drug-resistant hypercholesterolemia with the heparin-induced extracorporeal low-density lipoprotein precipitation (HELP) system by selective plasma low-density lipoprotein removal

Weekly Treatment of Diet/Drug-Resistant Hypercholesterolemia with the Heparin-Induced Extracorporeal Low-Density Lipoprotein Precipitation (HELP) System by Selective Plasma Low-Density Lipoprotein Removal Daniel M. Lane, MD, PhD, Walter J. McConathy, PhD, L. 0. Laughlin, MD, Philip C. Comp, MD, PhD, Beat von Albertini, MD, Sandy M. Gibson, MD, Lee A. Bricker, MD, Patricia Kozlovskis, PhD, and Catharine Dorrier, MS

Heparin-induced extracorporeal low-density lip protein (LDL) precipitation (HELP) weekly therapy was evaluated for safety and efficacy in selectively reducing LDL cholesterol levels. Weekly treatments (25) were &en to high-risk hypercholestelc olemic patients (n q 33) with screening LDL the lesterol levels ~I.60 mg/dl despite prior diet and drug therapy. Lipids, lipoprotein cholesterol, ap lipoproteins A-l and B, and fibrinogen were mea sured on plasma samples before and after treatment. Mean plasma volume treated was 2.66 Iiters and mean treatment duration 1.7 hours. Therapy complications were infrequent and were primarily vascular access problems or hypoteu sion. Treatment goals were ~30% LDL cholesterol reduction with each treatment. In 98% of 666 HELP treatments, LDL cholesterol levels were m duced 230%. Mean LDL cholesterol levels were reduced 111.0 mg/dl(54%) with a time-averaged de crease of 39% over a 25week course. Mean HDL cholesterol was reduced only 6.2 mg/dl(l5%). Total cholesterol (134.4 mg/dr; 47% decrease) and apolipoprotein B (66.7 mg/dl; 63% decrease) levels were also reduced. fibrinogen decreased 156.2 mg/dl(56%) without bleeding compliw tions. HELP therapy can safely and selectively remove plasma LDL cholesterol, producing consistent reductions in LDL cholesterol, total chok?sterol and apolipoprotein B levels. (AmJCardiol1993;71:616-622)

From the Oklahoma Medical Research Foundation and Presbyterian Hospital, Oklahoma City, Oklahoma; George Washington University Medical Center, Washington, D.C.; Miami Heart Institute, Miami Beach, Florida; and the Biometric Research Institute, Inc., Arlington, Virginia. This study was supported in part by funds provided by B. Braun of America, Inc., Bethlehem, Pennsylvania, and Presbyterian Health Foundation, Oklahoma City, Oklahoma. Manuscript received June 8, 1992; revised manuscript received and accepted October 20. Address for reprints: Daniel M. Lane, MD, PhD, Oklahoma Lipid Consultation Group, 5300 North Grand Boulevard, Suite 205, Oklahoma City, Oklahoma 73 112.

816

THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 71

D

espite aggressive dietary management or use of pharmacologic agents for lowering cholesterol levels, or both, hypercholesterolemic patients may continue to maintain plasma low-density lipoprotein (LDL) cholesterol at levels associated with increased coronary heart disease risk.1-3 Standard plasmapheresisM partial ileal bypass surgery7 and liver transplantation* have been used to treat nonresponsive patients. At present, no definitive therapy is available for these patients. In 1983, Wieland and Seide19 developed a laboratory method for measuring plasma LDL cholesterol levels by which the divalent cations were replaced by an acidic pH in the heparin reagent mixture. Divalent cations produce complete precipitation of LDL by linking heparinapolipoprotein B complexes, a phenomenon that also occurs at an acidic pH (optimal pH of 5.12) in the absence of divalent cations. Heparin precipitation at an acidic pH was tested in vitro to selectively remove LDL cholesterol from plasma based on the ability of heparin to bind to a limited number of plasma proteins, most prominently apolipoprotein B, the structural protein of LDL.‘O Because the major apolipoprotein of high-density lipoproteins (HDL) does not bind heparin, HDL cholesterol is minimally precipitated by heparin. The technique has now been developed into a therapeutic system that removes LDL cholesterol selectively by treating plasma extracorporeally, a Ming confirmed in both animal and human studies.11J2 A clinical trial was initiated in the U.S. under an IIIvestigational Device Exemption from the U.S. Food and Drug Administration. This report presents the results from the U.S. clinical investigation for weekly heparininduced extracorporeal LDL precipitation (HELP) treatment during the first 2 years. On completion of 25 weekly HELP treatments, patients were treated biweekly, the results of which will be reported later. METHODS Description of HELP system: The HELP system consists of 3 microprocessor-controlled modules, automatically providing for separation, treatment and dialysis of blood with monitoring of the extracorporeal plasma circuit. All components in direct patient contact are disposable and include plasma filter, precipitate filter, heparin adsorber, dialyzer and their connecting tubing. APRIL 1, 1993

Through either vein-to-vein or arteriovenous fistula vas- tions were done at individual investigational sites since the methods were standardized by the Center for Discular access, plasma is separated from blood continuously by a plasma filter before heparin in an acidic ace- ease Control.14,15 The apolipoprotein (A-I, B) assays tate buffer is added to precipitate LDL. After filtration, were done at a centralized laboratory at the Oklahoma excess heparin and buffer are removed from plasma by Medical Research Foundationl’j which developed many heparin adsorption and bicarbonate dialysis before re- of the electroimmunoassay techniques for apolipoprotein mixing with blood for return to the patient. assay. The fibrinogen determinations were performed at Patient selection: Patients who had maintained ele- 2 sites by a method using excess thrombin.17 The assays vated LDL cholesterol levels (>160 mg/dl) despite diet for the Oklahoma and Miami sites were done at the speand drug therapy were recruited for the study. Admiscial coagulation laboratory of the University of Oklasion criteria consisted of 23 months on the equivalent homa College of Medicine. The fibrinogen levels at of a step one diet as outlined by the National Cholester- George Washington University Medical Center were ol Education Program Guidelines13 and >12 weeks of done at the special coagulation laboratory there. acceptable drug therapy without lowering the LDL choSafety analyses Evaluation of HELP therapy safelesterol level ~160 mg/dl. Almost all patients had been ty was based primarily on adverse events (e.g., bleedmaintained on diet and drug therapy for periods greatly ing, hypotension) and changes in cellular and chemical in excess of diet and drug admission requirements. Men components of the plasma, including the plasma proand women (postmenopausal or having undergone oo- teins. All patients had major laboratory studies (comphorectomy only) between 25 and 70 years of age were plete blood count, platelet count, chemical survey, eligible for the study. Any homozygous familial hyper- immunoglobulin, and iron studies) performed every 4 cholesterolemic patient could be admitted if 27 years weeks just before treatment. Because the safety paramold. eters showed little variation over the course of 25 treatPatients with coronary artery disease were excluded ments, only values obtained before the first treatment if they had congestive heart failure or if they had a ma- were compared with those present before the 25th weekjor cardiac arrhythmia. Patients with hematocrit ~30% ly treatment. or platelet count 1,000,000/mm3 were exStatistical analyses: Paired t tests were used to ascluded. Other exclusion criteria were hypothyroidism, sess changes over time for lipid, lipoprotein and blood fasting triglycerides >500 m&U, body weight >1.5 times pressure measurements. Pearson correlation coeffiideal weight, serum creatinine >2 mg/dl, positive human cients’* were computed to determine whether changes in immunodeficiency virus test, positive test for active hep- the different parameters (LDL cholesterol, total choatitis A or B, diagnosed malignancy, diastolic blood lesterol, HDL cholesterol, triglycerides, apolipoprotein pressure >lOO mm Hg (reported on 22 occasions 24 A-I and B, and fibrinogen) during therapy were related. hours apart), uncontrolled diabetes mellitus, and disorders associated with excessive bleeding or intracranial RESULTS bleeding. Patients aged <7 years with homozygous faPatient population: Patients were admitted at 3 inmilial hypercholesterolemia were excluded for safety vestigational sites: Oklahoma Medical Research Founreasons because of their small plasma volumes. dation/Presbyterian Hospital, Oklahoma City, Oklahoma; Treatment plan: After eligibility had been con- George Washington University Medical Center, Washfirmed and before the first weekly treatment was given, ington, D.C.; and Miami Heart Institute, Miami Beach, a baseline evaluation was performed which included Florida. Results for 33 patients treated during the first 2 complete history and physical examination, stress elec- years of the U.S. study are presented in this paper. The trocardiogram, and multiple blood tests (see later). mean age of patients was 47 years and 70% were men, HELP therapy was then given weekly for 25 treatments several of whom weighed >200 pounds. The mean screening LDL cholesterol level (after diet (for 6 months). Target plasma treatment volume was 3,000 ml for a single treatment. A HELP treatment was and drug therapy only) for all 33 patients was 289 mg/dl considered complete if 22,000 ml of plasma was treat- (range 152 to 815). Two patients who had screening ed. Evaluation after completion of weekly therapy in- LDL cholesterol values ~160 mg/dl were admitted to the cluded the same studies as the baseline examination. study since both had been documented to have levels in Efficacy end points Assessment of the therapeutic excess of 160 mg/dl while receiving diet and drug thersuccess was based on the effectiveness of the HELP sys- apy several times before study entry. The mean pretem for lowering lipid levels. A reduction of total and treatment LDL cholesterol obtained just before the first LDL cholesterol levels by 230%, the average reduction HELP treatment was 262 mg/dl, which served as the achieved with most lipid-lowering drugs given to pa- base level for evaluating response over the treatment tients on dietary therapy alone, was selected as the effi- course. This level was 9% lower than the one obtained cacy goal. Efficacy was evaluated in 2 ways: (1) effec- at screening and is comparable to the 9% reduction in tiveness of individual treatments, and (2) effectiveness of LDL cholesterol levels after dietary advice at screening of the Helsinki Heart Study.19 This is used as a more therapy across the 25-weekly treatment interval. methods: Routine complete blood count, conservative baseline parameter for evaluation of recoagulation and chemical studies were performed, ac- sponse over time. Mean HDL cholesterol level at screencording to routine laboratory methodology, in certified ing was 44 mg/dl (range 23 to 73), and 11 of the 33 patients had “high-risk” HDL cholesterol levels (<35 laboratories. The total cholesterol, triglyceride, HDL cholesterol and calculated LDL cholesterol determinamg/dl) (Table I). DIET/DRUG-RESISTANT HYPERCHOLESTEROLEMIA 817

TABLE

I Patient

Demographics-Treatments

Through

41

April

TABLE

1991 Total no. of patients Age at entry (year) Mean Range Sex Male Female Race Caucasian Black Other Height (inches) Mean Range Weight (pounds) Mean Range Blood pressure-systolic (mm Hg) Mean Range Blood pressure-diastolic (mm Hg) Mean Range LDL cholesterol (mg/dl) Mean Range HDL cholesterol (mg/dl) Mean Range HOL = high-density

lipoprotein:

LDL = low-density

33 47.4 15-65

29 (88%) -

disease

TABLE IV Technical Treatments

185 120-250

Treatment Yes

79 47 53 28 55

for Failure to Complete

Twenty-five low-density

Weekly

44 23-73

Reason treatments terminated early* Device-related inappropriate dialysate concentration Plasma volume/buffer volume User-related Clotted plasma filter Vascular access problem Insufficient heparin used Clotted extracorporeal system Patient-related Poor blood flow Marked hypertriglyceridemia Patient dehydration

-

lipoprotein.

(patients 10 5 3 3 3 PtsJEvents

OF CARDIOLOGY

12114 8113 9111 8 11 24 17 28.2

VOLUME

completed

Total

289 152-815

factors

JOURNAL

Reasons

No

80 60-100

= elecrrocarolograpny.

THE AMERICAN

17&! 45 mg 1,125 mg 2,408 mg 938 mg

April

No. (%) 136 110-210

The factors associated with heart disease for the 33 patients are listed giving number of patients and number of factors or events (Table II). Hypertension was present in 30% of the patients, whereas diabetes mellitus, cerebrovascular disease and peripheral vascular disease were less common. Prior coronary artery bypass graft surgery or angioplasty was quite common, with 48% of the patients having had one or the other (total of 27 procedures) before HELP therapy. Nine of the 33 patients had previously coniirmed myocardial infarction, whereas a positive family history for coronary artery disease was found in almost 3/4of the patients. In addition, over l/z had smoked or were smoking when treatments started. 818

[n = 331 Through

68.0 62-74

Coronary artery bypass grafts Coronary angioplasty Myocardial infarction Angina pectoris ECG evidence of coronary artery disease Family history of coronary artery disease Smoking history Mean pack-years tui

16 26 18 10 10 1

(patients

*All patients had received diet and drug therapy before admission. received multiple drug therapy before heparin-induced extracorporeal lipoprotein precipitation therapy.

4 (12%)

Systemic hypertension Diabetes mellitus Insulin-requiring Cerebrovascular disease Peripheral vascular disease artery

Prior Drug Therapy

Cholestyramine Lovastatin Gemfibrozil Niacin Probucol Fish oil

23 (70%) 10 (30%)

TABLE II Coronary Artery Disease Risk Factors [n = 331 through April 1991)

Coronary

Ill

71

672 (98) 14 (2) 686 (100)

l(O.15) l(O.15) 2 (0.29) 2 (0.29) l(O.15) l(O.15) 4 (0.58) lfO.15) l(O.15)

All patients were on the equivalent of the step one dietary regimen as outlined in the National Cholesterol Education Program Guidelines.t3 To assure that the patients followed a step one diet, a 3-step procedure was used for dietary treatment. First, at the time of screening, patients were evaluated as to whether they were on a step one diet, counseled about the use of a step one diet and given a copy of this diet from the National Cholesterol Education Program guidelines. Second, patients were regularly reinforced on the step one dietary requirement throughout the treatment period. Third, each patient received consultation from a dietitian during the course of weekly treatments. In addition, a computer analysis to evaluate compliance with the 3&y diet was completed for a limited number of patients. The patients tested satisfied the step one requirement for the 3 days evaluated. The mean duration of dietary therapy for all patients was in excess of 7 years (mean ~I00 weeks). Prior lipidlowering drug therapy had also been extensive in these patients (Table III). Multiple drug lipid-lowering therapies before HELP therapy were common (25 of the 33 patients). Of the 33 patients, 24 continued drug therapy (at least 1 drug) throughout the course of 25 weekly HELP treatments. No additions to pre-HELP diet or medication regimens were permitted during the treatment course, except as warranted for patient safety.

APRIL 1,

1993

was the most common reason for patient-related failure to complete. Where plasma volume treated was >2,000 ml but ~3,000 ml, difficulties were most often due to LDL precipitate occluding the precipitate filter, which automatically stopped additional plasma filtration from blood. Efficacy results for individual treatments: Mean pre- and post-treatment data for the 686 weekly treatments given from April 1989 to April 1991, mean changes in mg/dl, and mean percent reductions are listed in Table V. The reductions in total cholesterol (47%) and LDL cholesterol (54%) were similar, with the percent reduction in LDL cholesterol level greater as projected. Total cholesterol was reduced 230% in 97% of the 686 weekly HELP treatments. Similarly, LDL cholesterol was reduced 230% in 98% of the weekly treatments. Levels of apolipoprotein B, the structural protein of LDL, were reduced almost exactly the same percentage (53%) as LDL cholesterol.

Technical results: From the first treatment in April 1989 through April 1991, 33 patients were given at least 1 weekly treatment with the HELP system in the U.S. Nine patients had not completed weekly therapy or had discontinued weekly treatments before 6 months (usually due to vascular access problems or patient failure to maintain the treatment schedule). During the 2-year period, 686 weekly treatments were administered, of which 600 were given to the 24 patients completing all 25 weekly treatments. Of the 686 weekly treatments, 98% of the treatments were considered complete. Mean treatment volume for the weekly treatments was 2,657 ml, or 89% of the 3,000 ml goal, and the average time for a treatment was 1.7 hours (range 0.3 to 3.3). Treatment time tended to be shorter as the number of treatments given increased. Reasons for failure to complete a treatment are listed in Table IV Inability to maintain blood flow from the patient to the device despite adequate vascular access TABLE

V Treatment

Efficacy

Results (patients

Before

Weekly Total C LDL-C Apolipoprotein Triglycerides HDL-C Apolipoprotein Fibrinogen

B

A-l

C = cholesterol;

No.

Mean

686 680 636 686 686

278.5 200.4 164.9

639 479

Treatment (mgidl) Range

Mean

76-611 49-476 36-3123

42.2 122.9

13-77 32-251

270.1

109-590 llpoprotm

" 1 2

0

' 3

" 4 5

" 6

' 7 8

Range

Mean

Pretreatment

Mean

63-447

-134.4

89.4 76.2 98.1 36.0 100.3

19-387 26-277 ii-1148 lo-72 26-184

-111.0 -88.7 -90.4 -6.2 -22.6

112.0

37-277

-158.2

cholesterol;

LDL-C = low-density

%

Treatment +

Mean

p Value

-47.2 -54.2 -52.7 -49.4 -14.5 -18.0 -58.0

lipoprotein

<0.0001


cholesterol.

Levels

' ' ' ' ' "'I ' ' 9 10 111213141516171819202122232425

Weekly -

Change

144.1

Mean LDL-C

0

April 1991)

After Treatment (mg/dl)

101-690

188.5

HDL-C = high-density

[n = 331 through

'

I"'

Number

Pre/Post

-C

FlGURE 1. Changes in mean lowdensity lipoprotein cholesterol (LDL-C) levels precipitation therapy for patients (n = 24) completing 25 weekly treatments. LDL cholesterol level.

Mean

Posttreatment

during heparitinduced Value at treatment

DIET/DRUG-RESISTANT

extracorporeal LDL 0 is the mean screening

HYPERCHOLESTEROLEMIA

819

TABLE VI

Complications Study-Treatments

Through April

1991

Complication Device-related Hypotension Fatigue Wheezing User-related Vascular access problems Prolonged PTT or ACT* Low flow rate due to high venous pressure Patient-related Chills/shivering Nausea andioryomiting Fever Dizziness/syncope Ache Hyperventilation Elevation of liver enzymes Ankle swelling Total

Total No. of Events (n = 33 pts.) no. (%I

Total No. of Pts. Reporting Complication

7 (1.0) 4 (0.6) l(O.1)

7 4 1

14 (2.0) 4 (0.6) l(O.1)

8 2 1

4 (0.6) 2 (0.3) 2 (0.3) 1 to.11 l(O.1) l(O.1) 1 to.11 l(O.1) 44t

4 2 2 1 1 1 1 1 36

*Includes reports on patients who had heparinired central venous which blood samples were drawn. TMore than 1 symptom may be reported in 1 event. ACT = activated clottingtime; P T T = partial thromboplastin time.

lines through

The mean 49% reduction in triglyceride from pretreatment levels was similar to the reduction in LDL cholesterol and apolipoprotein B levels. Triglyceride levels before treatment varied widely in the patient population, primarily because several patients had combined cholesterol and triglyceride elevations. The mean LDL cholesterol reduction was larger than the reduction in HDL cholesterol, conlirming the specificity of the HELP system. HDL cholesterol levels decreased an average of 6.2 mg/dl for a mean 15% decrease. Absolute reductions in apolipoprotein A-I levels, the major protein of HDL cholesterol, were larger in mg/dl than for HDL cholesterol as expected, but the mean percent reduction (18%) was similar to the mean HDL cholesterol reduction. Reductions in the lipid and lipoprotein parameters were evaluated using the Pearson correlation analysis. Mean plasma LDL cholesterol parameters (levels before and after treatment, reduction in mg/dl, percent reductions) were highly correlated (p
results across 25treatment

interval:

Twenty-four patients completed the 25-week treatment schedule. Over this therapeutic course, 79% of the patients achieved a reduction of 230% in LDL cholesterol levels (from the initial level before treatment from the 820

THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 71

lirst HELP treatment to the mean for pre/post-treatment levels for the last 5 treatments). This represents a timeaveraged decrease of 39% over the 25-week treatment period. Total cholesterol levels were reduced 230% over the treatment course in 75% of patients (18) for a timeaveraged mean total cholesterol reduction of 31%. In Figure 1, data are shown for mean LDL cholesterol level changes for the 24 patients who completed all 25 weekly treatments. From a mean screening LDL cholesterol level of 298.3 mg/dl (n = 24) after diet and drugs, the mean LDL cholesterol level before treatment had been reduced to ~200 mg/dl after 3 to 4 treatments, whereas the mean level after treatment was ~100 mg/dl. The lower pre- and post-treatment values were maintained through the 25 weekly treatments. Thus, weekly treatment with the HELP system reduced the pretreatment LDL cholesterol levels to approximately 2/3of the screening level and reduced the post-treatment LDL cholesterol levels to approximately l/3 of the screening level. From a mean screening level of 298 mg/dl after diet and drug therapy (which, as discussed, was higher than the mean pretreatment level for the first HELP treatment), the mean pre/post LDL cholesterol levels were reduced approximately 50% with weekly treatments. No clinical cardiac event occurred in the 33 patients treated during the 2-year study period despite the history of inadequate diet/drug response and increased frequency of coronary artery disease risk factors. Improvement was also found in parameters associated with coronary artery disease. Both the systolic and diastolic blood pressure decreased significantly (p ~0.05) after 25 weekly HELP treatments, with a mean reduction in systolic blood pressure of 14.6 mm Hg and a mean reduction in diastolic blood pressure of 5.8 mm Hg. Electrocardiographic evidence of heart disease disappeared in 2 of the 10 patients who started HELP therapy with abnormal electrocardiograms. The most interesting observation was tinding that 3 of the 6 patients with angina pectoris before treatment no longer had anginal pain after 25 weekly treatments. The decrease in angina permitted reductions in or discontinuations of coronary vasodilator therapy, continning the improvement in anginal symptoms. Safety resulks: No replacement with packed red cells, plasma or albumin solution was required for any patient during or after any of the 686 weekly treatments. No life-threatening complications developed, although minor complications were seen as expected with extracorporeal plasma therapy. The most common problem was with vascular access, which usually developed in patients with a history of previous surgical interventions (Table VI). Hypotension was the next complication most often seen and may be related to reductions in plasma volume, since hypotension occurred most frequently in patients taking diuretics and antihypertensives. Reducing the dose or discontinuing the medication usually eliminated subsequent episodes of hypotension in affected patients. Fatigue, chilling (primarily due to low room temperature) and prolonged clotting times were the other minor complications seen. All of these events were easily resolved and the increased clotting times were not associated with significant bleeding.

APRIL 1,1993

After 25 weekly treatments, mean total white blood cell count decreased minimally during the treatment interval, but the mean platelet count increased. Despite reductions during individual treatments, all 3 major immunoglobulin parameters increased slightly between the tirst and 25th treatment. There were reductions in the iron parameter levels over the course of treatment, specifically plasma ferritin levels, which fell from 73 to 22.5 p&liter for an almost 70% reduction. This decrease was not associated with an equivalent reduction in plasma iron. There were minimal changes in other laboratory measures with means after completion of 25 weekly treatments well within the normal range. The most encouraging result of HELP therapy was the patient’s subjective response to treatment. Severe fatigue after a treatment, common with plasmapheresis, was rarely seen and all working patients returned to work, even to hard physical labor, after their treatments. When asked to compare their health status to the start of therapy, 72% believed their health to be “much better” or “somewhat better” after 6 months of therapy.

lar access was a problem as with all extracorporeal therapy systems. As delined by the criteria established as study goals, the HELP system is effective therapy for severe hypercholesterolemia. Large reductions in LDL cholesterol and total cholesterol levels (means of 54 and 47%, respectively) were achieved with almost every treatment. The cholesterol reductions were confirmed by an equivalent reduction (53%) in the apolipoprotein B levels, the LDL protein component for which the precipitation process is speciiic. The reductions in LDL cholesterol were maintained over the course of 25 weekly treatments with an approximate 40% decrease from the level before therapy on a time-averaged basis. This LDL cholesterol reduction by HELP therapy was additive to the reductions already achieved with diet and drug therapy. HDL cholesterol levels were minimally reduced with HELP treatment compared with changes with plasmapheresis, a tinding that was continned by apolipoprotein A-I level changes. Concomitant reductions were also produced in triglyceride and fibrinogen levels, but no excessive bleeding resulted from removal of the latter. DISCUSSION The ability to reduce blood pressure significantly Clinical trials have shown that elevated LDL choles- while reducing LDL cholesterol levels is important. terol levels, even in patients receiving lipid-lowering Concomitant reductions in blood pressure and cholesterdrugs, are associated with the progression of coronary ol levels have been previously shown to be required for artery disease,2G22 especially in patients with preexist- reductions in coronary artery disease risk.” As the maing disease.23 Reducing those levels by diet and drug jor symptom of ischernic coronary artery disease, the therapy significantly below the 160 mg/dl level has been disabling effect of angina pectoris is a major therapeuassociated with both reduced progression of existing le- tic problem in the management of coronary artery dissions and fewer new lesions developing, although re- ease. Three of 6 patients treated weekly no longer had gression of existing lesions was somewhat variable.21.24 angina after 25 treatments, an unexpected benefit from The National Cholesterol Education Program13 has es- HELP system therapy. The reduction in anginal pain tablished guidelines for treating patients with elevated may be related to the reduction in blood viscosity preLDL cholesterol levels with diet and drug therapy, but viously reported. ** The improvement in anginal sympwhen patients fail to achieve the recommended reduc- toms and the absence of clinical cardiac events agree tions, no specilic recommendations were made other with the suggestion by Vogel29 that a reduction in nonthan referral to a lipidologist. Consequently, no standard fatal cardiovascular events and improved survival may treatment currently has been established for patients who best be achieved by aggressive lipid management. continue to maintain LDL cholesterol levels in excess of The present investigation demonstrated that the 160 mg/dl after diet and drug therapy. To date, therapy HELP system is a safe and effective therapy for severe has consisted of a variety of measures including combi- hypercholesterolemia which has not responded adenation drug therapy, plasmapheresis, partial ileal bypass quately to diet and drug therapy. The system selectively and even liver transplantation. The HELP system was removes LDL cholesterol from plasma without producdeveloped to provide therapy for patients who fail to re- ing major complications and without requiring replacespond to diet and drugs, especially when patients have ment of plasma proteins after treatments. Mean reducpreviously existing coronary artery disease.25 tions in LDL cholesterol levels with each treatment exThis 2-year clinical trial of weekly HELP therapy in ceed 50%, almost 40% on a time-averaged basis, and the U.S. confirmed tindings of European studies show- are an addition to reductions already produced by diet ing that the HELP system was safe for treating diet and and drug therapy. Thus, the HELP system is a new, drug-resistant hypercholesterolemic patients.25,26 Cyto- lipid-lowering therapy that provides an interventional logic and chemical studies demonstrate that HELP ther- treatment for severely affected hyperlipidemic patients. apy removed minimal amounts of normal plasma constituents with the exception of plasma iron components. Acknowkdgment: We are especially indebted to Richard I. Nevin, Jr., RPh, for his unstinting support of Supplemental oral iron was adequate for iron-deficient patients; no replacement therapy for reduced plasma this investigation from its inception to its completion. transferrin or fen-inn levels was required. In addition, no We are also indebted to Jenifer Perry, RN, Sandra Madiclinically significant changes in cellular or chemical lev- son, RN, Olga Alvarado, RN, and the Unit staffs for the els were produced by the 25 weekly treatments. Treat- excellent care they gave the research subjects. The comment with the HELP system device was not associated pilation of data was possible through the efforts of our with major clinical complications and its effectiveness data coordinators, Jan Keefe, RN, Vallerie Dudley, was not limited by safety problems. Maintaining vascu- Linda Ann Lane, MEd, Susan Sheehan, RN, and MariDIET/DRUG-RESISTANT HYPERCHOLESTEROLEMIA 821

lyn orfuss, PhD. The manuscript was prepared with the assistance of Kathy Hampton. We thank Robert S. Lees, MD for his advice and review of the manuscript.

REFERENCES 1. Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAMA 1984;251:351-364. 2. Kane1 WB, D’Agostino RB, Stepanians M, D’Agostino LC. Efficacy and tolerability of lovastatin io a siw-month study: analysis of gender, age and hypertensive stams. Am J Car&l 1990;66:1B-10B. 3. Shear CL, Franklin FA, Stinnett S, Hurley DP, Bradford RH, Cbremos AN, Nash DT, Langendorfer A. Expanded clinical evaluation of lovastatin (EXCEL) smdy results. Effect of patient characteristics on lovastatin-induced changes in plasma concentrations of lipids and lipoproteins. Circulation 1992;85:1293-1303. 4. Apstein CS, Zilversmit DB, Lees RS, George PK. Effect of intensive plasmaphersis on the plasma cholesterol concentration with familial hypercholesterolemia. Atherosclerosis 1978;31: 105-l 15. 5. Thompson GR, Lowenthal R, Myant NB. Plasma exchange in the management of homozygous familial hypercholesterolemia. Lmcet 1975; 1: 1208-1211. 6. Thompson GR, Miller JP, Breslow JL. Improved survival of patients with hornozygous familial hypercholesterolemia treated with plasma exchange. Br Med J 1985;291:1671-1673. 7. Buchwald H, Varco RL, Matts JP, Long JM, Fitch LL, Campbell GS, Pearce MB, Yellin AE, Edmiston WA, Smink RD, Sawin HS, Campos CT, Hansen BJ, Tuna N, Karnegis JN, Sanmarco ME, Amplatz K, Casteneda-Zuniga WR, Hunter DW, Bissett JK, W&x FJ, Stevenson JW, Leon AS, Chalmers TC, and the POSCH Group. Effect of partial ileal bypass surgery on mortality and morbidity from coronay heart disease in patients with hypercholesterolemia. Report of the Program on the Surgical Control of the Hyperlipidemias (PGSCH). N Engl J Med 1990,323: 946955. 8. Bilhetier DW, Goldstein JL, Gmndy SM, Starzl ‘IE, Brown MS. Liver mansplantation to provide low-density lipoprotein receptors and lower plasma cholesterol in a child with homozygous familial hypercholesterolemia. N Engl J Med 1984;311:1658-1664. 9. Wieland H, Seidel D. A simple specific method for precipitation of low density lipoproteins. J Lipid Res 1983;24:904-909. 10. Fuchs C, Wiidisch M, Wieland H, Armstrong VW, Rieger J, Koestering H, Scheler F, Seidel D. Selective continuous extracorporeal elimination of low-density lipoproteins from plasma by heparin precipitation without cations. In: Plasma Separation and Plasma Fractionation. Basel: Karger, 1983:272-280. 11. Armstrong VW, Windisch M, Wieland H, Fuchs C, Rieger J, Koestering H, Nebendahl K, Scheler F, Seidel D. Selective continuous extracorporeal elimination of low-density lipoproteins with heparin at acidic pH. Tram Am Sot Artif Intern Organs 1983;29:323-328. 12. Armstrong VW, Eisenhauer T, No11 D, Wieland H, Scheler F, Seidel D. Extracorporeal plasma therapy: the H.E.L.P. system for the treatment of hyper-betalipoproteinemia. In: Recent Aspects of Diagnosis and Treatment of Lipoprotein Disorders. New York: Alan R. Liss, 1988:327-335. 13. The Expett Panel. Report of the National Cholesterol Education Program Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults.

822

THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 71

Arch Intern Med 1988;148:36-69. 14. Manual of laboratory operations. Lipid and Lipoprotein Analysis. National Institutes of Health, Bethesda, MD: (DHEW publication no. 75-628) 1974;1:9-59. 15. Wamick GR. Enzymatic methods for quantitation of lipoprotein lipids. Methods Enzymol 1986;129:101-123. 16. Alaupovic P, McConathy WJ, Fesmire J, Tavella M, Bard JM. Profiles of apolipoproteins and apolipoprotein B-containing lipoprotein paticles in dyslipoproteinemia. Clin Chem 1988;34:B13-B27. 17. Rossi E, Mondonico P, Lombardi A, Preda L. Method for the determination of functional (clottable) fibrinogen by the new family of ACL coagulometer. Thromb Res 1988;52:453-468, 16. SAS Institute, Inc. SAS Procedures Guide, Release 6.03 ed. SAS Institute Inc., 1988:123-149. 19. Manninen V, Elo MO, Frick MH, Haapa K, Heinonen OP, Heinsahni P, He10 P, Hummen JK, Kaitaniani P, Koskinen P, M%mpll H, M&lki&n M, MUtti M, Norola S, Pasternack A, Piarainen J, Rome M, Sjtiblom T, N&kill EA. Lipid alterations and decline in the incidence of coronary heart disease in the Helsinki heart study. JAMA 1988;260:64651. 20. Brensike. JF, Levy RI, Kelsey SF, Passamani ER, Richardson JM, Loh IK, Stone NJ, Aldrich RF, Battaglini JW, Moriarty DJ, Fisher MR, Friedman L, Friedwald W, Detre KM, Epstein SE. Effects of therapy with cholestyramine on progression of coronary arteriosclerosis: results of the NHLBI type II coronary intervention study. Circulation 1984;69:313-324. 21. Cashin-Hemphill L, Mack WJ, Pagoda JM, Samnarco ME, Azen SP, Blankenhorn DH. Beneficial effects of colestipol-niacin on coronary atherosclerosis. A Cyear follow-up. JAMA 1990;264:3013-3017. 22. Brown G, Albers JJ, Fisher LD, Schaefer SM, Lin J-T, Kaplan C, Zhao X-Q, Bisson BD, Fitzpatrick VF, Dodge HT. Regression of coronary atery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med 1990;323:128%1298. 23. LaRosa D, Cleeman JI. Cholesterol lowering as a treatment for established coronary heart disease. Circulation 1992;85:1229-1235. 24. Blankenhorn DH, Nessim SA, Johnson RL, Sammarco ME, Azen SP, CashinHemphill L. Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypass grafts. JAMA 1987;257:3233-3240. 25. Seidel D, Armstrong VW, Schuff-Werner P for the H.E.L.P. Study Group. The H.E.L.P..LDL-apheresis multicenter study, and angiogmphically assessed trial on the role of the LDL-apheresis in the seconday prevention of coronay heat disease. I. Evaluation of safety and cholesterol-lowering effects during the fast 12 months. Eur J Clin Invest 1991;21:375-383. 26. Eisenhauer T, Armstrong VW, Wieland H, Fuchs C, Scheler F, Seidel D. Selective removal of low density lipoproteins (LDL) by precipitation at low pH: First clinical application of the H.E.L.P. system. Kiln Wochmschr 1987;65:161-168. 27. Samuelsson 0, Wilhehnsen L, Anderson OK, Pennert K, Berglund G. Cardiovascular morbidity in relation to change in blood pressure and serum cholesterol levels in treated hypertension. Results from the prinxuy prevention trial in Gotebag, Sweden. JAMA 1987;258:1768-1776. 28. Schuff-Werner P, Schuetz E, Reitemeyer F, Oppermann M, Eisenhauer T, Armstrong VW, Koestering H, Go&e 0, Seidel D. Heparin-induced extracorporeal LDL precipitation (H.E.L.P.): rheological, hemostaseological and immunologicrd effects. In: Treahnent of Severe Hypercholesterolemia in the Prevention of Coronay Heart Disease. Basel: Karger, 1990: 196-204. 29. Vogel RA. Compartive clinical consequences of aggressive lipid management, coronary angioplasty and bypass surgery in coronay artery disease. Am J Cardiol 1992;69:1229-1233.

APRIL 1,1993