Use of apheresis in the age of new therapies for familial hypercholesterolaemia.

PURPOSE OF REVIEW: Lipoprotein apheresis has been first line therapy for homozygous familial hypercholesterolaemia (FH) and other severe and refractory forms of dyslpidaemia for over 40 years but the recent advent of novel and potent LDL-lowering compounds necessitates a reappraisal of its role. RECENT FINDINGS: During the past decade a substantial amount of evidence has accumulated describing the effect of LDL-lowering with apheresis and conventional drug therapy upon the cardiovascular outcomes associated with homozygous and statin-refractory heterozygous FH. This has necessitated re-defining the target levels of LDL cholesterol needed to arrest progression of atherosclerosis in these situations. At the same time, evidence has accrued regarding the pathogenicity of raised levels of lipoprotein (a) and the promising role of apheresis in mitigating the adverse effects of the latter. The latest advance in treatment has been the introduction of three classes of novel and potent LDL-lowering compounds in the shape of inhibitors of Propertin convertase subtilisin kexin 9 (PCSK9), microsomal triglyceride transfer protein and angiopoietin-like 3. SUMMARY: These recent developments raise the question of whether these compounds will be used as adjuvants to bolster lipoprotein apheresis in FH homozygotes or whether they will render it obsolete, as is already occurring with PCSK9 inhibitors in FH heterozygotes.

FH through the retrospectoscope.

After training as a gastroenterologist in the UK, the author became interested in lipidology while he was a research fellow in the USA and switched careers after returning home. Together with Nick Myant, he introduced the use of plasma exchange to treat familial hypercholesterolemia (FH) homozygotes and undertook non-steady state studies of LDL kinetics, which showed that the fractional catabolic rate of LDL remained constant irrespective of pool size. Subsequent steady-state turnover studies showed that FH homozygotes had an almost complete lack of receptor-mediated LDL catabolism, providing in vivo confirmation of the Nobel Prize-winning discovery by Goldstein and Brown that LDL receptor dysfunction was the cause of FH. Further investigation of metabolic defects in FH revealed that a significant proportion of LDL in homozygotes and heterozygotes was produced directly via a VLDL-independent pathway. Management of heterozygous FH has been greatly facilitated by statins and proprotein convertase subtilisin/kexin type 9 inhibitors but remains dependent upon lipoprotein apheresis in homozygotes. In a recent analysis of a large cohort treated with a combination of lipid-lowering measures, survival was markedly enhanced in homozygotes in the lowest quartile of on-treatment serum cholesterol. Emerging therapies could further improve the prognosis of homozygous FH; whereas in heterozygotes, the current need is better detection.

Survival in homozygous familial hypercholesterolaemia is determined by the on-treatment level of serum cholesterol.

Aims: Homozygous familial hypercholesterolaemia (FH) is a rare inherited disorder characterized by extreme hypercholesterolaemia from birth, accelerated atherosclerosis, and premature death. Many forms of lipid-lowering therapies have been used in the past, but definitive evidence of benefit has been lacking. We therefore undertook a retrospective survey of lipid levels and clinical outcomes of FH homozygotes treated with a combination of lipid-lowering measures between 1990 and 2014 in South Africa and the UK. Methods and results: We divided 133 previously statin-naive homozygotes into quartiles according to their on-treatment levels of serum cholesterol and compared the occurrence of any death, cardiovascular death, and major adverse cardiovascular events (MACE) between the quartiles during 25 years of follow-up, using Cox and competing risks regression analysis. Patients in Quartile 4, with an on-treatment serum cholesterol >15.1 mmol/L, had a hazard ratio of 11.5 for any death compared with those in Quartile 1, with an on-treatment cholesterol of < 8.1 mmol/L. Those in Quartiles 2 and 3 combined, with on-treatment cholesterol of 8.1-15.1 mmol/L had a hazard ratio of 3.6 compared with Quartile 1. These differences were statistically significant (P < 0.001) and remained so after adjustments for confounding factors (P = 0.04). Significant differences between quartiles were also evident for cardiovascular deaths and MACE. Conclusion: These findings provide unequivocal evidence that the extent of reduction of serum cholesterol achieved by a combination of therapeutic measures, including statins, ezetimibe, lipoprotein apheresis, and evolocumab, is a major determinant of survival in homozygous FH.

Lipoprotein apheresis in the management of familial hypercholesterolaemia: historical perspective and recent advances.

At present, lipoprotein apheresis, combined with high-dose statin and ezetimibe therapy, is the best available means of treating patients with homozygous and statin-refractory heterozygous familial hypercholesterolaemia (FH). However, the extent of cholesterol-lowering achieved is often insufficient to meet the targets set by current guidelines. The recent advent of three new classes of lipid-lowering agents provides new hope that the latter objective may now be achievable. These compounds act either by reducing low-density lipoprotein (LDL) production by inhibiting apolipoprotein B synthesis with an antisense oligonucleotide (mipomersen) or by inhibiting microsomal triglyceride transfer protein (lomitapide), or by enhancing LDL catabolism via monoclonal antibody-mediated inhibition of the activity of proprotein convertase subtilisin/kexin 9 (PCSK9) (evolocumab). Depending on the outcome of current trials, it seems likely that these compounds, used alone or combined with lipoprotein apheresis, will markedly improve the management of refractory FH.

International Atherosclerosis Society guidance for implementing best practice in the care of familial hypercholesterolaemia.

This contemporary, international, evidence-informed guidance aims to achieve the greatest good for the greatest number of people with familial hypercholesterolaemia (FH) across different countries. FH, a family of monogenic defects in the hepatic LDL clearance pathway, is a preventable cause of premature coronary artery disease and death. Worldwide, 35 million people have FH, but most remain undiagnosed or undertreated. Current FH care is guided by a useful and diverse group of evidence-based guidelines, with some primarily directed at cholesterol management and some that are country-specific. However, none of these guidelines provides a comprehensive overview of FH care that includes both the lifelong components of clinical practice and strategies for implementation. Therefore, a group of international experts systematically developed this guidance to compile clinical strategies from existing evidence-based guidelines for the detection (screening, diagnosis, genetic testing and counselling) and management (risk stratification, treatment of adults or children with heterozygous or homozygous FH, therapy during pregnancy and use of apheresis) of patients with FH, update evidence-informed clinical recommendations, and develop and integrate consensus-based implementation strategies at the patient, provider and health-care system levels, with the aim of maximizing the potential benefit for at-risk patients and their families worldwide.

The scientific basis and future of lipoprotein apheresis.

Lipoprotein apheresis plays a vital role in the management of the severe hyperlipidemias that predispose to atherosclerosis. Determinants of efficacy are the acute reduction in lipoproteins achieved by each apheresis procedure, their frequency, and the fractional catabolic rates and hence pool sizes of low-density lipoprotein (LDL) or lipoprotein (a) (Lp(a)) of the patient being treated. A useful criterion of the efficacy of apheresis plus lipid-lowering drug therapy is the decrease in the interval (time-averaged) mean of serum total or LDL cholesterol or Lp(a) between procedures, expressed as the percent decrease in the interval means below the maximal levels of these lipoproteins when off all treatment. Recent advances in lipid-lowering drug therapy may diminish the use of lipoprotein apheresis but will not abolish its unique role as a therapeutic "last chance saloon," especially for children and pregnant women with homozygous familial hypercholesterolemia.

Lipoprotein apheresis.

PURPOSE OF REVIEW: Lipoprotein apheresis is being performed with increasing frequency, but better data collection and recording of clinical outcomes are needed. Setting up registries would facilitate this process. RECENT FINDINGS: This review appraises recent articles that discuss the need for national registries and requirements for setting them up, the efficacy of lipoprotein apheresis in homozygous familial hypercholesterolaemia and patients with coronary disease secondary to raised levels of lipoprotein (a), and its role in the management of acute pancreatitis secondary to severe hypertriglyceridaemia. SUMMARY: Lipoprotein apheresis seems to be going through a growth spurt, presumably reflecting better implementation of treatment guidelines or a broadening of indications for its use.

Severe hypercholesterolaemia: therapeutic goals and eligibility criteria for LDL apheresis in Europe.

PURPOSE OF REVIEW: Despite the use of currently available lipid-lowering therapies, a significant proportion of patients with severe hypercholesterolaemia do not reach treatment goals and consequently remain at increased risk for cardiovascular disease (CVD). On the basis of clinical experience, these patients tend to have the most severe forms of familial hypercholesterolaemia or markedly elevated LDL cholesterol (LDL-C) levels but are unable to tolerate statin therapy. RECENT FINDINGS: LDL apheresis is currently the best treatment option (or treatment rescue) to bring these patients closer to therapeutic LDL objectives, and has been shown to reduce the risk of CVD along with LDL-C levels. However, criteria for LDL apheresis eligibility and the percentage of patients receiving treatment vary widely from country to country across Europe. Despite the proven benefits of LDL apheresis, access to this procedure remains limited because of its high cost and low availability, reflecting inherent limitations of this treatment modality. SUMMARY: There is a need to both better define the patient population eligible for LDL apheresis and to create unified European guidelines governing the use of apheresis. In addition to improving access to apheresis where appropriate, new therapies are needed to further decrease LDL-C and reduce the ongoing CVD risk in patients with severe hypercholesterolaemia.

Plasminogen activator inhibitor-1 removal using dextran sulphate columns. Evidence of PAI-1 homeostasis.

Patients with high plasma plasminogen activator inhibitor-1 (PAI-1) antigen levels are prone to develop thrombosis. Lowering PAI-1 levels may offer a therapeutic option and help to better understand PAI-1 metabolism. We examined the effect on plasma PAI-1 levels of LDL-apheresis using dextran sulphate (DS) columns in 12 patients (9 male, 3 female, 49 +/- 10 years) with heterozygous familial hypercholesterolaemia and coronary artery disease. One plasma volume equivalent (2.3-4.0 l) was treated during each procedure (at flow rates of 23 +/- 2 ml/min). Lipids and PAI-1 antigen levels were measured in plasma before and immediately after 19 aphereses (once in 7 patients, twice in 3 patients and three times in 2 patients) and also at 3 and 7 days post apheresis in five of these patients and in the column eluates from 8 of these patients. DS-apheresis reduced plasma cholesterol (50 +/- 8%), triglyceride (45 +/- 27%), apolipoprotein B (59 +/- 10%) and PAI-1 antigen levels from 10.2 +/- 5.2 to 6.0 +/- 3.1 ng/ml (P = 0.005). The PAI-I changes were independent of circadian variation. PAI-I bound to the DS-columns (3.51 +/- 1.03 ng/ml filtered plasma) and the percent of filtered PAI-1 that was bound correlated inversely (r = -0.81, P < 0.02) with basal PAI-1 levels indicating a high affinity saturable binding process. In four patients, plasma PAI-1 levels post-apheresis were higher than expected based on the amount of PAI-removed by the DS columns. The difference between the expected and actual PAI-1 level post apheresis, reflecting PAI-1 secretion or extracellular redistribution, correlated inversely with basal PAI-1 levels (r = -0.83, P = 0.01). PAI-1 levels returned to baseline pre-apheresis values 7 days post apheresis. PAI-1 antigen may be removed from plasma without adverse effect, resulting temporarily in its extracellular redistribution and restoration to baseline levels over one week. PAI-1 redistribution particularly when baseline pre-apheresis values were low may reflect a homeostatic mechanism to maintain sufficient PAI-1 levels. Procedures that could selectively remove PAI-1 from plasma may offer a treatment option for those with very high plasma PAI-1 levels and thrombosis.

Atherosclerosis in cholesterol-fed rabbits and in homozygous and heterozygous LDL receptor-deficient humans.

A phenocopy is an environmentally-defined phenotype that mimics another, genetically-determined phenotype. The severity of hypercholesterolaemia, extent of down regulation of LDL receptor expression and aortic root localisation of atherosclerosis in cholesterol-fed rabbits strikingly resemble the cardinal features of homozygous familial hypercholesterolaemia (FH) in humans, suggesting that the former is a phenocopy of the latter. This review compares the metabolic and pathological consequences of induced hypercholesterolaemia in rabbits with those of homozygous FH and contrasts their ease of reversibility on resumption of a normal diet with the refractoriness to lipid-lowering therapy of homozygotes, in whom major adverse cardiovascular events and survival depend upon the prevailing level of serum cholesterol. The monofactorial nature of the atherosclerosis in both situations corroborates Anitschkow's concept that "Cholesterin ist alles." In contrast, atherosclerosis in heterozygous FH differs in several respects from that of homozygotes, notably the lack of aortic root involvement and in its multifactorial aetiology, with raised LDL cholesterol, male gender, low HDL cholesterol and raised lipoprotein (a) all contributing to its clinical expression. In angiographic trials of LDL-lowering therapy regression of coronary lesions was observed in FH heterozygotes whereas they progressed in non-FH subjects. Similarly, carotid artery plaques progressed less in FH heterozygotes than in non-FH subjects, in both instances despite FH patients having higher LDL cholesterol levels on treatment. These findings suggest that, compared with non-FH subjects, atherosclerotic lesions in FH heterozygotes may be hyper-responsive to LDL-lowering therapy, whereas treatment of homozygous FH remains a major challenge.

Measurement of the reflectivity of the intima-medial layer of the common carotid artery improves the discriminatory value of intima-medial thickness measurement as a predictor of risk of atherosclerotic disease.

Our aim was to assess the predictive value of a measurement of intima-medial layer (IML) reflectivity in the differentiation of pathological from physiological increases in intima-medial thickness (IMT). Both common carotid arteries (CCA) of familial hypercholesterolemia (FH) patients and age- and sex-matched controls (no cardiovascular risk factors) were imaged using a 10- to 15-MHz linear array transducer (n = 30). Images of the CCA far wall were analyzed in the IMT "plug-in" of "HDI Lab." The IML reflectivity, averaged over an 8- to 12-mm length of arterial wall, was expressed as a ratio of reflectivity at a point 0.21-mm deep to the intima-medial interface divided by the reflectivity at the intima-medial interface, termed the intima-medial reflectivity index (IMRI). The risk of atherosclerosis was assessed in terms of IMT alone and IMT coupled with IMRI. Defining high risk of atherosclerosis in FH, in terms of both IMT alone and IMT coupled with IMRI, produced an appropriate, when compared with cholesterol-years score, statistically significant stratification (p < 0.01 and p < 0.005). Analysis of the low-risk subjects revealed a tendency to define a subject as "high risk" based on a physiological increase in IMT, but when IMRI is included in the assessment, all controls are correctly identified as low risk. This method of quantifying the reflectivity of the IML improved the discriminatory performance of IMT increase as an indicator of atherosclerotic risk by enabling a smaller, therefore earlier, increase in IMT to be considered pathologic when accompanied by an increase in IMRI.

Additive effects of plant sterol and stanol esters to statin therapy.

Plant sterol and stanol esters each have similar additive effects in lowering low-density lipoprotein cholesterol when combined with statins. They differ in that plasma plant sterols increase when plant sterol esters are used for this purpose, especially in patients with familial hypercholesterolemia, but decrease when plant stanol esters are used.

History and development of plant sterol and stanol esters for cholesterol-lowering purposes.

Plant stanol esters provide a novel approach to lowering plasma low-density lipoprotein (LDL) cholesterol by dietary means. Their development was preceded by a long period of research into the cholesterol-lowering properties of plant sterols and, recently, plant stanols. Both classes of compound competitively inhibit the absorption of cholesterol and thus lower its level in plasma. Initial impressions were that stanols were more effective and safer than sterols, but the negative outcome of a study led to the recognition that the lipid solubility of free stanols was very limited. This was overcome by esterifying them with fatty acids, with the resultant stanol esters being freely soluble in fat spreads. This led to the launch of Benecol (margarine; Raisio Group, Raisio, Finland) in 1995. The coincident publication of the year-long North Karelia study conclusively demonstrated the long-term LDL-lowering efficacy of plant stanol esters. Variables that might influence the efficacy of stanol esters include dose, frequency of administration, food vehicle in which the stanol ester is incorporated, and background diet. The effective dose is 1 to 3 g/day, expressed as free stanol, which, in placebo-controlled studies, decreased LDL cholesterol by 6% to 15%. This effect is maintained, appears to be similar with once-daily or divided dosage, and is independent of the fat content of the food vehicle. Short-term studies suggest that equivalent amounts of plant sterol and stanol esters are similarly effective in lowering LDL, the main difference being that plasma plant sterol levels increase on plant sterols and decrease on plant stanols. The clinical significance of these changes remains to be determined.

Comparison of efficacy of plant stanol ester and sterol ester: short-term and longer-term studies.

Published data suggest that the cholesterol-lowering effect of dietary plant sterol esters is less marked in longer-term than in short-term studies, whereas plant stanol esters maintain their efficacy. To investigate this further, healthy subjects and patients with familial hypercholesterolemia (FH) receiving statins were randomized to receive plant sterol ester 1.6 g/day or plant stanol ester 1.6 g/day or 2.6 g/day for 2 months. There was no difference among the 3 groups in the pooled low-density lipoprotein (LDL)-lowering response of FH patients and healthy subjects, but the effect of plant sterol diminished at 2 months and was not significantly different from baseline. This was accompanied by increases in serum plant sterols and a significant decrease in 7alpha-hydroxy-4-cholesten-3-one, a marker of bile acid synthesis, especially in FH patients not taking bile acid sequestrants. In contrast, plant stanol esters lowered significantly both LDL cholesterol and plant sterols at 2 months and had no effect on bile acid synthesis. Slight decreases in serum lipid-soluble antioxidants occurred with both plant sterol and stanol esters. Our findings suggest that absorption of dietary plant sterols downregulates bile acid synthesis, which attenuates their cholesterol-lowering efficacy. We conclude that plant stanol esters are preferable for the long-term management of hypercholesterolemia.

Managing homozygous familial hypercholesterolaemia from cradle to grave.

OBJECTIVE: To describe the phenotypic and genotypic features and management of clinically homozygous familial hypercholesterolaemia (FH). METHODS: An analysis of current knowledge based on personal experience and published evidence. RESULTS: Atherosclerotic involvement of the aortic root is common in homozygous FH and can cause death before age 5. Receptor negative patients are at greatest risk, irrespective of whether they have identical mutations (homozygous) or dissimilar mutations (compound heterozygous). CONCLUSIONS: Lipoprotein apheresis combined with high dose statin and ezetimibe slows but does not arrest progression of atherosclerosis. Adjunctive use of novel compounds such as lomitapide and evolocumab should facilitate achieving the latter objective by enhancing the reduction in LDL cholesterol.

Improved cardiovascular outcomes following temporal advances in lipid-lowering therapy in a genetically-characterised cohort of familial hypercholesterolaemia homozygotes.

BACKGROUND AND AIMS: There is a paucity of data concerning the influence of lipid-lowering therapy on cardiovascular (CV) outcomes in patients with homozygous familial hypercholesterolaemia (FH). To redress this a retrospective analysis was undertaken of the demographic features, lipid levels, low density lipoprotein receptor and Autosomal Recessive Hypercholesterolaemia gene mutations, CV outcomes and vital status of 44 FH homozygotes referred to a single centre in the UK between 1964 and 2014. METHODS: Data were obtained from past publications, case records and death certificates. Differences in categorical and continuous variables between living and dead patients were analysed using Fisher's exact test and an independent t-test respectively. RESULTS: During the 50 years covered by this survey 13 patients have died, 30 are still alive and 1 was lost to follow up. The mean age of Alive patients was 32.6 ± 11.5 versus 28.3 ± 14.9 years in Dead ones (P = 0.31) and they were born 18 years later (P = 0.0001). Pre-treatment serum total cholesterol (TC) was similar in Alive and Dead (20.2 ± 5.1 v 21.3 ± 4.4 mmol/l, P = 0.52) but on-treatment TC was lower in Alive than Dead (8.1 ± 2.8 v 14.5 ± 6.0 mmol/l, P = 0.0001) and CV adverse events were far less frequent (eg aortic stenosis, 33% v 77%, P = 0.02). CONCLUSIONS: The lower on-treatment TC and fewer CV adverse events in FH homozygotes still living reflect advances in apheresis and drug therapy since the 1990s. Further improvements in prognosis can be expected with the impending introduction of novel lipid-lowering agents.

LDL apheresis.

Low density lipoprotein (LDL) apheresis provides a safe and effective means of treating patients with homozygous familial hypercholesterolaemia (FH). It also has a role in preventing the progression of coronary artery disease in heterozygotes and others with severe dyslipidaemia who are refractory to or intolerant of high doses of lipid-lowering drugs. Established methods involve either adsorption of apolipoprotein B-containing lipoproteins by affinity columns containing anti-apolipoprotein B antibodies or dextran sulphate, or their precipitation at low pH by heparin, in each instance after first separating plasma from blood cells with a cell separator. The most recently developed method enables lipoproteins to be adsorbed directly from whole blood, using polyacrylate columns. All 4 methods have proved to be similarly efficient when used weekly or biweekly to lower LDL cholesterol and Lp(a) without unduly reducing HDL cholesterol. Economic constraints restrict the use of LDL apheresis to the treatment of potentially fatal disorders such as FH, where there is clear evidence of benefit compared with conventional therapy. Widening the indications to include the treatment of other dyslipidaemic disorders such as steroid-resistant nephrotic syndrome, post-transplant donor vessel disease, stroke and prevention of re-stenosis after coronary angioplasty requires evidence from controlled trials that is currently lacking.

The evidence-base for the efficacy of lipoprotein apheresis in combating cardiovascular disease.

OBJECTIVE: To review the evidence supporting the use of lipoprotein apheresis to treat severe forms of dyslipidaemia that predispose to cardiovascular disease and are refractory to conventional therapy. METHODS: Review of relevant publications based on personal knowledge and a search of the literature from the past 10 years using PubMed. RESULTS: There is good evidence that drastic lowering of LDL by lipoprotein apheresis increases longevity in homozygous familial hypercholesterolaemia (FH) and decreases cardiovascular morbidity in FH heterozygotes refractory to or intolerant of statins. Lipoprotein apheresis may also decrease cardiovascular events in patients with raised levels of Lp(a) but further data are needed. CONCLUSIONS: Lipoprotein apheresis currently provides a therapeutic life-line for a small number of very high risk patients. It remains to be seen what effect the recent emergence of several novel and powerful lipid-lowering drugs will have on its future role in that respect.