The Italian Consensus Conferences on low density lipoprotein-cholesterol apheresis

Phlebotomy has been used to reduce levels of unfavourable substances in the body for over 3,000 years. In the past, this non-selective procedure was widely used for very different therapeutic purposes and it was thought that it could bring people back to health. Stories about people undergoing multiple incisions in their veins were quite common and there even are reports of people having bled to death. In 1799, George Washington died after having several liters of blood drained within 24 hours; accounts differ with respect to the amount of blood he lost, mentioning anything between 2 to 5 litres¹. In 1914, Abel performed the first experimental apheresis (a Greek word meaning “taking away”) in uremic dogs²; he was the first to use the term plasmapheresis. Over the following decades, techniques evolved to deplete just plasma for plasma exchange, e.g. in hyperviscosity syndrome. In 1965, the first centrifuge was used as a cell separator³. The first plasma exchange in homozygous familial hypercholesterolaemia (FH) was described in 1975⁴, and the following years confirmed the benefit of its long-term use on cardiovascular health and survival^5,6. Different ways were tried to selectively remove low density lipoprotein-cholesterol (LDL-C). In 1981, LDL-C was removed by immunoadsorption and this was termed LDL-apheresis. The effects were first shown in vivo in pigs, and then it was used safely over nine months in patients with familial hypercholesterolaemia^7,8. Today, several systems are available that can be used to very efficiently and selectively reduce apolipoproteinB100 containing lipoproteins, namely LDL-C and lipoprotein(a) [Lp(a)], from plasma or whole blood. A brief summary of the background to therapeutic LDL-apheresis and its techniques and effects is provided by Stefanutti in this issue of the Journal⁹.

All techniques reduce LDL-C and Lp(a) by about 60–70% per treatment¹⁰. LDL-C and Lp(a) increase again rapidly in the first few days following a first order kinetic (Kroon formula: caveat apheresis was performed biweekly)^8,11. Therefore, apheresis has to be repeated regularly and the time-averaged lipoprotein levels have to be calculated. Apheresis usually has to be repeated every week; in some patients who respond very well to the concomitant lipid lowering medications a biweekly treatment might be sufficient^12,13.

Lipoprotein apheresis is generally well tolerated and safe¹⁰. The only contraindication is the use of ACE-inhibitors, due to a bradykinin reaction. Therefore, ACE-inhibitors have to be stopped and other antihypertensive drugs have to be selected well before starting lipoprotein apheresis. Side effects are usually not severe and are easily managed. Technical problems, namely venous access problems, and hypotension, are the most common side effects¹³. Apheresis is safe enough to be used even in children and pregnant women. The German Lipoprotein Apheresis Registry gives impressive confirmation of the safety of the procedure over the years. In 2014 (unpublished data), 4.44% adverse events were documented in 4,667 treatments in 930 patients (3.46%=1 adverse event, 1.01%>1 adverse event). The most common adverse events were: problems of venous access (1.91%), hypotension (1.2%), dizziness (0.45%), and technical problems (0.39%) (data of 2012 and 2013¹⁴).

Apheresis is applied as a “last resort” therapy in high-risk patients to reach treatment goals in addition to maximally tolerated lipid lowering (combined) medication, or if lipid lowering medications are not tolerated or not tolerated in sufficient doses. It has been shown to have beneficial effects on endothelial function and myocardial perfusion in patients with hypercholesterolaemia^15,16 and hyperlipoproteinaemia(a)¹⁷.

In FH patients undergoing lipoprotein apheresis, LDL-C levels are significantly reduced¹⁸ and these high-risk patients benefit from this treatment option. Cardiovascular events can be reduced in homozygous FH patients¹⁹, and cardiovascular morbidity and mortality can be significantly reduced in heterozygous FH²⁰. Consequently, it has been postulated that, in homozygous FH, apheresis should be initiated as early in childhood as technically possible. Safe venous access and tolerance of the extracorporeal volume are the criteria which should determine when to start treatment in homozygous FH.

A meta-analysis of coronary angiographic trials, including studies of the use of diet, lipid-lowering drug therapy, or apheresis, showed that apheresis might be more effective in reducing progression of coronary heart disease¹⁰. In the three groups studied, progress was seen in 46, 33, and 18%, respectively; regression or no change was seen in 54, 67, and 82%, respectively. Despite the long-lasting availability of lipoprotein apheresis and the positive data regarding long-term safety and cardiovascular benefits, there is no international guideline for the indication(s) of lipoprotein apheresis. Some countries and medical societies have drafted guidelines; several countries for the indications for LDL-apheresis and a few countries for Lp(a)-apheresis. However, this does not necessarily mean that treatment is reimbursed because the apheresis filter sets are very expensive. In addition, apheresis is an elaborate treatment and specialised centres are not available everywhere; thus, apheresis is not used as often as indications would require. Another reason is that no data from huge randomised controlled double-blind trials are available. Some reasons for this are the expensive therapy that can just be applied in specialised centres, that potential participants live widespread, and that sham therapy is hardly possible.

In this issue of the Journal, Stefanutti reports on the Italian Consensus Conference on LDL-apheresis⁹. Two different medical specialties and various medical societies engaged in cardiovascular diseases and in apheresis, thus reflecting the multidisciplinary approach, discussed and defined a consensus document on important aspects of this special kind of therapy. Most importantly, the participants agreed on the indications for initiating LDL-apheresis. Both consensus conferences put homozygous FH and compound homozygous FH at the top of the list of pathologies to be treated with this approach, which is in line with international guidelines and national consensus agreements of other countries^10,21–25.

This is due to the fact that in homozygous FH and severe cases of heterozygous FH it is impossible to lower LDL-C levels sufficiently by lipid lowering medications, even if used in the highest doses and widest combinations. As a consequence, cardiovascular morbidity and mortality is very high, and children affected by homozygous FH suffer from cardiovascular disease or die at a very young age if not treated early enough²⁶.

The first conference saw a second indication for patients with heterozygous or other primary hypercholesterolaemia plus: a) if LDL-C is not sufficiently reduced by combined pharmacotherapy and a special diet; b) in the presence of severe atherosclerosis; or c) if coronary angioplasty or surgery is necessary. In homozygous FH and compound heterozygous FH children, apheresis should be started as early as possible. The first efficacy parameter is an LDL-level as low as possible over time. The cardiovascular effects should be regularly evaluated to decide whether apheresis should be continued or stopped.

The 2009 Consensus has a board scope. Besides homozygous and compound heterozygous FH, further genetic constellations going along with high cardiovascular risk are named: autosomal recessive hypercholesterolaemia, heterozygous FH, elevated lipoprotein(a), other genetic dyslipoproteinaemias associated with high risk, and severe hypercholesterolaemia in patients with progressive cardiovascular disease.

Familial hypercholesterolaemia is the most widely accepted indication for apheresis. In Germany²¹, apheresis is indicated in homozygous FH without defined threshold levels or further requirements. The second group comprises patients with severe hypercholesterolaemia if LDL-C can not be decreased to target levels despite maximal lipid lowering medication. Typically, these are patients with severe heterozygous FH or with established cardiovascular disease (CVD). In Austria²⁵, homozygous FH and severe heterozygous FH (LDL-C>190 mg/dL) in primary prevention, FH with LDL-C more than 160 mg/dL in secondary prevention, and more than 130 mg/dL and progressive atherosclerosis are considered to be indications. In Britain¹⁰, the indication is seen in homozygous FH with total cholesterol more than 350 mg/dL or a less than 50% decrease on drug therapy, and in patients with heterozygous FH or an at-risk family history if coronary disease is progressive and if LDL-C is above 200 mg/dL or decreased by less than 40% by combination drug therapy.

The European guidelines for the management of dyslipidaemias²² briefly mentioned apheresis in severely affected individuals. In Japan²⁴, apheresis is covered in homozygous FH and in heterozygous FH if total cholesterol exceeds 400 mg/dL under diet therapy and does not decrease to 250 mg/dL or less by drug therapy in patients with coronary heart disease. In the United States²³, the FDA approved indications for apheresis are homozygous FH with LDL-C ≥300 mg/dL, heterozygous FH without CVD and LDL-C ≥300 mg/dL, or with high-risk characteristics and LDL-C≥200 mg/dL, or with very high-risk characteristics (established cardiovascular disease or diabetes) and LDL-C≥160 mg/dL.

Elevated levels of Lp(a) are stipulated or recommended as an indication for apheresis in the different guidelines of Germany²¹, Italy²⁷, United Kingdom¹⁰, and Austria²⁵ in consideration of specified conditions. This is confirmed by newer retrospective data²⁸ and a prospective trial²⁹ showing that lowering high levels of Lp(a) via apheresis reduces cardiovascular morbidity.

Lipoprotein apheresis is time consuming, expensive, and not available everywhere, and is, therefore, under-used despite its acknowledged benefits. It is to be hoped that, in the future, the new medical treatment options, especially Lomitapide and PCSK9-inhibitors, will promote the early diagnosis of severely affected patients, resulting in earlier and optimised therapy. This should include all available measures, including apheresis, to reduce the risk of early CVD and death.