Familial hypercholesterolemia/autosomal dominant hypercholesterolemia: Molecular defects, the LDL-C continuum, and gradients of phenotypic severity.

BACKGROUND: Familial hypercholesterolemia (FH) is a common inherited disorder in which the severity of atherosclerosis is generally proportional to the extent and duration of elevated plasma low-density lipoprotein cholesterol (LDL-C) levels. Homozygous FH (HoFH) is generally considered the most severe condition and results in very high LDL-C levels that respond only partially to statin therapy. The diagnosis of HoFH is complicated by its presentation as a phenotypic spectrum involving multiple genes. OBJECTIVE: The objective here is to review the genetics, continuum of LDL-C concentrations, and phenotypic severity of FH. METHODS: Multiple PubMed searches were conducted as described in the main text of this article. RESULTS: Traditionally, FH has been considered an autosomal co-dominant disorder whereby both heterozygotes (HeFH) and homozygotes are affected. Recently, additional genes and loci for monogenic FH have been characterized that allow for the identification of double mutations in the known genes and loci and the description of novel forms of double heterozygous FH. Phenotypic expression and clinical severity of untreated HeFH, double HeFH, compound HeFH, and HoFH vary with some overlap both between and within the genotypes. In addition, there is overlap in LDL-C levels of treated HeFH and treated HoFH. CONCLUSIONS: These discoveries raise the possibility that new combinations of molecular defects could modulate the severity of hypercholesterolemia. These defects are unlikely to represent true homozygosity. However, they are likely to result in a phenotype consistent with HoFH or severe HeFH, which will be important as new therapies become available with indications specifically for HoFH.

Aflibercept Plus FOLFIRI vs. Placebo Plus FOLFIRI in Second-Line Metastatic Colorectal Cancer: a Post Hoc Analysis of Survival from the Phase III VELOUR Study Subsequent to Exclusion of Patients who had Recurrence During or Within 6 Months of Completing Adjuvant Oxaliplatin-Based Therapy.

The aim of this post hoc analysis of the VELOUR study (ClinicalTrials.gov NCT00561470) was to investigate the treatment effect of adding aflibercept to second-line infusional 5-fluorouracil (5-FU), leucovorin and irinotecan (FOLFIRI) in patients with metastatic colorectal cancer (mCRC) who had failed any prior oxaliplatin-containing regimen. Adjuvant rapid relapsers (ARR), who were enrolled directly following relapse during or within 6 months of completion of oxaliplatin-containing adjuvant chemotherapy (N = 124, including 17 patients who also received bevacizumab as part of their adjuvant therapy), were excluded from the original VELOUR intention-to-treat (ITT) population (N = 1226). After exclusion of the ARR, overall survival (OS) in the ITT minus ARR (ITT-ARR) population (N = 1102) was longer in the aflibercept plus FOLFIRI arm than in the placebo plus FOLFIRI arm [hazard ratio (HR) 0.78, 95 % confidence interval (CI) 0.68-0.90; median survival difference 1.87 months]. In the subgroup of patients assigned to the prior bevacizumab stratum at randomization, OS was numerically longer in the aflibercept plus FOLFIRI arm than in the placebo plus FOLFIRI arm (HR 0.81; 95 % CI 0.63-1.04; median survival difference 2.14 months). Comparison of the post hoc analysis results with the primary analysis from VELOUR suggests that the inclusion of the directly enrolled ARR may have understated the aflibercept treatment benefit for both bevacizumab-pretreated and bevacizumab-naïve patients in the strictly second-line setting although no definitive conclusion may be inferred. The benefit associated with the addition of aflibercept to second-line FOLFIRI in patients with mCRC was observed whatever the timing of first-line disease progression. There were no unexpected safety concerns.

Time course of safety and efficacy of aflibercept in combination with FOLFIRI in patients with metastatic colorectal cancer who progressed on previous oxaliplatin-based therapy.

BACKGROUND: Patients with metastatic colorectal cancer (mCRC) previously-treated with oxaliplatin benefit significantly from the addition of aflibercept to FOLFIRI in relation to overall survival, progression-free survival and response rate. PATIENTS AND METHODS: The results for efficacy and safety over the time course of the VEGF Trap (aflibercept) with irinotecan in colorectal cancer after failure of oxaliplatin regimen trial were analysed based on data from 1226 patients randomised to receive FOLFIRI plus either aflibercept (n=612) or placebo (n=614). Hazard ratios (HR) by 6-month time period were estimated using a piecewise Cox proportional hazard model. Severity of adverse events (AEs) was graded using National Cancer Institute Common Terminology Criteria, version 3.0. RESULTS: The estimated probabilities of survival were 38.5% versus 30.9% at 18 months, 28.0% versus 18.7% at 24 months and 22.3% versus 12.0% at 30 months, for the aflibercept- and placebo-treated arms, respectively. The proportional improvement in the HR over time was consistent with the survival probability results; survival at 24 months was improved by 50% and almost doubled at 30 months. The majority of worst-grade AEs occurred within the first four cycles of treatment and in a small percent of treatment cycles and were mostly reversible. Common chemotherapy- and anti-vascular epithelial growth factor (VEGF)-associated AEs occurred rarely and in a small proportion of cycles with the majority being of single occurrence. CONCLUSIONS: The addition of aflibercept to FOLFIRI showed a continued and persistent improvement in overall survival over time in patients with mCRC. Although grade 3-4 AEs were more frequent in the aflibercept arm, they occurred in early treatment cycles and decreased sharply following initial presentation.

Familial hypercholesterolemia and estimation of US patients eligible for low-density lipoprotein apheresis after maximally tolerated lipid-lowering therapy.

Familial hypercholesterolemia (FH), an autosomal-dominant inherited disorder, can occur in either the heterozygous (HeFH) or homozygous (HoFH) state, and is characterized by high levels of serum low-density lipoprotein cholesterol (LDL-C). Although potent statins and maximally tolerated lipid-lowering therapy (LLT) have greatly reduced the risk of premature coronary heart disease (CHD) and death, all patients with HoFH and many with severe HeFH remain far from treatment goals and are thus at risk of cardiovascular disease. LDL apheresis is the treatment of choice for these patients but remains underutilized. No formal studies or epidemiologic data have estimated the prevalence of HoFH. An HeFH prevalence of 1:500 and a simplified Hardy-Weinberg equilibrium model was used to determine the probability of finding HoFH as 1:1 million in the general population. A US population of approximately 314.8 million was used to determine the number of cases of HoFH and HeFH. The following key parameters were used to estimate the prevalence of severe HeFH: baseline pretreatment LDL-C level and distribution of patients with FH, posttreatment LDL-C level and distribution after maximally tolerated LLT, and baseline percentage of patients with HeFH who have CHD. We assumed an HeFH prevalence of 1:500 and used statistics for a Gaussian distribution after the posttreatment means and standard deviations of LDL-C levels in patients with HeFH receiving maximally tolerated LLT, as has been documented by data from clinical trials and cross-sectional studies. These estimates do not include the statin-intolerant population. The objective of this analysis was to determine the prevalence of the US population with severe HeFH with or without CHD who still will be eligible for LDL apheresis despite maximally tolerated LLT. We estimated that there are 315 US patients with HoFH and 650,000 with HeFH. The estimated prevalence of the severe HeFH population eligible for apheresis is approximately 1:20,000 (range, 1:11,700-1:62,500). This estimate suggests that, based on the efficacy of maximally tolerated LLT and CHD status, approximately 15,000 (approximately 2.4%) of the 625,000 patients with HeFH who are maximally treated will still be eligible for LDL apheresis.