OBJECTIVE: To assess the effectiveness and safety of low-density lipoprotein 
(LDL) apheresis performed with the heparin-induced extracorporeal LDL 
precipitation (HELP) system for the treatment of patients with refractory 
homozygous (HMZ) and heterozygous (HTZ) familial hypercholesterolemia (FH). 
BACKGROUND ON FAMILIAL HYPERCHOLESTEROLEMIA: Familial hypercholesterolemia is a 
genetic autosomal dominant disorder that is caused by several mutations in the 
LDL-receptor gene. The reduced number or absence of functional LDL receptors 
results in impaired hepatic clearance of circulating low-density lipoprotein 
cholesterol (LDL-C) particles, which results in extremely high levels of LDL-C 
in the bloodstream. Familial hypercholesterolemia is characterized by excess 
LDL-C deposits in tendons and arterial walls, early onset of atherosclerotic 
disease, and premature cardiac death. Familial hypercholesterolemia occurs in 
both HTZ and HMZ forms. Heterozygous FH is one of the most common monogenic 
metabolic disorders in the general population, occurring in approximately 1 in 
500 individuals. Nevertheless, HTZ FH is largely undiagnosed and an accurate 
diagnosis occurs in only about 15% of affected patients in Canada. Thus, it is 
estimated that there are approximately 3,800 diagnosed and 21,680 undiagnosed 
cases of HTZ FH in Ontario. In HTZ FH patients, half of the LDL receptors do not 
work properly or are absent, resulting in plasma LDL-C levels 2- to 3-fold 
higher than normal (range 7-15mmol/L or 300-500mg/dL). Most HTZ FH patients are 
not diagnosed until middle age when either they or one of their siblings present 
with symptomatic coronary artery disease (CAD). Without lipid-lowering 
treatment, 50% of males die before the age of 50 and 25% of females die before 
the age of 60, from myocardial infarction or sudden death. In contrast to the 
HTZ form, HMZ FH is rare (occurring in 1 case per million persons) and more 
severe, with a 6- to 8-fold elevation in plasma LDL-C levels (range 15-25mmol/L 
or 500-1000mg/dL). Homozygous FH patients are typically diagnosed in infancy, 
usually due to the presence of cholesterol deposits in the skin and tendons. The 
main complication of HMZ FH is supravalvular aortic stenosis, which is caused by 
cholesterol deposits on the aortic valve and in the ascending aorta. The average 
life expectancy of affected individuals is 23 to 25 years. In Ontario, it is 
estimated that there are 13 to 15 cases of HMZ FH. An Ontario clinical expert 
confirmed that 9 HMZ FH patients have been identified to date.
DIAGNOSIS: There are 2 accepted clinical diagnostic criterion for the diagnosis 
of FH: the Simon Broome FH Register criteria from the United Kingdom and the 
Dutch Lipid Network criteria from the Netherlands. The criterion supplement 
cholesterol levels with clinical history, physical signs and family history. 
DNA-based-mutation-screening methods permit a definitive diagnosis of HTZ FH to 
be made. However, given that there are over 1000 identified mutations in the LDL 
receptor gene and that the detection rates of current techniques are low, 
genetic testing becomes problematic in countries with high genetic 
heterogeneity, such as Canada.
TREATMENT: The primary aim of treatment in both HTZ and HMZ FH is to reduce 
plasma LDL-C levels in order to reduce the risk of developing atherosclerosis 
and CAD. The first line of treatment is dietary intervention, however it alone 
is rarely sufficient for the treatment of FH patients. Patients are frequently 
treated with lipid-lowering drugs such as resins, fibrates, niacin, statins and 
cholesterol absorption-inhibiting drugs (ezetimibe). Most HTZ FH patients 
require a combination of drugs to achieve or approach target cholesterol levels. 
A small number of HTZ FH patients are refractory to treatment or intolerant to 
lipid-lowering medication. According to clinical experts, the prevalence of 
refractory HTZ FH in Ontario is between 1 to 5%. Using the mean of 3%, it is 
estimated that there are approximately 765 refractory HTZ FH patients in 
Ontario, of which 115 are diagnosed and 650 are undiagnosed. Drug therapy is 
less effective in HMZ FH patients since the effects of the majority of 
cholesterol-lowering drugs are mediated by the upregulation of LDL receptors, 
which are often absent or function poorly in HMZ FH patients. Some HMZ FH 
patients may still benefit from drug therapy, however this rarely reduces LDL-C 
levels to targeted levels. EXISTING TECHNOLOGY: PLASMA EXCHANGE An option 
currently available in Ontario for FH patients who do not respond to standard 
diet and drug therapy is plasma exchange (PE). Patients are treated with this 
lifelong therapy on a weekly or biweekly basis with concomitant drug therapy. 
Plasma exchange is nonspecific and eliminates virtually all plasma proteins such 
as albumin, immunoglobulins, coagulation factors, fibrinolytic factors and 
HDL-C, in addition to acutely lowering LDL-C by about 50%. Blood is removed from 
the patient, plasma is isolated, discarded and replaced with a substitution 
fluid. The substitution fluid and the remaining cellular components of the blood 
are then returned to the patient. The major limitation of PE is its 
nonspecificity. The removal of HDL-C prevents successful vascular remodeling of 
the areas stenosed by atherosclerosis. In addition, there is an increased 
susceptibility to infections, and costs are incurred by the need for replacement 
fluid. Adverse events can be expected to occur in 12% of procedures. OTHER 
ALTERNATIVES: Surgical alternatives for FH patients include portocaval shunt, 
ileal bypass and liver transplantation. However, these are risky procedures and 
are associated with a high morbidity rate. Results with gene therapy are not 
convincing to date.
THE TECHNOLOGY BEING REVIEWED: LDL APHERESIS An alternative to PE is LDL 
apheresis. Unlike PE, LDL apheresis is a selective treatment that removes LDL-C 
and other atherogenic lipoproteins from the blood while minimally impacting 
other plasma components such as HDL-C, total serum protein, albumin and 
immunoglobulins. As with PE, FH patients require lifelong therapy with LDL 
apheresis on a weekly/biweekly basis with concomitant drug therapy. 
HEPARIN-INDUCED EXTRACORPOREAL LDL PRECIPITATION: Heparin-induced extracorporeal 
LDL precipitation (HELP) is one of the most widely used methods of LDL 
apheresis. It is a continuous closed-loop system that processes blood 
extracorporeally. It operates on the principle that at a low pH, LDL and 
lipoprotein (a) [Lp(a)] bind to heparin and fibrinogen to form a precipitate 
which is then removed by filtration. In general, the total duration of treatment 
is approximately 2 to 3 hours. Results from early trials indicate that LDL-C 
concentration is reduced by 65% to 70% immediately following treatment in both 
HMZ and HTZ FH and then rapidly begins to rise. Typically patients with HTZ FH 
are treated every 2 weeks while patients with HMZ FH require weekly therapy. 
Heparin-induced extracorporeal LDL precipitation also produces small transient 
decreases in HDL-C, however levels generally return to baseline within 2 days. 
After several months of therapy, long-term reductions in LDL-C and increases in 
HDL-C have been reported. In addition to having an impact on plasma cholesterol 
concentrations, HELP lowers plasma fibrinogen, a risk factor for 
atherosclerosis, and reduces concentrations of cellular adhesion molecules, 
which play a role in early atherogenesis. In comparison with PE, HELP LDL 
apheresis does not have major effects on essential plasma proteins and does not 
require replacement fluid, thus decreasing susceptibility to infections. One 
study noted that adverse events were documented in 2.9% of LDL apheresis 
treatments using the HELP system compared with 12% using PE. As per the 
manufacturer, patients must weigh at least 30kgs to be eligible for treatment 
with HELP.
REGULATORY STATUS: The H.E.L.P.® System (B.Braun Medizintechnologie GmbH, 
Germany) has been licensed by Health Canada since December 2000 as a Class 3 
medical device (Licence # 26023) for performing LDL apheresis to acutely remove 
LDL from the plasma of 3 high-risk patient populations for whom diet has been 
ineffective and maximum drug therapy has either been ineffective or not 
tolerated. The 3 patient groups are as follows: Functional hypercholesterolemic 
homozygotes with LDL-C >500 mg/dL (>13mmol/L);Functional hypercholesterolemic 
heterozygotes with LDL-C >300 mg/dL (>7.8mmol/L);Functional hypercholesterolemic 
heterozygotes with LDL-C >200 mg/dL (>5.2mmol/L) and documented CADNo other LDL 
apheresis system is currently licensed in Canada.
REVIEW STRATEGY: The Medical Advisory Secretariat systematically reviewed the 
literature to assess the effectiveness and safety of LDL apheresis performed 
with the HELP system for the treatment of patients with refractory HMZ and HTZ 
FH. A standard search methodology was used to retrieve international health 
technology assessments and English-language journal articles from selected 
databases. The GRADE approach was used to systematically and explicitly make 
judgments about the quality of evidence and strength of recommendations.
SUMMARY OF FINDINGS: The search identified 398 articles published from January 
1, 1998 to May 30, 2007. Eight studies met the inclusion criteria. Five case 
series, 2 case series nested within comparative studies, and one retrospective 
review, were included in the analysis. A health technology assessment conducted 
by the Alberta Heritage Foundation for Medical Research, and a review by the 
United States Food and Drug Administration were also included. Large 
heterogeneity among the studies was observed. Studies varied in inclusion 
criteria, baseline patient characteristics and methodology. Overall, the mean 
acute relative decrease in LDL-C with HELP LDL apheresis ranged from 53 to 77%. 
The mean acute relative reductions ranged as follows: total cholesterol (TC) 47 
to 64%, HDL-C +0. (ABSTRACT TRUNCATED)