lipoprotein cholesterol in adults but less predictive of high total cholesterol, high low-density lipoprotein cholesterol, and high triglyceride levels in adults. We identified heterogeneity in the relative usefulness of each classification between cohorts. CONCLUSIONS: The separate use of NHANES cut points for high-density lipoprotein cholesterol and NCEP cut points for total cholesterol, low-density lipoprotein cholesterol, and triglycerides yielded the most accurate classification of adolescents who developed dyslipidemia in adulthood.

Westgard multirule for calculated laboratory tests.

BACKGROUND: In clinical laboratories, many test results such as low-density lipoprotein (LDL)-cholesterol can be calculated using the results of specifically measured tests. However, quality control programs deal only with measured tests and there is no adequate quality assessment procedure for calculated tests. I aimed to apply the Westgard multirule to calculated tests as a part of routine quality procedures. METHODS: I prepared a Levey-Jennings chart for calculated tests and all their measured components (Equation chart) and then applied the Westgard multirule to these tests. RESULTS: Applying the Westgard multirule to calculated LDL-cholesterol (and other calculated tests) was simple, and increased the reliability of the results of the calculated tests. CONCLUSIONS: Checking the reliability of only measured tests by quality control procedures before reporting patient results may be inadequate. Applying the Westgard multirule to calculated tests as part of total quality management will increase the reliability of test results.

Quality assessment of dyslipidemia in managed care: current best evidence should be used to benchmark quality.

Quality measurements in managed care allow purchasers of health care to distinguish between health plans. Existing measures (Health Plan Employer Data and Information Set goals) for treatment of dyslipidemia provide a limited snapshot about quality of care for members within commercial health plans. Newer evidence (ie, the Heart Protection Study) and consensus guidelines (the National Cholesterol Education Program) expand the definition of high-risk populations and emphasize pharmacotherapy in managing dyslipidemia. We believe that newer evidence and standards provide health plans with the best opportunity to accurately assess the quality of dyslipidemia care for their populations. We propose a broad framework that provides health plans with guidance on developing a new quality measure for dyslipidemia that focuses on pharmacotherapy.

Assessment of compliance with lipid guidelines in an academic medical center.

BACKGROUND: The importance of achieving a low-density lipoprotein cholesterol (LDL-C) level less than 100 mg/dL in patients with coronary artery disease (CAD) or cerebrovascular disease (CVD) is well established. Emerging evidence supports the recognition and management of secondary lipid goals, high-density lipoprotein cholesterol (HDL-C) level greater than 40 mg/dL, and triglyceride level less than 150 mg/dL. OBJECTIVE: To evaluate whether inpatient services within an academic setting were achieving/addressing primary and secondary lipid goals in patients with established CAD or CVD. METHODS: Patients with a discharge diagnosis of acute myocardial infarction, myocardial revascularization procedures, and/or ischemic stroke were identified. A retrospective chart review was done to assess adherence to the American Heart Association (AHA)/American College of Cardiology (ACC) guidelines for lipid management. RESULTS: On average, 63% of patients with CAD or CVD had a lipid panel assessed during their hospitalization. Of the patients who had a fasting lipid panel checked, only 40% (72/178) had an LDL-C level less than 100 mg/dL. Of those patients, only 31% (22) also had an HDL-C level greater than 40 mg/dL. Even fewer patients (24%; 17) met both primary and secondary goals. Of the 287 patients included in the study, 69% (199) were prescribed a statin, 3% (9) a fibrate, and 3% (8) niacin on discharge. CONCLUSIONS: Few patients with CAD or CVD met the AHA/ACC goals for lipid management, yet a significant number were not prescribed appropriate lipid-lowering therapy at discharge. This finding strongly suggests that more awareness in this area is needed.