May, 1997

LDL APHERESIS: A New Treatment For Severe Dyslipidemia

Rama Shankar, M.D., Fellow
Joseph E. Kiss, M.D.,Medical Director Hemapheresis and Blood Services


What can transfusion medicine offer to patients with hypercholesterolemia? Recent advances in affinity column technology now enable the efficient removal of LDL-cholesterol directly from the bloodstream by apheresis. This new therapeutic tool may reduce the risk of progressive atherosclerotic disease in hypercholesterolemic patients who are resistant to diet and drugs.

Introduction:

Hypercholesterolemia is a well known major risk factor for ischemic heart disease. Reduction in serum total cholesterol and the low-density lipoprotein-fraction, LDL-C, has been conclusively shown in randomized, controlled clinical trials to prevent the development and progression of atherosclerotic cardiovascular disease.

Lipids are transported in different lipoprotein fractions in blood. The protein moiety of the lipoprotein, apolipoprotein-B, and it’s degradation products, are the atherogenic elements. The apolipoprotein-B is in highest concentration in LDL-C and is present in smaller amounts in very low density lipoprotein-cholesterol (VLDL-C). High-density cholesterol (HDL-C) levels lack the atherogenic apolipoprotein-B component and relate inversely to coronary artery disease risk.

Familial hypercholesterolemia is an autosomal dominant disorder which results from mutations involving the gene encoding the LDL receptor. The rare homozygous form is characterized by premature atherosclerosis at a very young age (first 10 years of life); myocardial infarction-related mortality usually occurs by the age of 25 years. While not as severe, patients with the heterozygous form (frequency 1 in 500) are also at high risk for premature atherosclerotic disease. 

Adequate control of serum cholesterol levels is generally achieved by dietary modifications and/or drug regimens, including HMG-CoA reductase inhibitors, bile acid binding resins, and nicotinic acid. However, a subset of patients, particularly those with familial hypercholesterolemia, fail to respond. Additional treatment methods may be necessary to reduce LDL-C to safer levels in these individuals who are at high risk for atherosclerotic disease complications.

 

TECHNIQUE:

Two extracorporeal procedures, plasmapheresis and LDL-apheresis, have been shown to be effective in lowering LDL-C. However, plasmapheresis has the disadvantage of non-selective removal of all serum proteins including the "protective" cholesterol-HDL-C. The LDL-apheresis procedure selectively removes apolipoprotein-B containing cholesterol such as LDL-C and VLDL-C, sparing the HDL-C.

Several methods for LDL-apheresis have been developed. However, the only device currently approved by the Food & Drug Administration is a dextran sulfate adsorption system (Liposorber LA-15 , Kaneka America Corp.). This procedure acutely lowers LDL, VLDL, and lipoprotein(a) levels by 60-70%. The time-averaged lowering of LDL falls in the range of 40-60% depending on how often the treatment is performed (usually every 1-2 weeks). A considerable degree of compliance on the part of the patient is necessary, since long-term treatment is usually indicated.

Lipoprotein-apheresis is a safe and well tolerated procedure. As with all apheresis procedures, adequate venous access is required. Complications are infrequent and consist of hypotension, bradycardia, nausea, and headache.

 

CLINICAL RESULTS:

The efficacy of LDL-apheresis in lowering LDL-C and slowing the rate of atherosclerotic cardiovascular disease progression has been reported in a number of trials:

 

The LDL-Apheresis Regression Study (LARS) involved 13 centers and evaluated the effect of LDL-Apheresis on regression of coronary atherosclerosis.1 Coronary angiograms of 37 patients (7 homozygous FH, 25 heterozygous FH, and 5 non-FH) treated with LDL-Apheresis were assessed. Twenty-nine patients received the lipid-lowering drugs, Pravastatin or Probucol. All 37 patients underwent LDL-Apheresis for at least one year at varying frequencies. The LDL-C level was reduced from a baseline of 500 mg/dl in homozygous FH to 388 mg/dl pre-apheresis and 105 mg/dl post-apheresis (70% reduction). In heterozygous FH the baseline LDL-C was 311 mg/dl, pre-apheresis level was 188 mg/dl and post-apheresis level was 69 mg/dl (60% reduction). The evaluation of angiograms showed regression of atherosclerosis in 14 of 37 patients.

The German Multicenter LDL-Apheresis Trial was a four-center prospective study consisting of 32 FH patients (2 homozygous and 30 heterozygous).2 The average pre-apheresis LDL-C level was 249 mg/dl and was reduced to 83 mg/dl post-apheresis (60% reduction). All patients showed symptomatic improvement of angina and there was either no change or improvement in the stress test. Serial coronary angiograms showed stabilization of lesions in 16 (50%) of the patients.

The FH Regression Study was a prospective randomized study, looking at 42 patients with heterozygous FH treated either with a lipid-lowering drug, simvastatin, and biweekly LDL-Apheresis, or simvastatin and a resin for a period of 2 years.3 The time-averaged LDL-C levels were similar in the two groups, but the Lp(a) level was reduced to 23% compared to a 22% increase in the drug-alone group. Evaluation of the angiograms revealed no significant difference in the stenosis after 2 years of treatment between apheresis and the drug group, either on per patient basis or on a per lesion basis.

The Coronary Atheroma Regression Study (CARS), was a 20 patient, randomized, angiographic trial. Patients received either drug or drug and apheresis.4 There was a 51% reduction in the LDL-C (244 mg/dl to 120 mg/dl) in the drug alone group compared to a 74% reduction in the apheresis group. Improvement in exercise tolerance occurred in both treatment groups but was statistically significant in the apheresis group. No significant angiographic differences were noted.

SUMMARY:

Overall, these studies show that using LDL-apheresis can achieve a substantial lipid lowering effect in all or nearly all patients with severe hypercholesterolemia. The reduction was obtained regardless of prior response to dietary and/or drug interventions. Also noted was a reduction in angina and stress test improvement which did not correlate with the angiographic regression of the lesions. The rationale for this observation may be the improvement in blood flow due to changes in blood viscosity or blood vessel wall reactivity. While the clinical responses have been quite favorable, long-term benefits such as a reduction in, or prevention of, coronary heart disease have not been conclusively demonstrated.

LDL-apheresis appears to be a safe and effective treatment for patients with hypercholesterolemia who are refractory to drug and/or dietary interventions. In addition to patients with homozygous FH, the FDA recently approved LDL-apheresis use in patients with coronary artery disease and LDL-C levels greater than 200 mg/dl. In patients with no coronary artery disease, apheresis is recommended if the LDL-C level is 300 mg/dl.

 

REFERENCES:

Kroon AA, et al. Circulation. 1996; 93:1826.

Borberg, H, et al. In: Agishi T, et al, eds. Therapeutic plasmapheresis (XII). VSP; 1993;
p. 13-20.

Thompson GR, et al. Lancet. 1995; 345:811.

Tait, GW, et al. In Gordon BR, Gotto AM Jr. Eds. The treatment of severe hypercholesterolemia: can we impact disease course? Princeton: Excerpta Medica; 1992; p. 83-89.

For questions or additional information on LDL-apheresis, please contact
Dr. Joseph Kiss,   (412) 209-7326

 

Copies of the Transfusion Medicine Update can be obtained by contacting
Deborah Small, (412) 209-7320.