ReviewEfficacy criteria and cholesterol targets for LDL apheresis
Introduction
In its recent clinical guideline on familial hypercholesterolaemia (FH) the National Institute for Clinical Excellence (NICE) sanctioned the use of LDL apheresis to treat patients in the United Kingdom (UK) with, or at high risk of, cardiovascular disease who are refractory to or intolerant of lipid-lowering drugs [1]. Three categories of patients considered eligible had earlier been identified by the HEART-UK Working Group on LDL apheresis: (i) children and adults with homozygous FH whose serum total cholesterol remained >9 mmol/l or decreased by <50% on drug therapy; (ii) FH heterozygotes with progressive coronary artery disease (CAD) whose LDL cholesterol remained >5 mmol/l or decreased by <40% on maximal drug therapy or exceptionally, cases with lower levels of LDL; (iii) patients with lipoprotein (a) (Lp(a)) >60 mg/dl and progressive CAD whose LDL cholesterol remained >3.2 mmol/l despite drug therapy [2]. However, guidance concerning the target levels of total and LDL cholesterol to be achieved by LDL apheresis is lacking except for two brief reports, one from a group of German physicians [3] and the other from the American Society for Apheresis (AFSA) [4]. The former advocated lowering LDL cholesterol by >60% during each apheresis procedure and decreasing Lp(a) by >50% on a long-term basis whereas AFSA's goals were a 45–55% reduction in time-averaged (interval mean) levels of total cholesterol and 40–60% reduction in the corresponding levels of LDL and Lp(a).
The lack of detailed guidance on this important topic suggests that current recommendations on whom to treat should be supplemented by additional proposals specifying the target levels of cholesterol that need to be achieved in order to delay the onset or arrest progression of the aortic and coronary atherosclerosis to which FH homozygotes and heterozygotes, respectively are so prone. Defining such target levels has been facilitated recently by the publication of three follow-up studies of FH homozygotes undergoing apheresis, in whom the occurrence of cardiovascular involvement was documented in relation to the prevailing lipid levels [5], [6], [7]. These studies complement earlier data showing correlations between non-invasive indices of atherosclerosis in FH patients and the “cholesterol × years score” off and on treatment [8], [9].
Section snippets
The post-apheresis rebound in plasma cholesterol
The changes in serum or plasma cholesterol which occur following plasma exchange or LDL apheresis are illustrated in Fig. 1. The magnitude of the acute decrease depends upon the efficiency of the system used and the volume of plasma or blood treated during the procedure. This decrease is succeeded by a rapid curvilinear rebound over the next few days, followed by a slower rise during the second week which eventually reaches a plateau unless interrupted by another apheresis session. Repetition
Criteria of apheresis efficacy
The repetitive nature of apheresis and ensuing fluctuations in plasma lipids need to be taken into account when defining efficacy. Long-term apheresis performed at regular intervals results in repetitive, non-steady state changes in serum cholesterol which are best expressed by the interval or time-averaged mean between sequential procedures. Cumulative interval mean values can be averaged over periods of months or even years, thereby providing an overall estimate of efficacy in individual
Cardiovascular disease in FH homozygotes on apheresis
Data on the occurrence of cardiovascular disease in children and adults with homozygous FH have recently been reported from France [5] and the USA [6], [7]. As shown in Table 2, a total of 95 patients was followed up, 64 of whom were undergoing long-term plasma exchange or LDL apheresis, usually combined with a high dose of statin plus ezetimibe. Apheresis was commonly initiated between the ages of 7 and 9 and maintained for periods of 6–12 years.
Baseline levels of total or LDL cholesterol off
Target levels of cholesterol during long-term apheresis
The data discussed above imply that values for total or LDL cholesterol on apheresis need to be as low as or even lower than the levels quoted in those reports if premature cardiovascular disease is to be prevented. With this in mind it is proposed that target levels for homozygotes undergoing repetitive apheresis should be as follows:
- (i)
An acute reduction in total cholesterol of ≥65% or in LDL cholesterol of ≥70% on average during each procedure.
- (ii)
An interval mean total cholesterol of <7 mmol/l or
Detection and monitoring of cardiovascular disease in FH
The NICE guidelines listed numerous investigations which could be used to serially evaluate cardiovascular involvement in FH patients but gave few details of when and how often they should be performed [1]. The frequency of atherosclerosis of the aortic valve and root in homozygotes is well documented [24] and is best monitored by echocardiography [25]. Kolansky et al. [7] advocate performing this investigation at baseline and annually thereafter and carrying out a stress test if the results of
Conclusions
LDL apheresis has largely supplanted plasma exchange as a means of treating patients with drug-refractory hypercholesterolaemia, many of whom have homozygous FH, and is now recognised as the treatment of choice for the latter disorder [7]. However, guidelines regarding the level of plasma cholesterol which need to be achieved to prevent cardiovascular disease in such patients have hitherto been lacking, mainly because of insufficient evidence. The recent publication of follow-up data on a
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Cited by (0)
- 1
HEART-UK LDL Apheresis Working Group.