A randomized controlled trial of genetic testing and cascade screening in familial hypercholesterolemia.

PURPOSE: Family-based cascade screening from index probands is considered an effective way of identifying undiagnosed individuals with familial hypercholesterolemia (FH). The role of genetic testing of the proband in the success of cascade screening for FH is unknown. METHODS: We randomized 240 individuals with a clinical diagnosis of FH to genetic testing for FH (n = 160) or usual care with lipid testing alone (n = 80). The primary study endpoint was the proportion of probands with at least one relative enrolled in the study within one year after the notification of results. RESULTS: Proband median age was 59 (47-67) and 71% were female. Only 28 (12%) probands succeeded in enrolling a relative. While the genetic testing group had a higher proportion of probands with relatives enrolled (13.1%) compared with the usual care group (8.8%), this difference was not significant (p = 0.40). In subgroup analyses, enrollment of a relative was higher in the pathogenic variant group (22.7%) compared to the no pathogenic variant (9.5%) and usual care groups (8.8%) (p = 0.04). CONCLUSION: We observed a low rate of family participation in cascade screening despite repeated recommendations to probands. Compared to usual care, genetic testing did not improve family participation in cascade screening for FH. CLINICAL TRIAL NUMBER: NCT04526457.

Effects of vadadustat on hemoglobin concentrations in patients receiving hemodialysis previously treated with erythropoiesis-stimulating agents.

Background: Vadadustat, an inhibitor of hypoxia-inducible factor prolyl-4-hydroxylase domain dioxygenases, is an oral investigational agent in development for the treatment of anemia secondary to chronic kidney disease. Methods: In this open-label Phase 2 trial, vadadustat was evaluated in 94 subjects receiving hemodialysis, previously maintained on epoetin alfa. Subjects were sequentially assigned to one of three vadadustat dose cohorts by starting dose: 300 mg once daily (QD), 450 mg QD or 450 mg thrice weekly (TIW). The primary endpoint was mean hemoglobin (Hb) change from pre-baseline average to midtrial (Weeks 7-8) and end-of-trial (Weeks 15-16) and was analyzed using available data (no imputation). Results: Overall, 80, 73 and 68% of subjects in the 300 mg QD, 450 mg QD, and 450 mg TIW dose cohorts respectively, completed the study. For all dose cohorts no statistically significant mean change in Hb from pre-baseline average was observed, and mean Hb concentrations-analyzed using available data-remained stable at mid- and end-of-trial. There was one subject with an Hb excursion >13 g/dL. Overall, 83% of subjects experienced an adverse event (AE); the proportion of subjects who experienced at least one AE was similar among the three dose cohorts. The most frequently reported AEs were nausea (11.7%), diarrhea (10.6%) and vomiting (9.6%). No deaths occurred during the study. No serious AEs were attributed to vadadustat. Conclusions: Vadadustat maintained mean Hb concentrations in subjects on hemodialysis previously receiving epoetin. These data support further investigation of vadadustat to assess its long-term safety and efficacy in subjects on hemodialysis.

Clinical Trial of Vadadustat in Patients with Anemia Secondary to Stage 3 or 4 Chronic Kidney Disease.

BACKGROUND: Therapeutic options for the treatment of anemia secondary to chronic kidney disease (CKD) remain limited. Vadadustat (AKB-6548) is an oral hypoxia-inducible factor prolyl-hydroxylase domain (HIF-PHD) inhibitor that is being investigated for the treatment of anemia secondary to CKD. METHODS: A phase 2a, multicenter, randomized, double-blind, placebo-controlled, dose-ranging trial (NCT01381094) was undertaken in adults with anemia secondary to CKD stage 3 or 4. Eligible subjects were evenly randomized to 5 groups: 240, 370, 500, or 630 mg of once-daily oral vadadustat or placebo for 6 weeks. All subjects received low-dose supplemental oral iron (50 mg daily). The primary endpoint was the mean absolute change in hemoglobin (Hb) from baseline to the end of treatment. Secondary endpoints included iron indices, safety, and tolerability. RESULTS: Ninety-three subjects were randomized. Compared with placebo, vadadustat significantly increased Hb after 6 weeks in a dose-dependent manner (analysis of variance; p < 0.0001). Vadadustat increased the total iron-binding capacity and decreased concentrations of ferritin and hepcidin. The proportion of subjects with at least 1 treatment-emergent adverse event was similar between vadadustat- and placebo-treated groups. No significant changes in blood pressure, vascular endothelial growth factor, C-reactive protein, or total cholesterol were observed. Limitations of this study included its small sample size and short treatment duration. CONCLUSIONS: Vadadustat increased Hb levels and improved biomarkers of iron mobilization and utilization in patients with anemia secondary to stage 3 or 4 CKD. Global multicenter, randomized phase 3 trials are ongoing in non-dialysis-dependent and dialysis-dependent patients.

US physician practices for diagnosing familial hypercholesterolemia: data from the CASCADE-FH registry.

BACKGROUND: In the US familial hypercholesterolemia (FH), patients are underidentified, despite an estimated prevalence of 1:200 to 1:500. Criteria to identify FH patients include Simon Broome, Dutch Lipid Clinic Network (DLCN), or Make Early Diagnosis to Prevent Early Deaths (MEDPED). The use of these criteria in US clinical practices remains unclear. OBJECTIVE: To characterize the FH diagnostic criteria applied by US lipid specialists participating in the FH Foundation's CASCADE FH (CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia) patient registry. METHODS: We performed an observational, cross-sectional analysis of diagnostic criteria chosen for each adult patient, both overall and by baseline patient characteristics, at 15 clinical sites that had contributed data to the registry as of September 8, 2015. A sample of 1867 FH adults was analyzed. The median age at FH diagnosis was 50 years, and the median pretreatment low-density lipoprotein cholesterol (LDL-C) value was 238 mg/dL. The main outcome was the diagnostic criteria chosen. Diagnostic criteria were divided into five nonexclusive categories: "clinical diagnosis," MEDPED, Simon Broome, DLCN, and other. RESULTS: Most adults enrolled in CASCADE FH (55.0%) received a "clinical diagnosis." The most commonly used formal criteria was Simon-Broome only (21%), followed by multiple diagnostic criteria (16%), MEDPED only (7%), DLCN only (1%), and other (0.5%), P < .0001. Of the patients with only a "clinical diagnosis," 93% would have met criteria for Simon Broome, DLCN, or MEDPED based on the data available in the registry. CONCLUSIONS: Our findings demonstrate heterogeneity in the application of FH diagnostic criteria in the United States. A nationwide consensus definition may lead to better identification, earlier treatment, and ultimately CHD prevention.

Treatment Gaps in Adults With Heterozygous Familial Hypercholesterolemia in the United States: Data From the CASCADE-FH Registry.

BACKGROUND: Cardiovascular disease burden and treatment patterns among patients with familial hypercholesterolemia (FH) in the United States remain poorly described. In 2013, the FH Foundation launched the Cascade Screening for Awareness and Detection (CASCADE) of FH Registry to address this knowledge gap. METHODS AND RESULTS: We conducted a cross-sectional analysis of 1295 adults with heterozygous FH enrolled in the CASCADE-FH Registry from 11 US lipid clinics. Median age at initiation of lipid-lowering therapy was 39 years, and median age at FH diagnosis was 47 years. Prevalent coronary heart disease was reported in 36% of patients, and 61% exhibited 1 or more modifiable risk factors. Median untreated low-density lipoprotein cholesterol (LDL-C) was 239 mg/dL. At enrollment, median LDL-C was 141 mg/dL; 42% of patients were taking high-intensity statin therapy and 45% received >1 LDL-lowering medication. Among FH patients receiving LDL-lowering medication(s), 25% achieved an LDL-C <100 mg/dL and 41% achieved a ≥50% LDL-C reduction. Factors associated with prevalent coronary heart disease included diabetes mellitus (adjusted odds ratio 1.74; 95% confidence interval 1.08-2.82) and hypertension (2.48; 1.92-3.21). Factors associated with a ≥50% LDL-C reduction from untreated levels included high-intensity statin use (7.33; 1.86-28.86) and use of >1 LDL-lowering medication (1.80; 1.34-2.41). CONCLUSIONS: FH patients in the CASCADE-FH Registry are diagnosed late in life and often do not achieve adequate LDL-C lowering, despite a high prevalence of coronary heart disease and risk factors. These findings highlight the need for earlier diagnosis of FH and initiation of lipid-lowering therapy, more consistent use of guideline-recommended LDL-lowering therapy, and comprehensive management of traditional coronary heart disease risk factors.

Lomitapide for the management of homozygous familial hypercholesterolemia.

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder of low-density lipoprotein cholesterol (LDL-C) metabolism resulting in extremely elevated serum levels of LDL-C and premature atherosclerotic cardiovascular disease. Treatment typically involves multiple pharmacologic agents, as well as mechanical filtration using weekly or biweekly LDL apheresis. Despite combination lipid-lowering therapy, LDL-C levels and cardiovascular morbidity and mortality remain unacceptably high in HoFH patients. The European Commission and the US Food and Drug Administration approved the use of lomitapide, a novel medication designed to address this significant unmet need. Lomitapide is an orally administered inhibitor of microsomal triglyceride transfer protein that is indicated as an adjunct to a low-fat diet and other lipid-lowering treatments, including LDL apheresis where available for the reduction of LDL-C, total cholesterol, apolipoprotein B, and non-high-density lipoprotein cholesterol in adult patients with HoFH. The risks of transaminase elevations, hepatic steatosis, and gastrointestinal side effects, and the potential for drug interactions, require vigilant examination of the clinical and laboratory data and patient counseling prior to initiation of lomitapide, as well as regular monitoring during follow-up care. This article highlights important practical considerations for the use of lomitapide in the context of the evaluation and management of a HoFH patient case.

Differences in absolute risk of cardiovascular events using risk-refinement tests: a systematic analysis of four cardiovascular risk equations.

BACKGROUND: Current cardiovascular risk assessment guidelines incorporate judicious use of C-reactive protein (CRP), carotid intima-media thickness (CIMT), and coronary artery calcium (CAC) in selected populations and describe threshold levels for higher and lower cardiovascular risk for each of the three risk refinement tests. However, the effect of these suggested thresholds of relative risk on absolute global risk remains uncertain. METHODS: Systematic permutation of risk factors provided 10-year risk estimates using the Framingham risk score, equations derived from the Multi-Ethnic Study of Atherosclerosis (MESA) and the Atherosclerosis Risk in Communities (ARIC) study, and the Reynolds risk score. Low-, high-, and very-high-risk values of CAC, CIMT, and hsCRP were defined as: 0, 100, 400 Agatston units; 25th percentile without plaque, 75th percentile without plaque, 75th percentile with plaque; and 1.0, 3.0, 7.0 mg/L. RESULTS: Incorporation of low-, high-, and very-high-risk CAC values using the MESA risk score resulted in greater changes in absolute risk from the Framingham risk score than the addition of either CIMT or hsCRP values using the ARIC or Reynolds risk scores. CONCLUSIONS: Although certain values of CAC, CIMT, and hsCRP have been similarly designated as low, high, or very-high risk, incorporation of these thresholds into validated risk equations yielded substantially different levels of absolute cardiovascular risk. Use of available risk equations may be advisable to calculate absolute risk rather than relying on risk-marker thresholds derived from relative risk estimates.

Approach to the patient with extremely low HDL-cholesterol.

Patients with extremely low high-density lipoprotein-cholesterol (HDL-C) pose distinct challenges to clinical diagnosis and management. Confirmation of HDL-C levels below 20 mg/dl in the absence of severe hypertriglyceridemia should be followed by evaluation for secondary causes, such as androgen use, malignancy, and primary monogenic disorders, namely, apolipoprotein A-I mutations, Tangier disease, and lecithin-cholesterol acyltransferase deficiency. Global cardiovascular risk assessment is a critical component of comprehensive evaluation, although the association between extremely low HDL-C levels and atherosclerosis remains unclear. Therapeutic interventions address reversible causes of low HDL-C, multiorgan abnormalities that may accompany primary disorders and cardiovascular risk modification when appropriate. Uncommon encounters with patients exhibiting extremely low HDL-C provide an opportunity to directly observe the role of HDL metabolism in atherosclerosis and beyond the vascular system.

The underappreciated impact of heart disease.

The 2009 recommendations of the U.S. Preventive Services Task Force regarding mammography have called attention to the roles of prevention and screening in promoting women's health. We take this opportunity to raise awareness of another devastating illness in women, ischemic heart disease, and to suggest that screening for ischemic heart disease, by providing early detection and identifying women who would benefit most from intensified medical therapy, merits consideration.

Beyond high-density lipoprotein cholesterol levels evaluating high-density lipoprotein function as influenced by novel therapeutic approaches.

A number of therapeutic strategies targeting high-density lipoprotein (HDL) cholesterol and reverse cholesterol transport are being developed to halt the progression of atherosclerosis or even induce regression. However, circulating HDL cholesterol levels alone represent an inadequate measure of therapeutic efficacy. Evaluation of the potential effects of HDL-targeted interventions on atherosclerosis requires reliable assays of HDL function and surrogate markers of efficacy. Promotion of macrophage cholesterol efflux and reverse cholesterol transport is thought to be one of the most important mechanisms by which HDL protects against atherosclerosis, and methods to assess this pathway in vivo are being developed. Indexes of monocyte chemotaxis, endothelial inflammation, oxidation, nitric oxide production, and thrombosis reveal other dimensions of HDL functionality. Robust, reproducible assays that can be performed widely are needed to move this field forward and permit effective assessment of the therapeutic potential of HDL-targeted therapies.

Statin use in patients with extremely low low-density lipoprotein levels is associated with improved survival.

BACKGROUND: Aggressive lipid management has recently become the standard of care for patients with coronary heart disease. The safety and effectiveness of statin usage for patients with extremely low low-density lipoprotein (LDL) levels are less clear, however. The aim of this study was to investigate the safety and clinical outcomes of statin treatment in patients with LDL cholesterol levels below 60 mg/dL. METHODS AND RESULTS: A total of 6107 consecutive patients with LDL levels less than 60 mg/dL were identified from a tertiary care medical center or affiliated community clinic. Statin therapy was defined as a prescription during the 150 days after the low LDL value was obtained. The propensity to be treated with a statin was used to adjust the association of statin therapy and survival. A total of 4295 patients (70%) had at least 1 prescription for any medication during the 150-day observation period after the low LDL value. Their mean age was 65 years, 43% had prior ischemic heart disease, and 47% had diabetes mellitus. Statins were prescribed in 2564 patients (60%) after the low LDL value was observed. During a mean follow-up of 2.0+/-1.4 years after the observation period, there were 510 deaths. After controlling for the propensity to receive a statin, statin therapy was associated with improved survival (hazard ratio [HR], 0.65; 95% CI, 0.53 to 0.80). This lower mortality was also observed for subgroups of patients already taking statins at baseline (HR, 0.58; 95% CI, 0.38 to 0.88), those with extremely low LDL levels (<40 mg/dL, n=623; HR, 0.51; 95% CI, 0.33 to 0.79), and those without a history of ischemic heart disease (n=2438; HR, 0.58; 95% CI, 0.42 to 0.80). Statin use was not associated with an increase in malignancy, transaminase elevation, or rhabdomyolysis. CONCLUSIONS: Statin therapy in the setting of a very low LDL level appears to be safe and is associated with improved survival.

Emerging therapies for the management of decompensated heart failure: from bench to bedside.

While pharmaceutical innovation has been highly successful in reducing mortality in chronic heart failure, this has not been matched by similar success in decompensated heart failure syndromes. Despite outstanding issues over definitions and end points, we argue in this paper that an unprecedented wealth of pharmacologic innovation may soon transform the management of these challenging patients. Agents that target contractility, such as cardiac myosin activators and novel adenosine triphosphate-dependent transmembrane sodium-potassium pump inhibitors, provide inotropic support without arrhythmogenic increases in cytosolic calcium or side effects of more traditional agents. Adenosine receptor blockade may improve glomerular filtration and diuresis by exerting a direct beneficial effect on glomerular blood flow while vasopressin antagonists promote free water excretion without compromising renal function and may simultaneously inhibit myocardial remodeling. Urodilatin, the renally synthesized isoform of atrial natriuretic peptide, may improve pulmonary congestion via vasodilation and enhanced diuresis. Finally, metabolic modulators such as perhexiline may optimize myocardial energy utilization by shifting adenosine triphosphate production from free fatty acids to glucose, a unique and conceptually appealing approach to the management of heart failure. These advances allow optimism not only for the advancement of our understanding and management of decompensated heart failure syndromes but for the translational research effort in heart failure biology in general.