Comparison of Low-Density Lipoprotein Cholesterol Assessment by Martin/Hopkins Estimation, Friedewald Estimation, and Preparative Ultracentrifugation: Insights From the FOURIER Trial.

Importance: Recent studies have shown that Friedewald underestimates low-density lipoprotein cholesterol (LDL-C) at lower levels, which could result in undertreatment of high-risk patients. A novel method (Martin/Hopkins) using a patient-specific conversion factor provides more accurate LDL-C levels. However, this method has not been tested in proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor-treated patients. Objective: To investigate accuracy of 2 different methods for estimating LDL-C levels (Martin/Hopkins and Friedewald) compared with gold standard preparative ultracentrifugation (PUC) in patients with low LDL-C levels in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk (FOURIER) trial. Design, Setting, and Participants: The FOURIER trial was a randomized clinical trial of evolocumab vs placebo added to statin therapy in 27 564 patients with stable atherosclerotic cardiovascular disease. The patients' LDL-C levels were assessed at baseline, 4 weeks, 12 weeks, 24 weeks, and every 24 weeks thereafter, and measured directly by PUC when the level was less than 40 mg/dL per the Friedewald method (calculated as non-HDL-C level - triglycerides/5). In the Martin/Hopkins method, patient-specific ratios of triglycerides to very low-density lipoprotein cholesterol (VLDL-C) ratios were determined and used to estimate VLDL-C, which was subtracted from the non-HDL-C level to obtain the LDL-C level. Main Outcomes and Measures: Low-density lipoprotein cholesterol calculated by the Friedewald and Martin/Hopkins methods, with PUC as the reference method. Results: For this analysis, the mean (SD) age was 62.7 (9.0) years; 2885 of the 12 742 patients were women (22.6%). A total of 56 624 observations from 12 742 patients had Friedewald, Martin/Hopkins, and PUC LDL-C measurements. The median difference from PUC LDL-C levels for Martin/Hopkins LDL-C levels was -2 mg/dL (interquartile range [IQR], -4 to 1 mg/dL) and for Friedewald LDL-C levels was -4 mg/dL (IQR, -8 to -1 mg/dL; P < .001). Overall, 22.9% of Martin/Hopkins LDL-C values were more than 5 mg/dL different than PUC values, and 2.6% were more than 10 mg/dL different than PUC levels. These were significantly less than respective proportions with Friedewald estimation (40.1% and 13.3%; P < .001), mainly because of underestimation by the Friedewald method. The correlation with PUC LDL-C was significantly higher for Martin/Hopkins vs Friedewald (ρ, 0.918 [95% CI 0.916-0.919] vs ρ, 0.867 [0.865-0.869], P < .001). Conclusions and Relevance: In patients achieving low LDL-C with PCSK9 inhibition, the Martin/Hopkins method for LDL-C estimation more closely approximates gold standard PUC than Friedewald estimation does. The Martin/Hopkins method may prevent undertreatment because of LDL-C underestimation by the Friedewald method. Trial Registration: ClinicalTrials.gov Identifier: NCT01764633.

Role of the apolipoprotein B-apolipoprotein A-I ratio in cardiovascular risk assessment: a case-control analysis in EPIC-Norfolk.

BACKGROUND: An elevated apolipoprotein B-apolipoprotein A-I (apo B-apo A-I) ratio is a risk factor for future coronary artery disease (CAD). It is not known whether this ratio is better than traditional lipid values for risk assessment and prediction and whether it adds predictive value to the Framingham risk score. OBJECTIVE: To evaluate whether the apo B-apo A-I ratio is associated with future CAD events independent of traditional lipid measurements and the Framingham risk score and to evaluate the ability of this ratio to predict occurrence of future CAD. DESIGN: Prospective, nested case-control study. SETTING: Norfolk, United Kingdom. PARTICIPANTS: Apparently healthy men and women (45 to 79 years of age) in the European Prospective Investigation into Cancer and Nutrition-Norfolk. Cases (n = 869) were persons who developed fatal or nonfatal CAD. Controls (n = 1511) were persons without CAD who were matched for age, sex, and enrollment period. MEASUREMENTS: Total cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride, apolipoprotein, and C-reactive protein levels were measured directly. Low-density lipoprotein (LDL) cholesterol values were calculated by using the Friedewald formula. RESULTS: The apo B-apo A-I ratio was associated with future CAD events, independent of traditional lipid values (adjusted odds ratio, 1.85 [95% CI, 1.15 to 2.98]), including the total cholesterol-HDL cholesterol ratio, and independent of the Framingham risk score (adjusted odds ratio, 1.77 [CI, 1.31 to 2.39]). However, it did no better than lipid values at discriminating between CAD cases and controls (area under the receiver-operating characteristic curve, 0.670 for total cholesterol-HDL cholesterol ratio vs. 0.673 for apo B-apo A-I ratio [P = 0.38]) and added little to the predictive value of the Framingham risk score (area under the receiver-operating characteristic curve, 0.594 for Framingham risk score alone vs. 0.613 for Framingham risk score plus apo B-apo A-I ratio [P < 0.001]). In addition, it incorrectly classified 41.1% of cases and 50.4% of controls. LIMITATIONS: No participant was taking lipid-lowering medication, and diabetes was uncommon. CONCLUSIONS: The apo B-apo A-I ratio is independently associated with, but adds little to, existing measures for CAD risk assessment and discrimination in the general population. Other characteristics of the test, such as the ability to perform it on nonfasting samples, may still make it useful in some settings.

Comparison of short-term renal effects and efficacy of rosuvastatin 40 mg and simvastatin 80 mg, followed by assessment of long-term renal effects of rosuvastatin 40 mg, in patients with dyslipidemia.

BACKGROUND: An open-label, randomized, multinational, parallel-group trial compared the short-term (6-week) renal effects of rosuvastatin 40 mg and simvastatin 80 mg in patients with hypercholesterolemia. Most patients (93%) then entered an optional open-label extension (OLE) to assess long-term (up to 72 weeks) renal effects of rosuvastatin. METHODS: After dietary lead-in, 626 patients were randomized to rosuvastatin or simvastatin for 6 weeks, followed by an optional, single-arm OLE to assess longer-term effects of rosuvastatin on renal function, safety, and efficacy. RESULTS: The primary endpoint, a shift in urine dipstick protein from "none" or "trace" at baseline to "+" or greater in the first 4 weeks, was observed in 6.4% of patients receiving rosuvastatin and 1.0% of those receiving simvastatin. The incidence of shifts in urine dipstick protein at any time from none or trace to "++" or greater (proteinuria), was low (1.3%, rosuvastatin; 0.3%, simvastatin), transient and urine protein was predominantly of tubular or mixed origin. More patients achieved Third Adult Treatment Panel of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (NCEP ATP III) low-density lipoprotein cholesterol (LDL-C) goals with rosuvastatin vs simvastatin after 6 weeks (77.9% vs 60.4%). Results from the OLE (median rosuvastatin treatment = 47 weeks) were consistent with the randomized period. Mean serum creatinine levels remained stable, indicating no decline in renal function. CONCLUSION: A small proportion of patients treated with rosuvastatin 40 mg may experience a transient proteinuria, predominantly of tubular origin and not associated with declining renal function. Rosuvastatin modified lipid levels effectively, enabled more patients to attain LDL-C goals, and demonstrated a favorable benefit/risk profile.

Assessment of reaching goal in patients with combined hyperlipidemia: low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, or apolipoprotein B.

It is well established that patients with combined hyperlipidemia, defined as elevated triglyceride levels between 200 and 500 mg/dL and elevated low-density lipoprotein cholesterol >130 mg/dL, are at increased risk for coronary artery disease. The optimal assessment of reaching lipid goals in patients with combined hyperlipidemia is still far from settled and has been an area of revision and modification in recent guidelines. Although controversy remains as to the best single measurement to be used in treatment goals, current focus is on the use of low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B. This article reviews the use of these 3 biomarkers in assessing cardiovascular risk, and the strategies for managing combined hyperlipidemia.

Identification and treatment of individuals at high risk of coronary heart disease.

Low-density lipoprotein (LDL) cholesterol reduction remains the cornerstone of coronary heart disease (CHD) prevention. The most dramatic and consistent reductions in LDL cholesterol and CHD risk are achieved with statin therapy. Identification of individuals at high CHD risk is important, not only for initiating appropriate treatment and minimizing morbidity and mortality but also for optimizing the cost-effectiveness of such treatment. A simple method for identifying high-risk individuals is to identify those with preexisting atherosclerotic disease, diabetes, or familial hypercholesterolemia (FH). Treatment options for achieving LDL cholesterol goals in high-risk patients include statins, bile acid sequestrants, niacin, and plant stanols. Statin therapy should be instituted at a dose likely to result in achievement of LDL cholesterol goals based on average response; it should then be aggressively titrated if the goals are not achieved. If LDL cholesterol goals are not achieved with maximal statin therapy, combination with a bile acid sequestrant, niacin, and/or stanols should be considered. Options likely to be available in the near future include more efficacious statins with greater potential for reducing LDL cholesterol in all patients but especially in high-risk patients, such as those with FH, enabling a greater proportion to achieve LDL cholesterol goals. Other options that may soon be available as additive agents to statins to achieve greater LDL cholesterol reductions include bile acid transport inhibitors and cholesterol absorption inhibitors.