The Safety, Efficacy, and Cost Effectiveness of Therapeutic Apheresis

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The Safety, Efficacy, and Cost Effectivenessof Therapeutic Apheresis

July 1983

NTIS order #PB84-114842



Recommended Citation:

Health Technology Case Study 23: The Safety, Efficacy, and Cost Effectiveness of

Therapeutic Apheresis (Washington, D. C.: U.S. Congress, Office of Technology Assess-ment, OTA-HCS-23, Jun e 1983). This case study w as per formed as a par t of OTA’s assess-

ment of Medical Technology and Costs of the Medicare Program.

Library of Congress Catalog Card Number 83-600554

For sale by the Superintendent of Documents,U.S. Government Printing Office, Washington, D.C. 20402



PrefaceThe Safety, Efficacy, and Cost Effectiveness of

Therapeutic Apheresis is Case Stud y #23 in OTA’sHealth Techn ology Case Study Series. It was p re-pared in response to a request by the SenateFinance Committee, Subcommittee on Health,and is part of OTA’s project on Medical Tech-nology and Costs of t he Medicare Program, re-

quested by the H ouse Comm ittee on Energy andComm erce and its Subcomm ittee on Health andthe Environment. A listing of other case studiesin the series is included at the end of this preface.

OTA case stud ies are designed to fulfill twofunctions. The primary purpose is to provideOTA with specific information that can be usedin forming general conclusions regarding broaderpolicy issues. The first 19 cases in th e H ealth Tech-nology Case Study Series, for example, were con-du cted in conjunction w ith OTA’s overall projecton The Implications of Cost-Effectiveness

Analy sis of M edical Technology. By examiningthe 19 cases as a grou p a nd looking for comm onproblems or strengths in the techniques of cost-effectiveness or cost-benefit analysis, OTA wasable to better analyze the potential contributionthat those techniques might make to the manage-ment of medical technology and health care costsand quality.

The second function of the case stud ies is toprovide useful information on the specific tech-nologies covered. The design and the funding lev-

els of most of the case studies are such that theyshould be read primarily in the context of the as-sociated overall OTA projects. Neverth eless, inman y instances, the case studies do represent ex-tensive reviews of the literature on the efficacy,safety, and costs of the specific technologies andas such can stand on their own as a u seful contri-bution to the field.

Case studies are prepared in some instances be-cause they have been specifically requested bycongressional comm ittees and in others becausethey have been selected through an extensive

review process involving OTA staff and consulta-tions with the congressional staffs, advisory panelto the associated overall project, the Health Pro-gram A dvisory Comm ittee, and other experts invarious fields. Selection criteria were developedto ensure that case studies provide the following:

examples of types of technologies by func-tion (preventive, diagnostic, therapeutic, andrehabilitative);examples of types of technologies by physicalnature (drugs, devices, and procedures);examples of technologies in different stagesof developm ent and diffusion (new, emerg-

ing, and established);examples from d ifferent ar eas of medicine(e.g., general medical practice, pediatrics,radiology, and surgery);examples add ressing m edical problems thatare important because of their high frequen-cy or significant impacts (e.g., cost);examp les of technologies with associated highcosts either because of high volume (for low-cost technologies) or high individual costs;examples that could provide informationmaterial relating to th e broader p olicy andmethodological issues being examined in theparticular overall project; andexamples with sufficient scientific literature.

Case studies either are prep ared by OTA staff,are comm issioned by OTA and performed und ercontract by experts (generally in academia), or arewritten by OTA staff on the basis of contractors’papers.

OTA subjects each case study to an extensivereview pr ocess. Initial dr afts of cases are review -ed by O TA staff and by m embers of the advisorypanel to the associated project. For commission-ed cases, “comments are provided to authors, alongwith OTA’s suggestions for revisions. Subsequentdrafts are sent by OTA to numerous experts forreview and comment. Each case is seen by at least30, and sometimes by 80 or more outside review-ers. These reviewers m ay be from relevant Gov-ernm ent agencies, pr ofessional societies, consu merand pu blic interest grou ps, med ical practice, andacademic medicine. Academicians such as econ-omists, sociologists, d ecision ana lysts, biologists,and so forth, as appropriate, also review the cases.

Although cases are n ot statemen ts of officialOTA position, the review process is designed to

satisfy O TA of each case stud y’s scientific quali-ty and objectivity. During the various stages of the review and revision process, therefore, OTAencourages, and to the extent possible requires,authors to present balanced information andrecognize d ivergent points of view.

. . .

1 1 1



OTA Staff for Case Study #23

H. David Banta, Assistant Director, OTA Health and Life Sciences Division

Clyde J. Behney, Healt h Program Manager

John C. Langenbru nner, Study Director

Anne Kesselman Bum s, Project Director

Cynthia King, Analyst

Pamela Simerly, Research Assistant

Kerry Britten Kemp, Division Editor

Virginia Cwalina, Administrative Assistant

Jenn ifer Nelson , SecretaryMary Walls, Secretary

OTA Publishing Staff

John C. Holmes, Publishing Officer

John Bergling Kathie S. Boss Debra M. Datcher Joe HensonGlenda Lawing Lind a Leahy Donna Young



AdvisoryCosts of

Frank Baker

Panel on Medical Technology andthe Medicare Program

Stuart Altman, Panel Chair

Dean, Florence Heller School, Brandeis Univ ersity

Vice President

W ashington State Hospital A ssociation

Robert Blend onSenior Vice President The Robert W ood Johnson Foundat ion

Jerry CromwellPresident

Health Economics Research

Chestnut Hill., Mass.

Karen DavisJohns Hopkins UniversitySchool of Hy giene and Public Health

Robert DerzonVice President

Lewin & Associates

Washington, D. C’.

Howard Frazier Director Center for the Analy sis of Healt h Practi ces

Harvard school of Public Health

Clifton Gau sCenter for Health Policy Stud-esWashington, D.C.

Jack HadleyUrban InstituteW ashington, D. C.

Kate IrelandChairman, Board of GovernorsFrontier Nursing ServiceWendover, Ky.

Judith LaveGraduate School of Public Health

University of Pittsburgh

Mary Marshall filegate

Virginia House of Delegates

Walter McNerney Northw estern University

Morton MillerPresident National Health Council New York, N. Y.

James Mongan Executive Director

Truman M edical Center Kansas City , Mo.

Seymour Perrylnstitute for Health Policy AnalysisW ashington, D. C.

Robert Sigmond Blue Goss of Greater Philadelphia

Anne Somers Department of Evironment and

Community and Family Medicine Rutgers University

Paul TorrensUCLA School of Public Healt h

Keith WeikelGroup Vice President

AMI McLean, Va.

vi



Contents

Chapter

Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

CH APTER 1: INTRODUCTION AND SUM MARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Backgrou nd an d Scop e of th e Case Study... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Ap he resi s: Defi n ition s, De scrip tion s an d D evel op me nt s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Scientific and Medical Aspects of Apheresis: Issues and Evidence . . . . . . . . . . . . . . . . . . . . . . . . . . .

Cost Effectiveness and Reimbursement Policy: Issues and Evidence . . . . . . . . . . . . . . . . . . . . . . . . . .Im plication s for Policy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Organiza tion of th e Case Stu dy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

CHAPTER 2: APHERESIS: DEFINITIONS, DESCRIPTIONS, AND DEVELOPMENTS.. . . . . . . . .Historical Develop men t . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Th e Scientif ic an d Me dical Bas is for Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Th e Treatmen t Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Organizational Settings and Staffing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Frequ ency, Inten sity, and Du ration of Blood C omp one nt Exchange . . . . . . . . . . . . . . . . . . . . . . . . .Circulato ry Access and Rep lacem en t Flu id s. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Dr ug Th erapy Used With Ap heresis . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Equip men t Tech nology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Cen tri fu gal System s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Membrane Separation Devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Future Technological Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .FDA Device Regu lation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

CHAPTER 3: SCIENTIFIC AND MEDICAL ASPECTS OF APHERESIS: ISSUES AND EVIDENCEMethod ological Issu es . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Treatmen t D esign . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Research Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Patien t Se lection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Outcom e M easu res . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Safety: A Re view of th e Eviden ce . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Efficacy an d Effectiven ess: A R evie w of th e Evid en ce . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Protein-Related Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .An tibod y-Related Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Im mu ne-Com plex Re lated Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Cel l-Re lated Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Con clusions an d Di rection s fo r Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

CHA PTER4: COST EFFECTIVENESS AND REIMBURSEMENT POLICY: ISSUES AND EVID ENCECost Effectiven ess . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Estimatin g Costs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Cost Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Th ird-Par ty Reim bursem en t . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Federal Pol icie s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Private Sector Pol icie s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

CHAPTER 5: IMPLICATIONS FOR POLICY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Appendixes

A. Health Program Advi sory Com mitte e an d Ackn ow ledgm ents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .B. Aph eresis for Hemolytic-Uremic Syn drom e . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .C. Apheresis for In hib ito rs to Factor VIII . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .D. Ap heresis in Gu illain -Barre Syn drom e . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Glossary

Air-emboli: A bubble of air obstructing a blood vessel.Anaphylaxis: An unusual or exaggerated allergic

reaction.Antibodies: The chemicals in the human body’s de-

fense system that identify foreign substances, lock onto them, and trigger the body’s immune attack on foreign substances. The body makes more than

a million antibodies, each different and each capableof recognizing and attacking only one substance—one typ e virus, one type of bacteria, and so on.

Anticoagulant: Substances inhibiting normal bloodclotting.

Antigen: A large molecule, usually a p rotein or car-bohydrate, which wh en introduced in the body s t im-ulates the produ ction of an an tibody that will reactspecifically with the antigen.

Atrophy: A wasting away; a diminution of the sizeof a cell, tissue, organ, or part.

Autoimmu ne: Directed against the body’s own tissue.In autoimmune diseases, pathological antibodies areprodu ced th at attack th e body’s own n ormal tissue,

such as kidney cells in glomerulonephritis or thenerve/muscle junction in myasthenia gravis.

Cost-benefit analysis (CBA): An analytical techniquethat comp ares the costs of a p roject or technologi-cal application to the resultant benefits, with both

costs and benefits expressed by the same measure.

This measure is nearly always monetary.Cost-effectiveness analysis (CEA): An analytical tech-

niq ue th at compares the costs of a project or of alter-native projects to the resultant benefits, with costsand benefits/effectiveness expressed by differentmeasures. Costs are usually expressed in dollars, butterms such as “lives saved, ” “disability avoided, ”“quality-adjusted life years saved,” or any other rele-

vant objectives. Also, when benefits/effectivenessare difficult to express in a common metric, theymay be presented as an “array. ”

CEA/CBA: A composite term referring to a family of analytical techniques th at are employed to comparecosts and benefits of programs or technologies. Theterms as used in this case study means “cost-effec-tiveness analysis/cost-benefit analysis.”

Cytapheresis: A type of therapeutic aph eresis involv-ing th e selective removal of specific blood cells (redcells, white cells, and/or platelets).

Cytotoxic: A specific toxic action on cells of specialorgans.

Discounting: A procedure used in economic analysis

to reduce to present value those costs and effects thatoccur in futu re years. Discountin g is based on twopremises: 1) individu als prefer to receive ben efitstoday rather than in th e future, and 2) resources in-

vested today in alternative programs could earn areturn over time.

Drug: Any chemical or biological substance that maybe app lied to, ingested by, or injected into hum ans,in ord er to prevent, treat, or diagnose d isease orother medical conditions.

Effectiveness: Same as efficacy (see be low) except that

it refers to average or actual conditions of use.Efficacy: The probability of benefit to individuals in

a defined p opulation from a med ical technology ap-plied for a given medical problem under ideal con-ditions of use.

Erythrocytapheresis: A type of cytapheresis involving

the removal of red cells.Extracorporeal: Outside the body, as in extracorporeal

tubing for membrane apheresis equipment.Glomerulonephritis: A variety of nephritis character-

ized by in flammation of the capillary loops in th eglomeruli of the kidney.

Granulocytes: Any cell containing granules, especial-ly a leu kocyte containing certain types of granules

in its cytoplasm.Hemolysis: Separation of th e hemoglobin from the red

cells and its appearance in the plasma.Hybridoma: A hybrid cell resulting from the fusion

of two cells: a lymph ocyte produ cing an antibod yand a myeloma (or tumor cell), which grows wellin culture and allows hybridoma to be established

permanently. The antibodies from a given hy-bridoma are identical (“monoclinal”).

Hyperviscosity: Excessive thickness of blood.Hypocalcemia: Reduction of the blood calcium b elow

normal .Immu ne complexes: Antigen-antibody complexes that

can be deposited in tissue. In immune-complex re-

lated diseases, such as rheumatoid arthritis, thisdeposition occurs and produces severe inflammationand tissue damage.

Immu noglobutin: A protein of animal origin endow ed

with k nown antibody activity. Immu noglobulinsfunction as specific antibodies an d are respon siblefor the humoral aspects of immunity. They arefound in the serum and in other body fluids andtissues. There are five basic classes of immu no-globulins—IgA, IgD, IgE, IgG, and IgM.

Immunosuppressive: The artificial prevention ordiminution of the immune response.

Incidence: In epidemiology, the number of cases of dis-ease, infection, or some other event having its onset

during a prescribed period of time, in relation to theun it of popu lation in wh ich it occurs. Inciden ce isa measure of morbidity or other events as they hap-pen over a period of time.

ix



Inpatient care: Care that includes an overnight stayin a medical facility.

Leuk ocytes: The w hite cells of blood.Leuk aph eresis: A type of cytapheresis involving th e

reduction of excess wh ite cells, as in leuk emia.Locke’s solution: A solution of sodium chloride,

calcium chloride, potassium chloride, sodium bicar-

bonate, and dextrose.Lymp haph eresis: A type of cytapheresis involving the

removal of lymphocytes (certain white cells) without

depletion of plasma components, making anyplasma replacemen t, therefore, un necessary.Lymphocytes: A type of leuk ocyte, chiefly a p roduct

of lymphoid tissue, which participates in humoraland cell-mediated immunity.

Lymp hok ines: The b iologically active solub le factorproduced by white blood cells.

Lyrnphop lasmaph eresis: A type of cytapheresis involv-ing a combination of lymphopheresis and plasma-pheresis: the removal of both lymphocytes andplasma, usually during a single procedure, and re-quiring the use of replacement fluids.

Medicaid: A Federal program that is ad ministered andoperated individually by each participating State

government th at provides med ical ben efits to cer-tain low-income persons in need of health and med-ical care.

Medical technology: The drugs, devices, and medicaland surgical procedures used in medical care.

Medicare: A nationwide, federally administered healthinsurance program authorized in 1965 to cover the

cost of hospitalization, medical care, and some re-lated services for eligible persons over age 65, per-sons receiving Social Security Disability Insurance

payments for 2 years, and persons with end-stagerenal disease. Medicare consists of two separate butcoordinated programs—hospital insurance (Part A)and supplementary medical insurance (Part B).

Health insurance protection is available to insuredpersons without regard to income.Monoclinal antibodies: Antibodies derived from a

single source or clone of cells which recognize onlyone kind of antigen.

Myeloma: A malignant disease in w hich tum or cellsof the antibody-producing system synth esize exces-sive amoun ts of specific proteins.

Ou tpatient care: Care that does n ot include an over-night stay in th e facility in which care is provided.

Paraproteinemias: Presence in the blood of a parapro-tein (immunoglobulin produced by a clone of neo-plastic plasma cells proliferating abnormally), suchas a cryoglobulin or a macroglobulin, in amounts

not normally observed.Pathogen: A specific causative agent of disease.Plasma: The fluid portion of blood in which particulate

components are suspended.Plasma exchange: An often used therapeutic applica-

tion of apheresis, in which a large volume (up to

5 liters) of plasma is rem oved and replaced b y anequivalent volume of fluids such as fresh frozenhuman plasma, plasma substitute, or combinationof albumin, calcium, and normal saline, depending

on the need of the individual patient. Some research-ers make a distinction between plasma exchange an d

plasma infusion. In th e former case, plasma isremoved and replaced by a colloid solution, com-monly albumin, fresh frozen plasma, or simpledonor plasma. Although the plasma replacement in

early cases was initiated only for purp oses of expan-sion of the blood vessel “intravascular” volume, laterinvestigators suggested that the administration of fresh frozen plasma had an independent therapeuticeffect. This led some investigators to administer itwithout apheresis; this is described in the literatureas plasma infusion.

Plasma perfusion: A multiple separation technique intherapeutic apheresis whereby th e patient’s plasmais first isolated from the cellular elements and subse-quently passed through a filtration medium (eitherabsorptive columns or membranes) to remove un-wanted plasma components. The filtered plasma isthen returned to the patient along with the cells.

Plasmaph eresis: Strictly defined , a type of aph eresisthat involves the removal of small amounts of plas-ma. The prim ary use of this procedure is in the col-lection of source plasma for subsequ ent p rocessinginto serum fractions, and it has been traditionallyfound in blood banks and in the plasma collectionindustry.

Platelets: Oval-shaped structures found in the bloodof all mammals and chiefly known for their role inblood coagulation.

Plateletapheresis: A type of cytapheresis involving the

reduction of abn ormally high levels of platelets.Prevalence: In ep idemiology, the nu mb er of cases or

disease, infected persons, or persons with disabilities

or some other condition present at a particular time,in relation to the size of the pop ulation. Prevalenceis a measure of morbidity at a point in time.

Proteins: The functional and structural componentsof cells.

Purpura: A group of disorders characterized bypurplish or brownish-red discoloration, easily visi-ble through the epidermis, caused by hemorrhageinto the tissues.

Randomized clinical trial (RCT): An experimentaldesign involving the random assignment of humansubjects either to an experimental group (in whichsubjects receive the treatment being studied) or to

a control group (in which subjects do not receive

the treatment being studied). Also referred to as“randomized controlled clinical trial” or “controlledclinical trial.”

Registry: The collection of health or medically relateddata typically abstracted from a specific document(e.g., medical record or death certificate) using cri-

X



teria that are applied retrospectively. In practicalterms, registries generally cover discrete political or

geographic areas.Reliability: A measure of the consistency of a method

in producing results. A reliable test gives the same

results when applied more than once under the sameconditions. Also called “precision. ”

Remission: Abatement or diminu tion of the symptomsof a d isease.

Risk: A measure of the probability of an adverse or

untoward outcome and the severity of the resultantharm to health of individuals in a defined popula-

tion and associated with u se of a medical technol-ogy applied for a given m edical problem u nderspecified conditions of use.

Safety: A jud gmen t of the acceptability of risk (seeabove) in a specified situation.

Technology: The application of organized kn owledgeto practical ends.

Technology assessment: A comprehensive form of pol-icy research that examines the technical, economic,

and social consequen ces of techn ological app lica-tions. It is especially concerned with unintended, in-direct, or delayed social imp acts. In h ealth p olicy,the term h as also come to m ean any form of policy

analysis concerned with medical technology, es-pecially the evaluation of efficacy and safety. Thecomprehensive form of technology assessment isthen termed “comprehensive technology assess-ment .“

Validity: A measure of the extent to which an observed

situation reflects the “true” situation. Internal validi-ty is a measure of the extent to wh ich stud y resultsreflect the true relationship of a “risk factor” (e.g.,

treatment or technology) to the outcome of interestin study su bjects. External validity is a measure of the extent to which stud y results can b e generalizedto the population that is represented by ind ividuals

in the study, assuming that the characteristics of thatpopu lation are accurately specified.

Vasculitis: Inflamm ation of a blood vessel.

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1.

Introduction and Summary



1.

Introduction and Summary

BACKGROUND AND SCOPE OF THE CASE STUDY

For several centuries, one of the chief thera-

peutic methods besides the administration of herbswas to attempt to remove noxious substances

from the bod y—either by a general purgin g, often

with drastic laxatives, or still more dramatical-

ly, by bloodletting. It has been said that several

important persons, Louis XIII of France and

George Washington, for instance, were probably

killed by such therapy (43,137).

In the past decade, the medical community hasincreasingly used therap eutic aph eresis, * a tech-nology * * initially m ind ful of the an cient p racticeof bloodletting. In therapeutic apheresis, a pa-

tient’s plasma and / or blood cellular parts areseparated and then removed from the blood andreplaced by substitute plasma or a related p hysio-logical solution. It is believed that abnorm al orharmful substances or cells are thereby removed,leading to a cure or arrest of the disease. Resultsreported in the scientific literature have beendram atic, and ap heresis is being u sed to treat anincreasing number of medical conditions. Skep-ticism over the validity of such claims an d alsothe high costs of apheresis, however, havetouched off recent controversies over this p ro-cedure’s use.

Therapeutic apheresis is not a new procedur ebut the extent of its use has grow n, and may con-tinue to grow, substantially and rapidly. From1977 through 1980, procedure volume increased

q There is some debate over the proper terms for the proceduresdescribed in this case study. The term “plasmapheresis” has beenused in the medical literature since 1914. Some argue that the moretechnically correct and appropriate noun to describe the separationand removal of blood components is “apheresis” (see, e.g., 67). Inany case, the reader should be aware that the terms “plasmapheresis”and “apheresis” are used rather interchangeably in the literature aswell as in common usage (73).q *The Office of Technology Assessment (OTA) defines technol-

ow as the practical application of organized knowledge. The termmeul’cal technology, as used in this case study, is a drug, device,or medical or surgical procedure used in medical care. (The termmay also apply to the organizational and supportive systems within

which medical care is delivered, but those systems are not the focusof this case study. ) (95).

more than 500 percent, from around 5,000 to over40,000 procedures per year (108). These estimateswere develop ed retrospectively, because there has

been no formal reporting system. In the late

1970’s, the rate of growth far outpaced the esti-

mates. The now defunct National Center for

Health Care Technology, for example, original-

ly estimated use in 1979 at “hundreds of pro-

cedures, ” only to learn later that the actual pro-

cedure volume that year hovered around 16,000

(34). This phenomenal rate of growth between

1977 and 1980 led in turn to general estimates of

a half million procedures per year by 1985. Very

recently, however, these estimates have been re-

vised downward because of increased concern by

health care professionals and third-party payers

alike over th e techn ology’s safety, effectiveness,

and costs (35).

At present, apheresis is primarily accepted as

an acute therapy in a small group of relatively

obscure d iseases, and the n umb er of patients un-dergoing treatment totals approximately 20,000

(70). Like an other n ew techn ology of recent years,

the computer, therapeutic apheresis might in somerespects be characterized as a “solution looking

for problems.” This is evidenced by the fact that

apheresis is being evaluated as a chronic treatmentmodality for several major diseases, including

rheumatoid arthritis, multiple sclerosis, and cer-

tain forms of cancer. These disorders represent

a potential patient population of hundreds of

thousands of cases in this country. Because pa-

tient ben efits for these disord ers have often beenonly par tial, temporary, or equivocal, the em er-gence of efficacy an d , especially, cost concernsis not surprising.

The costs of apheresis have, in fact, become aparticularly volatile issue. Therapeutic apheresis

may be found to have great potential for reduc-ing illness and death. The potential number of med ical conditions and size of the p atient p opu la-tion that could be covered, in combination w iththe costs of ap heresis treatm ent ($400 to $1,200

3



4 q Health Technology Case Study 23: The Safety, Efficacy, and Cost Effectiveness of Therapeutic Apheresis

per treatment, with a significant nu mber of treat-ments need ed per patient), how ever, point to apossibly vast expend iture of fund s on ap heresis—in the billions of dollars. This cost issue has beenfurther highlighted because some Am ericans al-ready qu estion the resource expenditures of over$1 billion per year for each of three established

therapies: coronary byp ass surgery, kidney dial-ysis and transplants, and treatment of newbornsin neonatal intensive care units (2).

Major market opportunities for equipment,

supplies, and services have been forecast for

apheresis technology in the next decade. As a

result, therapeutic apheresis has been the subjectof investor interest and increased indu stry par-ticipation. Vigorous research, development, andmarketing activities have been undertaken bycompanies in the United States, Europe, andJapan. Major American participants include

Haemonetics Corp., International Business Ma-chines (IBM), Baxter Travenol, Cobe Laborato-

SUMMARY

Apheresis: Definitions,and Developments*

Descriptions,

Apheresis is a p rocedu re in w hich blood is sep-arated into its basic comp onen ts (red cells, w hitecells, platelets, and plasma), and one or more of these is selectively remov ed from the blood . It is

app lied therapeutically for the pu rpose of curing,alleviating, or treating a disease or its symptoms.The procedur e can take several forms, though itis usually accomplished by removing venousw hole blood from th e body, separating the bloodinto cellular and noncellular (plasma) parts or“fractions,” and returning the cellular fraction tothe patient. Just as in kidney dialysis, blood flowsfrom a patient to a m achine where it is treatedand then returned to the patient by way of an ex-tracorporeal (i.e., outside th e body) blood tu b-ing set.

The idea of apheresis first originated in 1914,but it was n ot until World War II that hu man

q A number of the scientific and medical terms used in this casestudy are defined in the Glossary,

ries, Parker-Hannifin, Cordis-Dow, and MilliporeCorp. These companies have developed severalnew therapeutic techniques in response to p ercep-tions of a need to reduce present costs. Thesetechniques are discussed in later chapters, al-though a d escription or analysis of the industryor market that has developed around the technol-

ogy of therapeutic apheresis is beyond the scopeof this study.

This case stud y w as prep ared a s part of OTA’spr oject on “Med ical Technology and Costs of theMedicare Program.” The entire p roject is beingconducted in response to requests by the HouseCommittee on Energy and Commerce and its Sub-committee on H ealth, and the Subcomm ittee onH ealth of the Senate Com mittee on Finance. Thisparticular portion of the project responds to aspecific request by the Senate Finance Commit-tee’s Subcommittee on Health for scientifically

based information on the effectiveness of thera-peu tic apheresis.

apheresis was considered and used as a means of meeting the increased d emand for plasma. Overthe last 20 years, the collection an d processing of donor p lasma has evolved into a m ajor industry

as the demand for plasma fractions, such as al-

bu min, has in creased. The first successful therapeutic use of apheresis was reported in the late

1950’s, and during the next few years, reports ap-peared on the ap plication of apheresis to severaldiseases. Recent ad vances du ring the p ast decadein basic research, in equipment, and in the tech-nique of apheresis have provided a rationale forcarrying out apheresis on a much larger scale andin a w ider variety of diseases. To d ate, apheresishas been u sed in the treatment of over 75 diseases,and an additional 41 diseases have been identifiedas possible cand idates for this therapy.

The rationale for performing apheresis is to re-move one or more components of blood that con-

ceivably contain and carry pathogenic substanceslinked to a patient’s disease process. Variousdiseases have been increasingly associated withthese “abnorma l” blood comp onents in the cir-culation, and these comp onents are believed to



6 q Health Tehnology Case Study 23: The Safety, Efficacy, and Cost Efectiveness of Therapeutic Apheresis

Aph eresis ap pears to be a relatively safe pro-cedu re, though it is not without at least short-termrisks. The long-term risks of removing usefulblood components have been termed “w orrisome”and are un clear at best. Apheresis device equip-ment can also be termed effective in the sense thatthe technology accomp lishes the intended removal

of plasma and cells. However, there is very littledefinitive evidence docum enting the wid espreadsuccess of the technology in actually improvinghealth. The use of apheresis has been generallyacknowledged as an effective treatment ap plica-tion for acute therapy in a small group of relative-ly obscure diseases. These include acquired myas-thenia gravis, primary macroglobulinemia (Wal-denstrom’s) and hyperglobulinemias, includingmultiple myeloma. There is certainly suggestiveevidence, too, that therapeu tic apheresis is suc-cessful in arresting the disease process for somepatients w ith other specific disease cond itions.

Convincing p roof of clinical efficacy, how ever,is still lacking in the wider variety of diseases inwh ich this treatment is being u sed.

Large prospective rand omized trials, man y of them fun ded by the National Institutes of Health,have been orga nized for several disease applica-tions in wh ich ap heresis therapy ha s been used,in order to more p recisely define w hat ad vantages,if any, these treatments may have. Further re-search w ill be needed to both compare p resenttreatment approaches with new and emergingblood filtration methods and to test related scien-

tific advances (e.g., the use of monoclinal anti-bodies).

Cost Effectiveness and ReimbursementPolicy: Issues and Evidence

In addition to the issues of health status or otherhealth outcome related effects (i.e., safety, ef-ficacy, and effectiveness) of apheresis, efficiencyissues must also be addressed. Two importantmethod s used to assess the costs and benefits of therapeu tic aph eresis, and d evelop comp arisonsamong effects, costs, and benefits are cost-benefit

analysis (CBA) and cost-effectiveness analysis(CEA). CBA is used to develop comparisons of the benefits of treatments a gainst the resou rcesthey consum e, with both benefits and costs ex-pr essed in dollars. It is difficult to cond uct a CBA

for apheresis, because even though the therap yhas reportedly lessened su ffering and helped p ro-long lives, reliable estimates of these benefits haveyet to be determined and quan tified. CEAs areused to evaluate the relative cost of alternativetreatments per unit of effectiveness (typicallyspecified in nonmonetary terms). CEAs for apher-

esis have not yet been conducted because suffi-cient data on outcomes for aph eresis and alter-native treatments are lacking.

Nevertheless, the task of evaluating treatmentscan include the context of costs, for which therehave been several general estimates. National ex-pend iture estimates on ap heresis therapy, w hichis currently performed on only selected patients,range from $3.2 milli on to $240 million . If, how-ever, apheresis therapy is extended in th e future

to the wid er array of diseases to wh ich it has been

only experimentally applied thus far, total treat-

men t costs could range from $650 million to over$7 billion per year.

Third-party payment will bean important in-

fluen ce on futu re adoption , use, and economic ef-fects of therapeutic apheresis, through the funding

and reimbursement policies of both private and

government insurance programs. Reimbursement

policies, like other aspects of therapeutic apher-

esis, have been the subject of some debate because

of the competing factors of cost and therapeutic

promise. The developmen t of most of these pol-icies ha s been recent. On Septem ber 15, 1981, theHealth Care Financing Ad ministration issued itsfirst national instructions for apheresis, announc-ing coverage under the Medicare Program for onlya small grou p of relatively rare disease indica-tions.* Med icaid covera ge regu lations vary fromState to State because of changes in Federal fund-ing policies, which provide States with some lati-tude in deciding how Federal funds are spent.Other governm ental program s, such as the De-partment of Defense’s CHAMPUS, as well as pri-

q On Apr. 20, 1983, Public Law 98-21 provided for extensivechanges in Medicare reimbursement policies for hospital-based care.Under the statute, whose provisions will be phased in over 3 years,

hospitals will receive a flat fee per patient, set prospectively, on thebasis of patient diagnosis in one or more of 467 diagnosis-relatedgroups (DRGs). It is unclear at this point how the DRG-based pay-ment system will affect the adoption and use of apheresis. Whatis certain, however, is that information on the effectiveness of thistreatment will be even more important as physicians and patientsface increasingly scarce resources.



Ch. l—Introduction and Summary q 7

vate medical insurers, also vary on which diseaseindications should be covered, p robably stemmingfrom a less than consistent scrutiny of the eviden ceon safety and efficacy. A widening of Medicareand private insurer coverage of therapeutic apher-esis for specific life-threatening complications(e.g., rheumatoid vasculitis) is probable in the

near future. But direct cost estimates and thepotential cost of possibly premature diffusionalone make it unlikely and unw ise that third-partypayers w ill supp ort any broad extension of ben-efits for ap heresis treatment u ntil more valid d atais generated. Until evidence is available, ther-apeutic apheresis will largely be viewed as an ex-perimen tal techniqu e, not to be considered as apart of routine care. In light of such a situation,present research and clinical trials being carriedout assume even greater importance.

Implications for Policy

Several recurring issues in need of further studyor resolution arise during an examination of apheresis technology. One issue, which arises be-cause the technology is still in the developmentstage, is w hat the app ropriate patient criteria foruse are, what th e app ropriate timing of interven-tion in the course of a disease is, and whether theprocedure to be followed in performing thera-peutic aph eresis is ad equately standard ized. Suchquestions are basic in th e developm ent of a tech-nology, and research to address these questionsis needed, as it forms a n ecessary founda tion forthe conduct of well-controlled testing and clinical

trials. Interim apheresis registries could track con-ditions of use and forma know ledge base for de-velopment of w ell-controlled stud ies.

A second issue, which arises where conditionsof use have been su fficiently stand ard ized, is thelack of and need for well-designed clinical trialsof apheresis. There has been a recent infusion of government and foundation funding to offset thehigh costs of such trials. Should costs continueto be a p roblem, one alternative might be to havethird-party payers, including Medicare, selectivelyreimburse for therapeu tic apheresis in return forclinical data. If implemented properly, this alter-native could substantially increase the quality of information available for public and private reim-bursem ent coverage d ecisions. Evidence of thetechnology’s cost effectiveness could result inyielding substantial budgetary savings. Even if theresults of such trials were disappointing, they

could lead the way to unexpected advances in re-search.

A third issue is the possibly transitional natureof apheresis technology. Advances in apheresisequipment, advances in related areas of basicbiomedical research, and emerging parallel devel-opments such as biotechnology, indicate thatpolicies affecting therapeutic apheresis must beconsidered in the larger context of present scien-tific and technological flux. Considerable atten-tion will be needed to establish the most rationaland prod uctive balance between development andsupport of apheresis technology and that of basicand applied research toward other technologiesof similar or m ore favorable prom ise.

ORGANIZATION OF THE CASE STUDY

This case study is organized into five chapters. Chapter 3 reviews research on the scientific and

Chapter 2 provides definitions and descriptions medical aspects of therapeutic apheresis. Included

of the various types of apheresis technology, along is a description of meth odological issues involvedwith perspectives on the history and etiology of in therapeutic apheresis evaluation. The evidenceapheresis use. It also describes the current treat- on the safety, efficacy, and effectiveness of thement process and futu re trends, especially as they procedure for the wide range of specific diseases

involve changes in a pheresis equipm ent d evices. and conditions is examined. The results of three



8 q Health Technology Case Study 23: The Safety, Efficacy, and Cost Efectiveness of Therapeutic Apheresis

method ological reviews of therap eutic apheresisfor treatment of hemolytic uremic syndrome, ac-quired Factor-VIII inhibitor , and Guillain-Barresyndrom e, prepared for this case stud y, are alsodiscussed. (The full reviews are presented as apps.B, C, and D.)

Chapter 4 focuses on reimbu rsement and cost-effectiveness issues. Data and estimates on th ecosts and benefits of providing therap eutic apher-esis and policy issues of the current system areconsidered in relation to safety and efficacy dataregarding treatment. In chapter 5, implications forpolicy are provided in light of several recurringissues th at emerge from an assessment of this tech-nology.

There are six appendixes to this case study. Ap-pendix A acknowledges the valuable assistanceof the Health Program A dvisory Comm ittee andseveral other individuals for their review an d ad-vice in pu tting together this report. Ap pend ixesB, C, and D contain the previously mentionedmethod ological reviews, w hile appen dix E brief-

ly discusses the cause an d pathological develop-ment of autoimmu ne d iseases. A full bibliographyof the scientific literatu re on th erapeu tic apheresis,compiled by the American Red Cross and orga-nized by disease categories, is included in appen-dix F. (The bibliograph y sp ecific to this case studycan be found in the References section followingthe app endixes. )



2 s

Apheresis: Definitions,Descriptions, and Developments



2

Apheresis: Definitions;

Descriptions, and Developments

Apheresis is a p rocedu re in w hich blood is sep-arated into its basic comp onen ts (red cells, whitecells, platelets, and plasma), and one or more of these is selectively remov ed from the blood . It isapp lied therapeutically for the pu rpose of curing,alleviating, or treating a d isease and/ or its symp -toms. The procedure is u sually accomplished byremoving venous w hole blood from the bod y,separating the blood into cellular and noncellular(plasma) parts or “fractions,” and returning thecellular fraction to the p atient (59,86). Just as with

kidney dialysis, blood flows from a patient to a

machine where it is treated and then returned tothe p atient by w ay of an extracorpor eal (i.e., out-side the body) blood tu bing set (39). *

In simplest terms, apheresis involves separating“bad blood” from good. Blood comprises fourbasic components: red cells, white cells, platelets,and plasma. A typical adult male has 3 trillion

red cells in the b lood. The red cells deliver ox-ygen throughout the body and carry carbon diox-ide back to the lungs, where it is exhaled. Forevery 800 red cells, the blood contains about 1white cell. The several types of white cells (leuko-

cytes) play key roles in the immunological defensesystem (lymphocytes), fight infections (granulo-cytes), and respond to foreign materials. Platelets,of which there are abou t 1 for every 20 blood cells,are spherical or oval bodies that help th e bloodto clot. Lastly, plasma, which contains large quan-tities of proteins, ions, and organ ic and inorgan icmolecules, makes u p a bout 55 percent of bloodvolum e, and is the straw -colored, fluid p ortionof circulating blood . The rationale for perform-ing aph eresis is to remove one or m ore of thesecomponents of blood that conceivably containspecific pathogenic substances linked to a p atient’s

disease process (2).

q In kidney dialysis, however, the dialysis device does not separatethe blood’s cellular and plasma components of blood, but ratherremoves only unwanted metabolizes and waste products from theblood (39).

A variety of diseases have been associated withabnormal p roteins or blood comp onents in the cir-culation, which are believed to initiate or ag-gravate the disease condition. Apheresis typical-ly has been u sed in diseases involving th ree maintypes of abnorm al levels of blood components:plasma protein, antibodies, and immune com-plexes.

Protein-related d iseases involve either excessivelevels of proteins in plasma (e.g., the macro-globulins in Waldenstrom’s syndrome) or exces-sive levels of other substances which are “carried”

in the blood by th e plasm a pr oteins (e.g., thyroidhormone in thyrotoxicosis). The antibody-relateddiseases are often termed “autoimmu ne” d iseases.Normally, antibodies are produced by the im-mune system to attack foreign substances (“an-tigens”) such as bacteria. However, in au toim-mu ne d iseases, pathological antibodies are p ro-du ced wh ich attack the body’s own n ormal tissue,such as kidney cells in glomerulonephritis or thenerve/ mu scle junction in m yasthenia gravis. Im-mune complexes are antigen-antibody complexesthat can be d eposited in tissue. In imm un e-com-plex related diseases, such as rheumatoid arthritis,this deposition occurs and prod uces severe inflam-mation an d tissue d amage (117).

The therapeutic goal of apheresis is to decreasethe levels (throu gh rem oval) of these abnorm alcomponents in the circulating blood. Physiciansreason that if they can properly identify and re-move th ese problem substances, the disease proc-ess may be controlled and the p atient’s clinicalcondition should improve.

Unfortunately, the effects of apheresis are notwell und erstood. For the most par t, its benefits

remain anecdotal and difficult to reproduce. Itseffects are not generally believed to be curative;rather, they are usually of a temporary nature.Often the procedu re is used in conjunction withother treatments, especially drug therapy, mak-ing it difficult to assess the effectiveness of

11



12 q Health Technology Case Study 23: The Safety, Efficacy, and Cost Efectiveness of Therapeutic Apheresis

apheresis therapy. The scientific and medical ap-plications of aph eresis an d correspond ing levelsof efficacy and effectiveness gained from suchtreatment are d iscussed at length in chap ter 3.

Apheresis can take several forms: plasmap her-esis, plasma exchange, plasma p erfusion, cyta-

pheresis, lymphapheresis, and lymphoplasma-pheresis. Strictly defined, pkrqdxmsis involvesthe removal of small amounts of plasma. The pri-mary use of this procedure is in the collection of source plasma for subsequent processing intoserum fractions, as has been traditionally foundin blood banks and in the p lasma collection in-dustry.

The plasma separation process, however, hasbeen increasingly u sed over th e last decade fortherapeutic uses. The therap eutic app lication mostoften includes tw o general techniques. In p lasma

exchange, a large volum e (up to 5 liters) of plasm ais removed and replaced by an equivalent volume

of fluids such as fresh frozen human plasma, aplasma substitute, or combinations of albumin,calcium, and normal saline, depending on theneed of the ind ividu al patient. * Plasma perfusion

refers to a multiphase separation technique inwhich the patient’s plasma is first isolated fromthe cellular elements and subsequently passedthrough a filtration medium (either adsorptive col-umn s or membranes) to remove unw anted plasmacomponents. The filtered plasma is then returned

*It is important to note that some researchers also make a distinc-tion between plasma exchange an d plasma infusion. In the formercase, plasma is removed and replaced by a colloid solution, com-monly albumin, fresh frozen plasma, or simple donor plasma. Al-though the plasma replacement in early cases was initiated only forpurposes of expansion of the blood vessel “intravascular” volume,later authors suggested that the administration of fresh frozen plasmahad an independent therapeutic effect. This led some investigatorsto administer it without apheresis; this is described in the literatureas plasma infusion.

HISTORICAL DEVELOPMENT

to the patient along with the cells (39,108). Only

recently has equipment for this technique been ap-

proved for general therapeutic use by the Food

and D rug Adm inistration (FDA) (see “Equipm entTechnology” section later in this chapter for a

more complete discussion of plasma perfusion).

Another form of therapeutic apheresis is cy-tapheresis, the selective removal of specific bloodcells (red cells, white cells, and / or platelets).Cytapheresis is usually subdivided according to

plateletapheresis (the redu ction of abnorm allyhigh levels of platelets), leukapheresis (the reduc-tion of excess white cells, as in leukemia), anderythrocytapheresis (the removal of red cells)(105). Cytapheresis can also include l y m p h -apheresis, the r emoval of lymp hocytes (certainwhite cells) without depletion of plasma com-ponents, making any plasma rep lacement, there-fore, unnecessary. Lymphoplasmapheresis is a

combination of lymphapheresis and plasmapher-esis: the removal of both lymphocytes andplasma, usually du ring a single procedure, andrequiring the u se of replacement fluids.

There are different types of hardw are used forperforming ap heresis. One is a centrifugal typ emachine that spins the blood in a cham ber anduses centrifugal force to separate the heavier partsof the blood from th e lighter ones. The filter typeuses a flat sheet or hollow fiber porou s membran eto separate the larger blood components from thesmaller. This typ e is only capable of remov ing

plasma from the cellular portion of the blood:plasma and plasma p roteins easily pass throughthe pores in the m embrane bu t the red cells, whitecells, platelets, and large p rotein m olecules are toolarge to pass. Thus, the filter-type device can onlyperform p lasmapheresis. Although the centrifugaltype of device is more versatile, the filter type hasfew er m oving parts a nd is easier to operate (39).

The idea of apher esis (from the Gr eek, aphair- of this work, they investigated the effect “of theesis, meaning “taking aw ay”) first originated in repeated removal of considerable quantities of 1914 with a group headed by John J. Abel at Johns blood, replacing the plasma by Locke’s solution,”Hopkins Medical School (l), which at tempted to and in fused the mixture back in to the dogs . Theydevelop an artificial kidney in dogs. In the course showed that dogs were able to tolerate the ex-




Table I.—Reported Use of Therapeutic Apheresis

Acute necrotizing hemorrhagic encephalomyelitisAcute disseminated encephalomyelitisAcute post-streptococcal glomerulonephritisAcute rheumatic feverAddison’s diseaseAdenocarcinoma of the colonAdenocarcinoma of the breast

Allergic granulomatosis and angiitisAmyloidosisAmyotrophic lateral sclerosis (ALS)Ankylosing spondylitisAplastic anemiaAtopic dermatitisAtrophic gastritis type AAutoimmune infertility & gonadal insufficiencyAutoimmune hemolytic anemia (AIHA)Autoimmune hypogammaglobulinemiaAutoimmune neutropeniaBehcet’s syndromeBone marrow transplantBronchial asthmaBronchogenic carcinomaBullous pemphigoidCardiac allograft rejection

Chronic membranoproliferative hypocomplementemicglomerulonephritisChronic active hepatitisCirculating anticoagulant (Anti-Factor Vlll)Cold agglutininsColon carcinomaCrohn’s diseaseCryogenic fibrosing alveolitisCryoglobulinemiaCutaneous vasculitisDermatitis herpetiformisDermatomyositisDiscoid lupus erythematosusDisseminated intravascular coagulation (DIC)Dressier’s syndromeEaton-Lambert syndromeEndomyocardial fibrosis

Erythema multiformFabry’s diseaseFelty’s syndromeGastric carcinomaGaucher’s diseaseGiant cell arteritisGlomerulonephritis in subacute bacterial endocarditisGoodpasture’s syndromeGraft versus host diseaseGraves’ diseaseGraves’ ophthalmopathyGuillain-Barre syndrome

AcuteChronicRelapsing

Hashimoto’s thyroiditisHemolytic uremic syndrome

Henoch-Schonlein purpura

Hepatic comaHerpes gestationsHodgkins diseaseHypercholesterolemiaHyperglobulinemic purpuraHypersensitivity pneumonitisHypersensitivity angiitis

HypertensionHypertriglyceridemiaHyperviscosity syndromeIdiopathic membranous glomerulopathyIdiopathic thrombocytopenic purpura (ITP)Idiopathic hypoparathyroidismInsulin resistant diabetes mellitus due to

anti-receptor antibodyJuvenile onset diabetes mellitusLipoid nephrosisLymphomasMalignant melonomaMixed connective tissue diseaseMultiple sclerosisMultiple myelomaMyasthenia gravisNecrotizing cutaneous angitis

NeuroblastomaOther neoplasmsPemphigus vulgarisPernicious anemiaPoisoning or overdose (paraquat, mushroom, digitalis)Polyarteritis nodosaPolymyositisPost-transfusion purpuraPrimary cardiomyopathyPrimary biliary cirrhosisProliferative/membranoproliferative glomerulonephritisPsoriasisPure red cell aplasiaRapidly progressive glomerulonephritisRaynaud’s diseaseRefsum’s syndromeReiter’s disease

Renal allograft rejectionReye’s syndromeRhesus iso-immunizationRheumatoid arthritisSarcoidosisSclerodermaSjogren’s syndromeSubacute bacterial endocarditisSystemic lupus erythematosus (SLE)Takayasu’s arteritisThrombotic thrombocytopenic purpura (lTP)Thyroid stormUlcerative colitisViral hepatitisWaldenstrom’s macroglobulinemiaWegener’s granulomatosisWhite cell isoantibodies

SOURCE: Off Ice of Technology Aseeesment, 19S3.



Ch. 2—Apheresis: Definitions, Decriptions, and Developments q 15

THE SCIENTIFIC AND MEDICAL BASIS FOR USE’

For therapeutic use, apheresis technology camealong at an opportune time—when there is agrowing support for the theories that a largenumber of chronic conditions occur because theantibodies of the immune system, instead of at-

tacking foreign substances as they are sup posedto, attack the body’s own tissues. This results ina build-up of so-called immune complexes, whichare carried in the blood (34).

Indeed, many d iseases that appear to respondto aph eresis seem to h ave common elements: theyreflect failures in the imm un e system, the bod y’sdefense network of sorts, which is designed to p ro-tect the individual against viruses, foreign cells,and some poisons. The cells of the immune systemcirculate in the blood an d lymph systems and alsoreside in specialized tissues such a s the thym us,

spleen, and lymph nodes. There are two princi-ple modes of immunity: humoral immunity andcell-med iated immu nity. Hu moral immu nity isrealized through antibodies, which are proteinsprod uced by lymp hocytes and wh ich circulate inthe blood system. They represent the m ajor de-fense against bacterial infections. Cellular im-munity is realized through lymphokines (alsolymphocyte prod ucts) which are responsible fora variety of phenom ena includ ing influencing mi-gration o f inflamm atory cells, allergic respon ses,dilation of the blood vessels, rejection of tissuegrafts, and other foreign matter.

The foreign agents eliciting imm un e responsesare called ant&ens, wh ich m ay be circulating pro-teins or other types of molecules, or also sub-stances on the surfaces of bacteria or foreigntissue. When ind ividuals are exposed to an an -tigen, their lymph ocytes respond by making an-tibodies specifically directed a gainst the an tigen.The antibodies have bind ing sites which attachto the antigen, and together they form aggregatescalled immune complexes. These complexes cir-

IUnless otherwise noted, this section is condensed from Frost &

Sullivan, Inc., Zn-Vivo Hernock+oxification and Hemoprocessing

Markets in t he U. S., New York, June 1981.

culate in the bloodstream and are subsequentlyprocessed and removed from the body by cellslocated in the liver, spleen, and other organ s. Itis in this mann er that foreign agents are elimi-nated.

The formation of immune complexes triggersmany other reactions. One of these is activationof the complement system, a set of proteins foundin the blood. Complement products can kill cellswith antigens on them, such as bacteria. They alsoattract inflamm atory cells to the area wh ere theantigen-antibody reactions a re taking place, andthese cells assist in clearing the an tigens.

Antigens also stimulate specific lymphocytes,Tlymphocytes, to proliferate and then differen-tiate. Some T lymphocytes differentiate into“helper cells” w hich assist the lymp hocytes inmaking antibodies; some differentiate into “killer”lymphocytes which can kill foreign cells havingantigen on their sur face; and some cells differen-tiate into “suppressor cells” which regulate the im-mu ne response by inhibiting further antibody pro-duction against the specific antigen.

The exact nature and extent of the immu ne re-sponse depend on many factors: the type of an-tigen, its route of entry into the bod y, the geneticmakeu p an d state of health of the host, the typesof antibodies mad e, and the relative proportionsof helper, killer, and suppressor cells generated.

A fundamental property of an individual’s im-mu ne system is that it distinguishes between theantigens on the body’s own tissues and those onforeign agents. Unfortunately, this system occa-sionally breaks down, and individuals mount im-mune responses, most often antibody production,directed against their ow n tissues. The d iseasesthat result from such a d isorder are referred toas “autoimmune diseases. ”

The cause and pathological development of autoimmu ne diseases are thought to be d ue toseveral mechanisms: inactivation reactions,

cytotoxic reactions, immune complex deposition,anaphylaxis, and delayed hypersensitivity. Thesemechanisms are briefly discussed in app endix E.




THE TREATMENT PROCESS

Until the advent of automated devices, theprocess of apheresis was exhausting and time-consuming, requiring 4 to 5 hours, for example,to remove about 1 quart of plasma. It was atedious manu al procedure in w hich the p atient’s

blood w as draw n one bag at a time, separated ina centrifuge so that the target components couldbe removed and the remaining blood returned tothe patient before draw ing another bag. Now,automated cell separators reduce the procedureto a simple, straightforward exchange which canbe comp leted in 2 to 4 hours. The patient is con-nected to the cell separator, which draws theblood, separates the components, and returns therest of the blood to the p atient. The volum e ex-change for each p rocedu re is calculated for eachpatient according to size and the type of treatmentmodality desired (73).

Organizational Settings and Staffing

Apheresis treatment is provided almost exclu-sively through larg e med ical school hospitals andcommun ity/ Red Cross blood banks. A few com-mercial, freestanding, independent centers havebeen established during the past 2 or 3 years;however, it appears that this trend maybe mod-erating.

Most of the existing therap eutic apheresis pr o-grams originally evolved in conjunction with thedonor facilities at community and hospital bloodbanks. However, some of the larger institutionshave since established indep endent hemap heresisunits (which undertake and perform hemodialysisand other blood filtration p rocedu res in ad ditionto apheresis) that perform leukapheresis andplateletapheresis in addition to plasma exchange.

The hemapheresis center is normally staffed bynu rses w ith special (usu ally “on-the-job”) train-ing in the operation of the cell separator equ ip-ment, ad ministration of replacement fluids, cir-culatory access techniques, and the treatment of apheresis complications. The operation of the unit

is directed by a ph ysician, often a hema tologist.

In most centers the actual procedure is con-du cted by one or tw o aph eresis nu rses. Usuallya p hysician (w ho is often the center d irector) is

required to be imm ediately available in the eventthat complications should develop. In many of the smaller facilities the supervising physician isin direct attendan ce during the p rocedu re, whilein the larger apheresis centers he or she is generally

on call within the unit (49,108).

Frequency, Intensity, and Duration ofBlood Component Exchange

The volum e and frequency of blood componentexchange depend to a large degree on the diseasebeing treated as well as the individual patientresponse. To date, temporal considerations havebeen more influenced by factors such as cir-culatory access and scheduling than by uniformprotocols, becau se the metab olism, kinetics, and

pathogenicity of the abnormal blood componentconstituents removed by apheresis have not beenlargely established (144). Therapy regimes thathave evolved from clinical studies vary as a result.Frequency of treatment ranges from an averageof 3 procedures in the m anagement of myelomato approximately 16 treatments p er year for pa-tients with chronic myasthenia gravis (thoughseverely deb ilitating rheum atoid arthritis may re-

quire up to 30 treatments in the first year, withthat n um ber d ecreasing th ereafter (47). The aver-

age for all reported diseases treated by apheresis

ranges from ap proximately 5 to 15 treatments per

year per patient, at a volume of 3.2 liters (therange is 2.0 to 4.5 liters per treatment) (108).

A survey of hospital and community bloodbanks by Scoville Associates (108) indicated,

however, an average of only 5.6 treatments perpatient during 1980. Average volume per ex-

change was 2.8 liters (1.5 to 3.5 liters). The dif-ference in treatment schedu les w as hypoth esizedto stem from several factors. For example, thehospital and blood bank averages included sched-ules for just 30 different disorders, many of whichwere treated on an acute basis only. Also, a major

objective in acute treatment settings is to obtainrapid patient response, and several centers re-ported th at they usually terminated ap heresis afterthree to four procedures if improvement is notapparent.



Ch. 2—Apheresis: Definitions, Descriptions, and Developments q 17

Circulatory Access andReplacement Fluids

The initial step in th e ap heresis procedu re in-volves the remova l of wh ole blood from the p a-tient for subsequent separation. Blood vessel ac-cess is not (because of relative infrequency) ascritical in this procedure as it is, for example, inchronic hemodialysis in end-stage renal diseaseap plications. The preferred access site is a simp lepuncture into the vein at the elbow. Such accessis adequate for most patients even with extendedseries of exchanges.

The cellular elements and replacement fluids arenormally returned to a vein in the other arm.Other return sites include the femoral vein, fore-arm, or through a small vein in the han d or foot.Sometimes repeated apheresis treatment requiressurgeons or other qualified staff to make a shu nt

or fistula, a sort of permanent “tap,” between anartery and a vein to give them ready access to thecirculatory system . Clotting and site infections canbe significant complications in the use of suchtaps.

Crystalloid solutions (saline, Ringer’s solution,Ha rtman ’s solution) are norm ally used routinelyas replacement fluid in sm all volum e apheresisprocedures. These involve removal of 1 to 2 litersof plasma every 2 to 3 weeks as in some cases of hyperviscosity syndrome. Crystalloid solutionshave the ad vantage of low cost. Larger volum e

exchanges ru n th e risk of protein dep letion, andas a rule, require the use of colloid replacementfluids such as albumin, fresh frozen plasma (FFP),or plasma protein fraction (PPF). Guidelines havebeen established by FDA for safe levels of plasmadonation w ithout protein replacement in the aver-age size adult.

The typical plasma exchange schedule, how-ever, involves the removal of between 2 to 3 litersof plasma at a frequency of two to four times perweek, and protein replacement is routinely utilizedin these cases. In general, little is know n aboutthe correlation between specific disease states andthe effectiveness of various replacement fluids.

Fluid volume r emoval is normally replaced onan equal basis. Since continued exchange willremove the rep lacement fluids as w ell as the p a-

tient’s own plasma, many centers are now begin-ning to u se a techniqu e whereby saline or dex-tran is adm inistered at the beginning of the pro-cedure, and the protein replacement portion (FFP,PPF, or albumin) is infused tow ard the end of theexchange, thus saving some d epletion of the m oreexpensive colloid solutions. This prop ortion of protein solution to total replacement fluid general-ly ranges between 30 to 50 percent (2,108).

Drug Therapy Used With Apheresis

Aph eresis used a lone has often provided onlytransient results because cells making deleteriousantibodies may not be affected. In fact, a “re-bound effect” can sometimes occur w hen aph eresisis used by itself, where p osttherapy antibody lev-els are even higher than initial levels. Apheresishas, as a result, often been more effective wh enused in combination with immunosuppressive,cytotoxic, and anti-inflammatory drugs. Examplesof these include cyclophosphamide, azathioprine,and steroids (e.g., pred nisone). In sp ecific diseasesthese drugs m ay be used individu ally, but theyare often administered together.

Steroids have many complex physiological ef-fects, and the effects of those that are responsi-ble for suppressing inflammation, immune re-sponses, and symptom s of autoimm une d iseasesare not completely understood. The basis of ac-tion of cytotoxic dr ugs is that they kill lymp h-

ocytes, and thus antibody production is de-creased.

With corresponding d rug therapy, then, the lowlevels of circulating antibodies and immune com-plexes rapidly achieved by aph eresis may be main-tained, since the rebound effect and the prod uc-tion of antibodies by lymphocytes are inhibitedby the drugs. Other internal repair mechanismscan then intercede, correcting or repa iring d am-age induced by the imm un e comp lexes or anti-bodies. For example, in myasthenia gravis, lower-ing the concentrations of antibodies allows new

muscle membrane proteins to be synthesized.Removal of circulating immu ne comp lexes ma yalso “desaturate” the immune complex clearingmechanisms in lymphoid tissues and allow th emto function better.




For some d iseases, apheresis, in combinationwith the d rugs, has been claimed to result in com-plete remission. For others, long-term benefitshave been reported. On the other hand, somediseases though t to be autoimmun e have not beenimproved with apheresis. Ultimately, the suc-

EQUIPMENT TECHNOLOGY

Centrifugal Systems

App roximatelys percent of therapeutic apher-esis procedu res are performed m anu ally by re-moving whole blood, spinning it down in a sta-tionary centrifuge and returning the cellular com-ponen ts to the patient as is done in source plasmacollection. Manual apheresis has the advantageof requiring relatively inexpensive equipm ent.

However, its use is limited to the removal of smallvolum es of plasma (1.0 liter or less) due to theinconvenience and ad ditional time requ irementsas compared to automated techniques. The rateof plasma removal using manual procedures runsapproximately 2.5 hours p er liter as comp ared to1.2 hours per liter for automated cell separationequipment. Also, the use of a “non-closed” (man-ual) system run s a higher r isk of infection andpresents the p ossibility of returning the w rong redcells to the p atient.

Most apheresis procedures are earned ou t usingautomated centrifuge equipment. There are twobasic types of automated centrifuge devices cur-rently in use for apheresis: the intermittent flowcentrifuge (IFC) and the continuous flow cen-trifuge (CFC). Both system s pr ovide a significantadvantage over manual apheresis because largevolumes of plasma m aybe processed quickly w ithless risk to the patient. IFC devices are manufac-tured and sold by Haemonetics Corp. The Hae-monetics Model 30 is used for a majority of thetherapeutic plasma exchange procedures per-formed in the Un ited States. This equipm ent w asoriginally designed for the collection of leukocytes

and platelets, but has been found to be effectivefor large-scale plasma exchange, lymphoplas-mapheresis, and lyrnphapheresis as well (57,108).

cessful treatment of autoimmune diseases willhopefully rely on more specific therapies, becausethese drugs are n ot without comp lications and candep lete sets of cells requ ired for other vital bod i-ly functions (42). Chap ter 3 m ore fully d iscussesscientific and medical issues of apheresis.

Generally, in the IFC system, blood is draw nfrom a blood vessel in the arm and pumpedthrough tubing into a disposable bowl placed inthe w ell of the centr ifuge. Several lines are alsoconnected to the bow l lead ing to collection bags.Anticoagulant is introdu ced into the lines to bemixed w ith the donor/ patient blood. As cen-trifugation begins, plasma is the first fraction of blood to be separ ated an d collected into a con-

tainer. Platelets and white cells are separated laterin the process and are then d iverted to other con-tainers. When th e process is completed, the pu mpaction reverses and the red cells remaining in thebowls are reinfused into the patient via a bloodvessel in the other arm. When the bowl is emptythe wh ole procedu re is repeated according to theeffect d esired (42).

The first CFC device, developed in the late1960’s by IBM in conjunction w ith the Na tionalCancer Institute, involved a rotating seal whichenabled the continuou s infusion of w hole blood

and removal of separated components from arotating centrifuge bowl. This basic CFC designwas commercialized by IBM as the Model 2990

and by American Instrument Co. (now a divisionof Travenol Labs) as the Aminco Centrifuge. Afew of these devices are still in use throughout theUnited States, but m ost have been replaced by th eHaemonetics 30 or the second generation IBMModel 2997, which employs a ring-shaped separa-tion channel in p lace of the previous centrifugebowl (108}.

Fenwal Laboratories (Division of Travenol

Labs) has d eveloped a series of CFC instrum ents(CS-3000 and Centrifuge II) in w hich the bloodand separated components pass to and from the



Ch. 2—Apheresis: Definitions, Descriptions, and Developments q 19

separation chamber through continuous tubing,without the requirement of a rotating seal. Acounter rotating mechanism is employed whichenables the tubing to be continuously unwoundwithout twisting or coiling (108).

The disposable equipment associated with

apheresis varies according to the technique used.In the mechanical plasma separation application,disposable consist of tubing to connect the pa-tient to the equ ipment an d vice versa. A dispos-able bowl is fitted into the centrifuge and theseparation takes place, then various bags are con-nected to the bowl to collect plasma an d/ or cel-lular components. Since the cellular componentsextracted du ring therapeu tic apheresis are n ot in-tended for reuse in other patients, the d isposableare simpler and less costly than those u sed in m ostblood ban king op erations (42).

Some new major developments in hard ware are

now undergoing clinical tests. These include ad-sorption columns and semipermeable membranesthat function as m olecular sieves.

Membrane Separation Devices

Membra ne separation devices have evolved asparallel flow (or flat sheet) or hollow fiber con-figurations similar to those found in basic typesof hemodialyzers. Membrane blood separatorscan only filter plasma from cellular components(as opposed to centrifugal systems that can alsobe u sed for specific cell separation (cytaph eretic)applications as well as for plasma exchange).Membrane systems, however, are expected toallow simp ler, more rap id and more p recise treat-ment. They are currently being reviewed by FDA(see the “FDA Dev ice Regulation” section of thischapter) for u se in this country.

The disposable associated with membraneapheresis represent the heart of the plasma separa-tion process. The plasma separation membranereplaces the centrifuge in this process. Tubing isused to form the extracorporeal circuit, very muchas in dialysis (42).

Membran e disposable are expected to be ini-tially priced higher than those required for cen-trifugal m achines, but it should be noted that inEurop e, especially in West Germ any, ma ny clini-

cians use Asahi-brand hollow fiber membr anesin pr eference to centrifugal systems despite thehigher costs. Membrane systems, in fact, aredominant in the European and Japanese markets,accounting for 70 to 80 percent of the procedu resperformed. If membrane systems become acceptedin U.S. markets, manufacturing costs could de-

crease su bstantially to r eflect economies of scale,although prices are not expected to approachthose for similar membranes used for dialysis ($15to $25 per p atient). Aph eresis mem branes w ill beinitially more expensive because th ey are m oredelicate and their quality constraints will be moredemanding in terms of pore size and wall thicknessconsistency (117).

Future Technological Directions

Curren t apheresis therapy most often entailsplasma replacement, which is not only expensive

but also removes norm al as well as adverse plasmaconstituents. Therefore, future systems will like-ly emph asize more selective removal of und esir-able comp onents and return of the pa tient’s ownplasma, p robably by one of the following tech-niques. (In most instances, however, the specificunwanted target components underlying the use-fulness of plasma exchange have not yet been pre-cisely identified. )

Cryoprecipitation.— Certain macromolecules inthe plasma w ill precipitate (come ou t of suspen-sion) wh en exposed to cold temp eratures. When

applied in conjunction with apheresis, the patient’splasma is circulated through a cold environment,where cryoprecipitation occurs. These precipitantare removed by filtration, and then the remain-ing plasma and cells are returned to the p atient.Other macromolecules in addition to unwantedimmune complexes are removed by this pro-cedure. How ever, most norm al plasma proteins,especially albumin, are retained. Parker-HannifinCo.’s Cryom ax system (see table 2) is likely to bethe first selective entry.

Mechanical Double Filtration. —Another ap-proach to avoiding the replacement of plasma intherapeutic apheresis is double filtration for

‘This section is drawn from L. F., Rothschild, Unterberg, Towbin,‘Therapeutic Apheresis,” New York, 1981.




Table 2.—Automated Blood Cell Separation Systems

Approximate Approximatemachine disposables Components

Manufacturer Models Introduced cost separated Membrane type

Continous-flow centrifuge Fenwal CS-3000

(Travenol/Baxter) Centrifuge IIIBM Biomedical 2997

197919811977

$32,000$19,700

$31,000

$65-$80$65-$80$65-$60

Cells, plasmaCells, plasmaCells, plasma

NoneNoneNone

NoneNoneNone

SheetHollow fiber

Hollow fiber

Hollow fiber

Hollow fiber

Hollow fiber

Hollow fiber

Intermittent-flow centrifuge Haemonetics 30

V-50PEX

197319801980

$21,600$28,800$25,600

$65-$80$30-$49$49 avg.

Cells, plasmaCells, plasmaCells, plasma

Continuous-flow membrane Cobe Laboratories Centry

TPEParker-Hannifin Cryomax

March 19821983

(expected)Late 1981in Europe

NA

$30,000$30,000

$80-$90$390

Plasma onlyPlasma only

$20,000 $75-$200 Plasma onlyFenwal PS-400(Travenol/Baxter)

Organon-Teknika Curesis(Netherlands)Asahi (Japan) Plasmaflo@

NA NA Plasma only

(expected)NA

NA $175-$400 Plasma only

Fresenius Plasmaflux@

(West Germany)Toray (Japan) Plasmax

NA NA

NA

Plasma only

NA NA Plasma onlyaDigpo8ableg cost eatirnatee are exclusive of other deposable items such as needles, seilne bags, transfer pecks, and PM’M9 aOIUtlOnS which ma y dso be u$ed Inconjunction with apheresls treatments.

NA - Not available.

SOURCES: L. F. Rothschild, Untertxg, Towb{n, 1981; Friedman, American Red Cross, 19S2; Colllns, Cobe Labs, 19S2; Cluryla, Du Pent, 19S2.

albumin recovery. This type of system is essen-tially similar to the Cryomax app roach, but theplasma fraction is not chilled to produce precipita-tion. After the plasma is separated from the cel-lular fractions by a membrane, it is passedthrough another membrane w ith smaller poresthat allow only sm aller p roteins, especially al-bum in, to pass w hile retaining the larger macro-molecules includ ing imm unoglobulins. The al-bumin fraction is then combined with the cellularfraction and r eturned to the patient. Album in re-covery systems are under investigation by severalgroups around the world.

Hemoperfusion.— This approach involves thepassage of wh ole blood th rough an ad sorptioncolumn (e.g., activated charcoal) to remove theunwanted substance(s) somewhat more selective-ly. This technique has been used primarily fordetoxification in acute chemical or drug poison-

ings, and is being investigated for use in renal andliver failur e. It offers desired sp eed in em ergencycases, but for broader usage is not a s prom isingas plasma perfusion (described below) due to un-

wan ted cellular adherence to the columns and po-tential release of particles from colum ns.

Adsorptive Plasma Perfusion. -This techniqueshould permit considerably greater selectivity inplasma component removal. It involves separa-tion of plasma from cells, passage of the plasma

through an adsorp tive column (which specifical-ly removes the unw anted substance), and r eturnof the plasma and cells to the patient. Beneficialresults in recurrent breast cancer treated withplasma exchange with on-line adsorptive columntreatment have been recently claimed. Future de-velopment of adsorptive plasma perfusion maywell involve columns containing monoclinal an-tibodies prod uced to specifically bind and , thus,selectively remove undesirable constituents.

Artificial Antibodies. —As previously dis-cussed, antibodies are synthesized by lymp hoid

tissue to bind to and inactivate antigens (generallyforeign substan ces). Antibod ies are mad e to bindvery selectively to sp ecific antigens like a k ey ina lock. Unwan ted p lasma antibodies could be re-



Ch. 2–Apheresis: Definitions, Descriptions, and Developments q 21

moved by allowing th em to bind to: 1) their nat-ural antigenic “lock,” which is held within a col-umn (“antigenic columns”); or 2) an artificiallyprod uced antibody to the patient’s normal and u n-wa nted antibody, which is held w ithin a colum nthrough wh ich the p lasma passes (“antibody col-um n”), i.e., the un wa nted a ntibody serves as anantigen to another manu factured antibody.

Artificial antibodies are currently produced foruse in d iagnostic tests using the imm un e responseof goats or other animals especially for radioim-mu noassays, a technique that allows an accuratemeasu rement of biological and ph armacologicalsubstances in the bloodstream and other fluids of the body. Recent advances in gene splicing tech-nology have given rise to monoclinal antibodyor hybridoma (hybrid cell) techniques whichallow the production of more specific antibodiesat less cost than conventional procedu res.

Based on curr ent technology, economic factorsmay delay the development of monoclinal an-tibody columns for on-line plasma processing, ex-cept in certain d iseases with only a few d efinabletypes of unw anted factors. Other diseases mayrequire a constellation of distinct antigens or an-tibodies held w ithin a column . Another potentialproblem for immu nological adsorption colum nsconcerns the quantity of unwanted substance tobe removed. If, for examp le, large quantities of immu ne complexes mu st be removed, large quan -tities of antibodies would be needed in the col-

umns. It is currently uncertain whether mono-clonal prod uction would be inexpensive enoughto allow columns with large quan tities of man u-factured antibodies to be economically feasible.

FDA Device Regulation

FDA regulations curr ently governing centri-fugal cell separators on the market only concernblood banking applications. The centrifugalapheresis devices have been classified into ClassIII (premarket approval or PMA) for use withdonors in the preparation of blood products,

3

although d ata ind icate m any clinicians are u singthem for therapy. Machines introduced prior to

321 CFR 864.9245.

the Med ical Device Amendm ents in 1976 have“grandfathered” approval, while centrifugalmachines introduced after 1976 have gained FDApremarket approval by being considered by FDAto be substantially equivalent to pre-1976 devices.

The membran e-based d evices being d eveloped,

and mostly being tested in clinical trials, were notpermitted to simply file a premarket notificationw ith FDA. * They are consider ed essen tially newdevices for which investigational device exemp-tions (IDEs) are required. IDEs are granted withsufficient demonstration of safety, after which theclinical protocols can then proceed. Results of theclinical trials are used in filing for premarket ap-proval. No attemp ts to reclassify separators asClass II devices, which w ould only require themanufacturers to meet certain product perform-ance standa rds specifications, are being p ursu edat present. It has been speculated that the in-

dustry, on its own initiative in the future, coulddevelop su ch standa rds for FDA ap proval (117).

In October 1981, the Gastroenterology-UrologyDevice Section of FDA’s General Medical DevicesPanel reviewed the Cobe Centry TPE System fortotal plasma exchange and recommended ap-proval of th e d evice for therap eutic app lications.On March 16, 1982, FDA granted the premarketapproval.

A second and third mem brane apheresis PMA(Parker-Hannifin’s Cryomax model and Asahi’sPlasmaflo model) were reviewed and recom-

mend ed for ap proval by FDA’s General MedicalDevices Panel in late 1982. These models are ex-pected to receive FDA’s prem arket app roval andto be generally marketed in early 1983 (21). Inaddition, there are currently in excess of 20 IDEsfor cond ucting clinical investigations w ith aph er-esis membrane devices which are manufacturedby five different manufacturers (39).

q Sec. 510(k) of the 1976 Medical Device Amendments requiresany distributor of a medical device intended to be marketed for thefirst time to file a notice with FDA at least 90 days in advance to

permit the agen~ to decide whether the device is determined to be“substantially equivalent” to devices already on the market beforethe passage of the 1976 amendments or, if not found to be substan-tially equivalent, whether the device needs premarket approval toassure safety and efficacy.

98-822 0 - 83 - 3 : QL 3



3

Scientific and Medical Aspects ofApheresis: Issues and Evidence



3 q

Scientific and Medical Aspects of

Apheresis: Issues and Evidence

Various types of apheresis procedures havebeen performed on a clinical basis for many years,but the n um ber of patients and types of diseasestreated have risen significantly in the last 5 years.This increase is par tially du e to increased un der-standing of the disease and p artially due to engi-neering ad vances in equipm ent technologies. By

almost any stand ard, treatment by apheresis is stillin relatively early stages of development—thereare no ideal protocols based on a thorough un-derstanding of reasons for its efficacy. Never-theless, there is an increasing flow of clinical data,

sometimes describing dram atic patient impr ove-ment, supporting the view that apheresis is arapidly emerging technology with significantpr omise (117). Such eviden ce of treatm ent effec-tiveness’ is even today, however, often based onunsystematically collected data. Because of the

*Ef&tiveness is the health benefit as measured under average con-ditions of use. Efficacy is the health benefit as measured under con-trolled conditions such as those in a randomized clinical trial (104).

METHODOLOGICAL ISSUESAn assessment of any m edical technology de-

pend s, in part, on the developmen t of a strategyfor identifying technologies to be evaluated, andon the development of clear-cut standard s for thequality of the evidence that should be considered(104,147). Proper research methods, as a result,

become essential to the evaluation of a technol-

ogy. Careful and systematic investigations are the

essential ingredients in establishing that observed

effects are due to th e medical intervention . Poorly

and haphazardly conducted research studies are

plagued with problems of validity and general-izability, and these same issues continue to hinder

attempts to perform assessments based on suchresearch (85).

paucity of high-quality research, conclusionsabout the safety, efficacy, and effectiveness of apheresis are necessarily limited, although sometentative conclusions and directions for treatmentcan be discerned.

The present chapter analyzes the method olog-ical problems in condu cting ap heresis research andexamines available evidence of the safety, ef-ficacy, and effectiveness of ap heresis. Follow inga discussion of methodological issues, severalmajor reviews of apheresis research will be sum-marized and evaluated. This chapter w ill furth er

include the findings of a primary literature reviewand assessment of apheresis in the treatment of three diseases—namely, hemolytic uremic syn-drome, acquired Factor-VIII inhibitor, and Guil-lain-Barré syndrome— where preliminary reportsand evidence have been “p romising” in utilizingapheresis as a therapeutic approach (57). (A fulldiscussion of these findings can be found in app s.B, C, and D.) Present and future research direc-tions for aph eresis w ill be considered last.

To be valid, and to perm it generalizations tobe draw n, there must be clarity about w hat is be-ing tested, what is being compar ed, wh ich sub-

ject popu lations are involved in the research, andwhat is being measured . Operationally, these fourfactors refer to treatment design, research design,patient selection, and outcomes (102,104).

Treatment Design

Treatment d esign involves the extent to w hich

clarity about the “active ingredients” of the pro-cedu re being tested can be achieved. Qu estionsto be answered includ e whether the p rocedu re in-volves a single treatmen t, a comb ination of treat-

25



26 q Health Technology Case Studies 23: The Safety, Efficacy, and Cost Effectiveness of Therapeutic Apheresis

ments, or a combination of treatment and non-treatment factors. Often, because apheresis pro-cedures involve a complex interplay of many fac-tors (i.e., are “multivariant”), resulting researchis confounded by inability to separate effects(85,117). The extent to which researchers canmeasure the imp act of any one compon ent of theprocedu re is limited w hen a ll patients receive orhave access to m ultiple compon ents concurrent-ly. Clarity of design is essential to being ab le toattribute outcomes to particular treatments orpackages of treatments.

Because it is an experimental therapy, the useof apheresis has not been stand ardized. Protocolsin various stud ies have varied considerably. Var-iables include type of replacement fluid, patientselection criteria, other medications, extendedrespirator and intensive care therapy, and inten-sity of plasma exchange (i.e., frequency and

volume exchanged in each treatment). Many dif-ferent protocols have been used for apheresis,even in the treatment of a single disease, so thatvariation in procedu res und oubtedly has led tovariation in results (117). These variations makeit difficult if not im possible to achieve som e levelof comparison between studies.

For examp le, apheresis is often u sed as an “ad- juvan t” or auxiliary therapy to imm unosu pp res-sive since dru g therap y is required to inhibit therebound reaction (see ch. 2). Although apheresisis used as an a djuvant therap y to anti-inflamma -

tory, immunosuppressive, or cytotoxic drugs, thisfact should not be viewed as a threat to its validi-ty: any improvement in the course of diseasewou ld not be attributable to the ph armacologicalagents alone, but r ather to the combined (or syn-ergistic) effects of aph eresis and dr ug therap y.There could be a validity problem, however, withthe application of the treatment when the con-comitant d rug therapy v aries across stud ies. Whenthere is differential improvement by type of drugused, the integrity of the definition of treatmentis called into question. Even though treatmentsare presented in the literature in a similar fashion,

they may, in fact, operate quite differently. It maybe the case tha t the comb ined (or syn ergistic) ef-fects of apheresis and dru g therapy m ay vary ac-cording to the strength of the dr ug and the fre-quency with which it is administered (85).

Even if standa rdized protocols could be devel-oped , however, it maybe d ifficult or und esirableto administer them. This is particularly prob-lematic if, for research pu rposes, assignment toone group or another is required. Use of shamtreatment in control groups, for example, couldvery w ell cause this group of patients to suffersome of the side effects of apheresis, raising theethical question of subjecting them to a potentiallyharmfu l techniqu e. (See the next section, “Safe-ty: A Review of the Evidence, ” for a discussionof the safety and risk issues of apheresis.) Anotherobvious ethical concern is whether treatment canbe denied patients in near-fatal, disease states inwh ich ap heresis has served as the treatment of lastresort. A third issue is the d ifficulty of setting u pa controlled trial for some rare au toimmu ne d is-eases such as Goodpasture’s syndrome, whichstrikes only 2 ou t of 100,000 peop le in the United

States every y ear (22,34). Even w ith au toimm un ediseases of more common occurrence, such as sys-temic lup us erythematosus, presentation of diseasesymptoms can occur with such broad variety thatsetting up controlled trials for these cond itions canbecome equa lly d ifficult (49).

A last treatment d esign p roblem has to do w ithpossible placebo effects of the ther ap y itself. Forexample, among the several explanations dis-cussed in the literatu re for impr ovement of pa-tients undergoing apheresis was the possiblepsychotherap eutic effects of such therap y. Fewstudies have involved dou ble blind protocols (withsham apheresis) which are necessary to eliminatethe p ossibility of “placebo imp rovement s” (85,117,138).

Research Design

A valid research d esign, perhaps m ost imp or-tantly, requires systematic comparison. At min-imum , these comp arisons involve the same grou pof patients measured before and after treatment;optimally, they involve two or more randomlyassigned groups tested before and after treatment

(147). The latter design is usu ally called a tru e ex-periment (25,122) or, in health care research, arandomized clinical trial (RCT). The advantageof this design, in comparison to nonrandom selec-tion design, is that differences in outcomes can



Ch. 3—Scientific and Medical Aspects of Apheresis: Issues and Evidence q 27

be attributed m ore confidently to the treatment,rather than preexisting differences in the samplepopulat ions tested (102,104).

Evaluating existing research on apheresis ther-apy poses difficulties in an y attemp t to d raw validconclusions. Other than references to prior treat-

ment regimens, comparative data on treatmentgroup s are typically not available. The great m a- jority of the reported studies are case reportswithout any concurrent control groups, blinding,rand omization, or other techniques used in con-trolled clinical trials.

Because of operational and ethical difficultiesdiscussed with treatment design issues (see last sec-tion), even well-controlled trials of apheresis haveoften suffered from small sample sizes. A smallsamp le size for RCTS, for examp le, can un derm inewhat would otherwise be considered a strongmethodological study (85).

Related to the issue of appropriate research de-sign is that multivariate analyses (useful for ex-amining differences by such factors as age, sex,disease state, and levels of disability) are largelyunavailable. Studies which statistically controloutcome data have not been conducted becausesuch analyses require large patient populationsand present difficulties both in data collection andana lysis. Their absence from the literatu re, alongwith the lack of controlled research, hinders in-formed d evelopm ent of treatment strategies tail-ored to subpopu lation needs (102,104).

Apheresis researchers, however, seek to gen-erate systematic experimental d esigns w ith com-parison group information and multiple, longi-tudinal outcome measures. This is reflected by theincreasing number of well-controlled studies bothrecently reported and presently being carried-out(see “Conclusions and Directions for Future Re-search” section of this chapter).

Patient Selection

Patient selection refers to d ecisions concerning

eligibility for treatment, selection for participa-tion in research, and availability for follow-upresearch. If the general population of apheresedpatients is not represented in the research sam plesbecause of p articular cha racteristics (e.g., poorer

prognosis, differing remittive drug regimens), thegeneralizability of the research findings is limitedand selection bias is bound to occur (102,104).

Perhaps the m ost severe samp ling p roblem inaph eresis stud ies stems from the u se of the therapyas a last resort, i.e., for the “w orst cases.” Typical-ly, aph eresis therapy ha s been initiated w hen p a-tients diagnosed with a specific disease do not re-spond to other conventional therapies, includingdrug therapies and other forms of dialysis suchas hem odialysis or peritoneal d ialysis. The ap -plication of apheresis in the most severe cases of rheum atoid arth ritis w ith m ultiple comp lications,for examp le, has been rep orted to correspond towh at Warn er (141) has labeled the “d esperationreaction, ” where patients and their physicians arehighly motivated to try any p romising therapybecause continued p ainful symp toms or death isthe likely outcome without the therapy and there

is no effective alternative treatment available.High m otivation can likely p lay an imp ortant rolein the patient’s response to a number of subjec-tively determined outcome criteria, producingoverly opt imistic results (85). At the same time,if only the “wor st cases” are selected for apheresis,its potential effectiveness may be underestimatedbecause of its initiation at too late a stage in thedisease process.

There is fur ther th e prob lem of statistical regres-sion. Accord ing to Wortm an a nd Saxe (147) “sta-tistical regression arises when patients are chosenbecause of their extreme valu e on a laboratorytest or other m easure relevant to treatments.” In-vestigators have found that subjects with high pre-treatment m easures tend to have lower scores afterthe treatment-when, in fact, no change has takenplace. This is the statistical regression effect an dit can deceive clinicians into believing that apher-esis has been effective wh en it really has not (85).

Outcome Measures

A recurring critical issue in any attempt toanalyze the effectiveness of a medical technology

is the selection of appropriate endpoints forevaluating the success or failure of the interven-tion. The way in which outcomes of apheresis

therap ies are measured significantly affects inter-

pretation of apheresis therapy research.




Measures of assessment of outcome have variedenormou sly, both across and w ithin disease in-dication categories. App ropriate outcome meas-ures h ave at times focused on clinical impr ove-ment (i.e., improvem ent in signs and symptom s)often w ith reports of d ramatic change. Clinicalimprovement m easures, as defined in some ap her-

esis studies, howev er, have been relatively “soft”or subjective endpoints where researchers fail toestablish standards for any of the criteria, butrather look for general improvement across seriesof measures (85). In other instances, outcomemeasures are lacking, not specified, or ill-definedin the w ritten rep orts.

Even when clinical outcome measures are welldefined, it is important that the appropriatemeasure is used. When an outcome measure suchas mortality is used to evaluate the effectivenessof apheresis therapy for hemolytic-uremic syn-drome (characterized by a decay of general kidneyfunction), for example, the benefits of apheresismay be substantially understated. Plasma ex-change may, for instance, bring about a tem-porary improvement in the patient’s clinicalstatus, but other intervening factors may u ltimate-ly cause the patient’s death. Most clinicians, how-ever, would p robably agree that the ultimate objective of apheresis therapy is to increase thelikelihood of survival, which suggests that sur -vival (or mortality) is an important outcomemeasure of the efficacy of apheresis and shouldnot be disregarded. The need for chronic dialysis,

on the other hand, could be a more appropriateoutcome measure for determining the ultimatesuccess of plasma exchange in the tr eatment of hemolytic-uremic syndrome, since renal failure isa major element of the syndrome (146).

Interpretation of clinical improvement for many

diseases treated by apheresis is further confounded

by th e variability produ ced b y a b asic “remitting-

exacerbating” nature of the illness. Specifically,

rheumatoid arthritis, systemic lupus erythemato-

SUS, myasthenia gravis, and Guillain-Barré syn-

drome p atients frequen tly experience abrupt and

pronounced improvements or worsening of theillness, and such spon taneous change can easilybe mistaken for therapeutic effect. This leads togreater variability in results in clinical studies andto difficulty in interpreting the results (115,117).

Outcome measures have also focused on hema-tologic and biochemical parameters, such as nerveconduction tests, and immunological changes.These measures have not necessarily demon-strated any correlation to clinical responses,though. Sometimes they h ave pr eceded or coin-cided with clinical changes, wh ile for other d iseaseindications, they have shown no association toa clinical response. In short, such outcomemeasur es may be n ecessary but insufficient in-dicators of the efficacy of apheresis (146). Simon(127), for example, recently reported the case of a wom an with pem phigus vulgaris (a sometimesfatal skin disease), wh ere ap heresis allowed the

disapp earance of both skin and tissue-fixed an-tibodies, but in which the patient continued tohave manifestations of the disease and subse-quently died.

Perhaps h ematologic and biochemical param-eters could be combined in some way as co-measures with clinical improvement outcomes.The problem of combining m ultiple evaluationcriteria and assessing the significance of the resu ltsis a difficult one. For examp le, researchers m aychoose to assign different weights to each outcomemeasure w hich w ould lead to d isagreement andperhaps a lack of consensus on the effectivenessof apheresis therapy for certain disease indications(146).

Finally, outcome measures probably suffer fromthe lack of systematic docum entation of adverseeffects. As a new technology is developed, used,and reported, researchers and practitioners mayalso champion the technology for a variety of per-sonal and professional reasons (104). Apheresistherapy reporting may have been biased by thetendency to report the more successful uses of thenew therap y (115).




SAFETY: A REVIEW OF THE EVIDENCE

The paucity of well-controlled trials creates dif-ficulties for an unr eserved assessment th at ap her-esis is a safe procedure. Doubts abou t short- andlong-term safety have neither been confirmed nordispelled. Plasmapheresis, in its u se for plasmacollection in blood banking, has been demon-strated as a relatively safe procedu re. Apheresisin its other forms does appear to carry somedegree of risk, however, and results in a n um berof complications, especially when applied repeat-edly for therapeu tic app lications (42).

Observational studies have generally assertedthe procedure to be relatively safe and welltolerated by most p atients, especially w hen per-formed by experienced personnel. Close and con-tinual monitoring of the patient (at least duringinitial treatments that establish individual tol-

erance levels), however, is usually recommendedto ensure that any complications be treated im-mediately should they occur. Unlike hemodialysis,wh ere patients receive their blood back almost un-changed, there is mu ch more room for error andmiscalculation, because of the new ness of the re-placement mixture (80).

Borberg (13) reported that in 205 plasma ex-

change p rocedures , 4 se r ious r eact ions (an -

aphylaxis, collapse) and 23 moderate reactions

(chills, stiffness, low blood calcium, fever) oc-

curred. He further stated that the incidence of side

effects was significantly redu ced as the ap heresisstaff gained experience with the procedure.

Wenz an d Barland (144) cond ucted a lo-yearhistorical survey on plasma exchange and re-ported it to be a relatively safe procedu re w henperformed by experienced personnel. Among therisks reported were massive extracorporeal bloodclotting an d viral hepatitis. How ever, there havebeen no clinical problems with hemorrhagic tend-encies despite decreases (30 percent) in platelet

counts following plasma exchange. Coagulation

parameters returned to normal levels within 4 to

24 hours following the exchange.In another study of the safety issue, Sutton, et

al. (130), reported that of 887 plasma exchange

procedu res performed over a 3-year period, minor

complications (chills, hypotension) occurred in

less than 7 percent of the exchanges. Citrate (ananticoagulant) toxicity (paresthesia and nausea)occur red in 5 to 15 per cent of the exchanges. Sut-ton, et al. (130), did not see an increased r isk of infection in these patients despite low levels of thethird component of complement and immun o-globulins following th e exchanges and the con-current use of immu nosup pressive dru gs. In ad-dition only two episodes of minor bleeding w erereported, a further argument that patients receiv-ing this type of therapy m ay not be pred isposedto b leeding (145).

Generally, the major risks associated withaph eresis may be grouped according to:

q

q

q

Problems of technique. —Manual apheresismay run a risk of infection an d also presents

the p ossibility of return ing the w rong cellsto the patient. Automated centrifuge ma-chines may create problems with hemolysis,platelet loss, or air-emboli entering th e pa-tient’s bloodstream.Complications associated with fluid trans-

fer. —Impro per control of fluid ba lance mayresult in hyp ertension or cardiac arrhythmiasin patients un dergoing p lasma exchange. Theinfusion of large volumes of intravenousfluids at room temp erature may lead to hypo-thermia or chill reactions.Side effects w ith replacement fluids. —Each

of the major types of protein replacementcarries particular risks. The use of freshfrozen plasma may introduce hepatitis. Im-mu nological reactions, includ ing chills, skineruptions, wheezing, and stiffness may oc-cur in patients who are allergic to certain an-tigens in transfused p lasma. The u se of plas-ma protein fraction or albumin may causehyp otensive reactions or may result in plate-let loss (108).

Long-term effects of fluid replacement arealso worrisome. Removing lymphocytes andlarge volum es of plasma repeatedly could d e-

crease immunocompetence levels, increasingthe probability of patients’ susceptibility topneumonia and the like. A related concernis the risk of removing th e cells that carrylong-term immunological memory-B-cell



30 . Health Technology Case Study 23: The Safety, Efficacy, and Cost Effectiveness of Therapeutic Apheresis

q

q

lymphocytes. Apheresis could make patientssusceptible to som e childh ood disease theyhad been immu ne to formerly. Such d iseasesare often more serious for adults than chil-dren (57,80).

Anticoagulant reactions. —The use of largeamounts of citrate may result in hypocal-

cemia (low blood calcium) which requires theaddition of calcium to the replacement fluids.The use of heparin a s an anticoagulant canresult in significant platelet loss (throm-bocytopenia) if the procedure is extendedover long periods (108).

Immunosuppressive drug reactions. —As- -

already discussed in chapter 2, the apheresisprocedu re is often accompan ied by an im-munosuppressive drug treatment regimen.These drugs are not w ithout complications,

either. Since th ey ar e relatively non specific,the immu ne system in general is sup pressed,and consequently patients on these drugs arepron e to infection. These potent dr ugs canalso dam age vital organs, sometimes result-ing in life-threatening inflammation and fi-brosis of lungs, heart, intestines, or kidneys

(42).

While all the above situations can result inserious complications, particularly for severely illpatients, many of these problems app ear to oc-cur rarely and often can be overcome by p romp tdiagnosis and attention. There have been sixknow n fatalities among the thou sands of aph eresisprocedures reported performed during the last 10

years (108).

EFFICACY AND EFFECTIVENESS: A REVIEW OF THE EVIDENCE

Ideally, for any procedure, criteria should existfor the selection of p atients; the intensity, frequen-cy, and du ration of the procedure; the choice of replacement fluids; the immunological parametersto be followed; and the clinical evaluation of theeffects of the procedure. However, after a decadeof use no firm g uid elines for aph eresis have beenestablished (144).

Despite the lack of well-controlled and general-

izable research on the efficacy and effectivenessof apheresis, there is a vast literatu re that d escribesand analyzes tr eatmen t effects. Because it is highlyanecdotal, discussion of the evidence has some-times been confined to speculation an d general-ities. Still, the am oun t of research has d ramatical-

ly increased and its quality has imp roved in re-cent years.

This section presents and analyzes the evidencefrom several reviews of available literature. Thediscussion includes the scientific and medicalassessments condu cted by the National Center for

Health Care Technology (NCHCT or Center) forMedicare coverage and reimbursem ent policy, *

q The National Center for Health Care Technology (now succeededby the Office of Health Technology Assessment) in the Departmentof Health and Human Services has been authorized by law since

and a number of assessments undertaken by med-ical associations a nd specialty societies. This sec-tion further presents evidence from original as-sessments comp leted for this case stud y on th reedisease indications for which apheresis therapyhas been used experimentally, with somewhatfavorable and hopeful results.

Medical app lications and effects of aph eresis areusually classified according to medical discipline,

such as neu rology and h ematology, or accordingto the type of abnormal blood component re-moval (i.e., protein, antibody, immune complex,or cell). This section will utilize the latter ap-proach. Table 3 classifies various diseases by bothcategories. For protein, antibody, and immune-complex comp onent rem oval, the ap heresis mo-dality generally employed is p lasma exchange,with lymphapheresis and lymphoplasmapheresisused to a lesser extent.

1978 to advise on issues related to the evaluation of health care tech-nologies for reimbursement purposes by the Health Care FinancingAdministration and other third-party payers. For a complete discus-sion concerning this process the reader is referred, for example, toreferences 103, 104,




Table 3.—Selected Diseases Treated With Apheresis

Medical Plasma exchange

discipline Protein related Antibody related Immune complex related Cytapheresis

Hematology Waldenstrom’smacroglobulinemia

Rheumatology

Neurology

Oncology Multiple myelomaNephrology —

Other ToxinsPoisons

HypercholesterolemiaThyroxtoxicosisPrimary biliary cirrhosisHypertriglyceridemia

Idiopathicthrombocytopenicpurpura (ITP)

Factor Vlll antibody

Rh disease —

Guillain-Barré syndrome (GBS)Myasthenia gravis (MG)Multiple sclerosis (MS)

a

Polymyositis

Transplant rejectionGoodpasture’s syndrome

(GS)

Thrombotic Sickle cellthrombocytopenic Polycythemiapurpura (lTP)

b

Rheumatoid arthritis(RA)

aRheumatoid

Systemic lupus arthritiserythematosus (SLE)

SclerodermaOther

Multiplesclerosis

Other cancers Some IeukemiasProgressive nephritis

Glomerulonephritis

apreferr~ aDheresls theraD~ not yet decirjed: clinical stuclles have employed plssmapheresis, Plasma exchange, Iymphapheresis, andior Iymphopl=mapheresis.DDi~cu3sd in th[s chap t e r Under”

C

’Antibody Re l a t e d Diseases.”

SOURCE: Adapted from L. F. Rothschild, Unterberg, Towbln, 1981.

Protein-Related Diseases

As d iscussed in chapter 2, protein-related dis-eases involve either excessive levels of proteins inplasma or excessive levels of other substanceswh ich are “carried” in the blood by the plasma

proteins.

Hyperviscosity Syndrome

The earliest therapeu tic use of plasmaph eresiswas in the management of hyperviscosity syn-drome associated with paraproteinemias. Thisgroup of diseases is characterized by the prod uc-tion of enormous am ounts of protein m oleculesknow n as imm unoglobulins, w hich are endow edwith known antibody activity. Waldenstrom's

macroglobulinemia results in the overproduction

of one type of immunoglobulin-IgM-and an in-

crease in plasma viscosity or thickening leadingto ocular, neurological, and cardiovascular prob-

lems. Multiple myeloma, a malignant tumor of

the bone marrow, involves excessive production

of other types of immunoglobulins—IgG, IgA,

IgE, or IgD—and may result in various symp tomsincluding hyperviscosity syndrome, excessivebleeding, and renal failure. Cryoglobulinemia ischaracterized by th e presence of abnorm al im-munoglobulins which “precipitate” or form an-tibody-antigen complexes in temp eratures below37 C. Symp toms includ e necrologic abnormali-ties, purpura, and “skin ulcers” (108).

Clinical studies as early as 1960 have general-

ly confirmed the effectiveness of massive plasma

exchanges in treating the hyperviscosity syn-drome. A major reason for these findings is thatpatients’ symptoms have classically correlatedwith levels of viscosity and direct removal of substances. Observers have rarely been led astray,with sym ptom s norma lly following the loweringof the viscosity levels in these disease states(58,108,127).

In Waldenstrom’s syndrome, there seems to belittle disp ute th at ap heresis is an effective palliativemeasu re in the rem oval of excess pr otein. In severecases, it pr obably rep resents the on ly effective




treatment modality (42,117). With multiple mye-loma, apheresis has been dem onstrated to be ef-fective in the a cute treatm ent of crises associatedwith this condition. Improvement is temporary,but it can perm it chemotherap eutic attemp ts tobring the d isease und er control. In terminal p a-

tients who fail to respond to chemotherapy,apheresis is finding use as a palliative measure toman age hyp erviscosity symptom s. The d isease isultimately fatal, but ap heresis has improved andprolonged the quality of life for some patients(117). Several groups have reported definiteresponses from apheresis for treating the symp -toms of cryoglobulinemia, but th ere are no kn ownresults of controlled stud ies for th is indication(58,108).

In February 1981, NCHCT in response to aMedicare coverage issue request, recomm endedthat, as a safe and effective therapy, apheresis be

covered in the “treatment of primary macro-globulinemia (Waldenstrom) and hyperglobu-linemias, including multiple myeloma. These in-dications would include hyperviscosity states andcryoglobulinemias associated with these condi-tions” (54). The Am erican College of Ph ysicians,through its Clinical Efficacy Assessment Project(for more information see, for example, 104), alsoseems ready to concur. In a d raft statement (4)prep ared for NCH CT, they call apheresis an “ef-ficacious and standard therapy in the treatmentof hyperviscosity synd romes such as those second -ary to Waldenstrom’s macroglobulinemia andmultiple myeloma. ”

Hypercholesterolemia

Likewise, aph eresis has been used to removeother direct substances in the plasma such ascholesterol. Familial hypercholesteroleznia is acommon, u sually inherited d isease characterizedby increases in plasma cholesterol leading tonodules of cholesterol forming on the skin orwithin the nervous system and to premature clos-ing of the arteries. The use of apheresis has beenun dertaken at several hemap heresis centers withvarying results. There has also been some anec-dotal evidence of cholesterol levels being loweredand resulting clinical improvem ents in patientssuffering from disorders related to primary biliary

cirrhosis, characterized by en largemen t of the liverand retention of bile (108).

Protein Boun d Factors

Certain classes of hormones, toxins and poisonshave also been found to be bound to plasma pro-

teins, and th is has provided the rationale for theuse of ap heresis in treating the life-threateningsymptom s that often result from th e presence of excessive concentrations of these substances.Again, the removal of these substances has oftencorrelated with clinical success, but controlledstudies have not been earn ed ou t. In m ost of theseconditions, however, apheresis is utilized only asa short-term, emergency measure (108,127).

Thyrotoxicosis is a cond ition that results fromexcessive p rodu ction of horm one by th e thyroidgland. Removal of the substance by apheresis has

been reported to alleviate crisis symptoms (a crisisstage is referred to as a thyroid storm).

Hepatic coma is thought to be d ue to the ac-cumu lation of protein bound toxins in the blood-stream as a resu lt of acute liver failure arising froma nu mber of causes such as acute viral hepatitis,cancer, or reaction to anesthesia. Plasma ex-change, and m ore recently plasma p erfusion, havebeen observed to be effective in reducing toxinsun til the liver has had a chance to regenerate itself.Plasma exchange regimes, though, remain highlyvariable for treatment of hepatic coma (108).

Refsum's disease is a chronic, hereditary diseasecharacterized by ocular disorder, loss of sensoryand motor function, and dry scaly skin. Equivocalresponses in individual cases have been rep orted(80).

Lastly, apheresis has been used in the treatmentof poisonings. The procedu re has been though tto be particularly applicable to those toxins thatare not removed by dialysis, such as mu shroom-poisoning. Protocols have varied w idely, accord-ing to setting and according to type and am ountof poison (108,144).

Antibody-Related Diseases

As d iscussed in chapter 2, these diseases areoften termed “autoimmune” diseases, in which




pathological antibodies are prod uced and , in tu rn,attack the body’s own normal tissues. Researchersbegan to look to ap heresis for treatmen t of thisclass of diseases because of the su ccess in rem ov-ing substances associated with hyperviscosity. It

was hypothesized that by removing the antibodies

which were thou ght to med iate the disease proc-

ess, clinical results would correlate in a fashionsimilar to those found when immunoglobulinswere removed for hyperviscosity symptoms (127).

The two examp les in this category with the m ostdata are myasthenia gravis and Goodpasture’ssynd rome, both discussed in this section.

Neu rological Disorders

Aph eresis has been app lied in the treatment of several diseases of the nervous system. Apheresisresearch h as been pu shed on by the d iscovery that

many of the necrologic diseases have immunecomp onents and perhaps may have an antibodyassociated with them that may be removed (127).Myasthenia gravis (MG) is characterized by severemuscular weakness (without atrophy) and pro-gressive fatigue. The symptoms are generallythought to result from an autoimmu ne attack onacetylcholine receptors in m uscles. Because ap her-esis removes the an ti-acetylcholine receptor a nti-bodies from plasma, it has been evaluated withapproximately 125 patients at five m ajor clinicalcenters over the p ast 4 years. Results have shownsignificant short-term improvements in selected

MG patients in clinical stud ies. The therapy isgenerally becoming considered appropriate insevere cases as w ell as for p atients w ho exhibitprogressive myasthenia symptoms d espite treat-men t with corticosteroids. It has also been favor-ably reviewed as being beneficial in the long termand among the m ost promising ap plications of plasma exchange in autoimm un e disease (42,108,

177,144). Add itional p resum ptive eviden ce of ef-

fectiveness is the Health Care Financing Admin-

istration’s (HCFA) reimbursement of apheresis for

acquired MG since September 1981. Whi leNCHCT never issued a formal assessment recom-

mending coverage of this indication, it did specify

in November 1980 that it had “no objection” to

HCFA’S preparation of a national coverage in-

struction for apheresis in treating acquired MG

(56).

Multiple sclerosis (MS) is a chronic neurologicaldisease characterized by patches of hardenedtissue in the brain or the spinal cord p rodu cingpartial or complete paralysis, jerking muscletremor, and a variety of other symptoms andsigns. The cause of MS is unknown, but there issome evidence to indicate that the presence of in-

creased amounts of immunoglobulins and anti-bodies in the nervous system may contribute tothe disease. It has been suggested and reportedthat tw o types of apheresis procedures—plasmaexchange and lymphap heresis—may be effectivein controlling MS throu gh rem oval of toxic bloodfactors (108,117).

Preliminary stu dies involving very small num -bers of patients have reported significant improve-ment in the majority of “progressive MS” patientstreated with plasma exchange. Several factors,however, make any conclusions from th ese studies

tentative: 1) a plasma factor “specific” for thedisease, such as an antibody, has yet to be iden-tified; 2) the disease has a relapsing and remit-ting nature w hich m akes conclusions from smallsamp les extremely tenuous; and 3) imm unosu p-pressive therapy, reported to be useful in MS byitself, accompan ied plasm a exchan ge in the stud ies(so that the effect of plasma exchange alone couldnot be determ ined) (117). An assessment of MSwas condu cted by NCH CT in response to a Medi-care coverage issue, and reviewed both publishedand ongoing research. The Center concurred withthe findings of the N ational Institute of Neuro-

logical and Comm unicative Diseases and Stroke(NIH) and the National Multiple Sclerosis Socie-ty that there is currently inadequate justificationfor the routine use of any form of apheresis in themanagement of MS. Although ap heresis is stillconsidered experimental, however, the Centernoted several controlled clinical trials about tobegin or underway that should help clarify theapp ropriate role for aph eresis in the treatment of MS (91).

Guillain-Barré syndrome (GBS) is a v iral in -flammatory disorder of the brain, characterizedby a gr eat increase in the p rotein in the cerebro-spinal fluid and in accomp anying loss of sensoryand motor function. The condition may be acuteor chronic, and is sometimes fatal. Several casesof GBS have been associated with swine flu vac-cinations (108,117).



34 q Health Technology Case Study 23: The Safety , Efficacy, and Cost Effectiveness of Therapeutic Apheresis

A prim ary review, including a m ethodologicalassessment, of the apheresis literature in the treat-ment of GBS was prep ared as part of this study.Case reports and small-scale, mostly uncontrolledtrials provid e suggestive evidence that ap heresisma y be effective for som e p atients w ith GBS. Be-cause of the low mortality and good prognosis

for most patients with GBS, however, the safetyof the procedure and indications for its use n eedto be delineated prior to nonexperimental use of plasma exchange in GBS.

The conditions for use of plasma exchange inacute GBS hav e been sufficiently stand ard ized toenable a controlled clinical trial of the p rocedu re.The potential cost saving and potential for short-ened disability make well-designed controlledstudies of this therapy important. Controlledstudies currently in p rogress should be adequ ateto provide data which address the essential clinical

questions. Until the results of these stud ies areavailable, though, the use of plasma exchange inGBS can only be considered an experimental pro-cedure (115). The full review and assessment of aph eresis for th e treatmen t of GBS is p resentedin append ix D.

Another n eurological disorder for w hich apher-esis has been reported (108) as a treatment ap-proach is amy otropic lat eral sclerosis (ALS), aprogressive disease marked by mu scular weaknessand atroph y. Norris, et al. (89), noted some im-provem ent in three of ten ALS patients wh o un -derw ent p lasma exchange sessions. This has notbeen confirmed by other stud ies, how ever, andno rationale yet exists as to why it should be ef-fective (43).

Lastly, two neurom uscular disorders, polymyo-sitis and dermatomyositis, have been reported(108) as respon sive clinically to ap heresis therap y.Both disorders, characterized by progressive mus-cular inflammation and weakness, have beenlinked to antimuscle antibodies. The evidence inboth disorders, however, is anecdotal. The Amer-ican College of Physicians (4) has called apheresisan “investigational therapy” in the treatment of

patients with polymyositis, but has also statedthat it “m aybe ind icated . . . . in p atients in thesevere, imm inently fatal polymyositis . . . . wh oare resistant to all other therapies. ”

Renal Diseases

Goodpasture's syndrome (GS) is characterizedby a combination of glomeru lonephritis (kidn eydisease) and pu lmonary hemorrhage. The inci-d ence of GS is ap p roxim ately 4,000 to 5,000 casesannually in th e United States. GS is believed tobe caused by an antibody directed against glom-erular (kidney) and alveolar (lung) basementmembran es and is characterized by a rap idly fail-ing course terminating in asphyxia from lunghemorrhage or in death from renal failure. His-torically, the treatment of GS has involved im-mun osuppressive/ anti-inflammatory drugs withonly modest success. The mortality rate for thisdisorder has typically run about 75 percent(22,108).

It is possible that apheresis removes enough cir-culating antibodies to alter the course of the

disease, but reports are m ixed. Again, there havebeen no controlled trials, but case studies andliterature reviews claim that aph eresis has beeneffective for those patients with mild to moderaterenal dysfunction, but who are suffering acutepu lmonary comp lications or w ho are experienc-ing rapidly progressive kidney deterioration(4,108,117,144). It has been speculated that earlydiagnosis and apheresis therapy could prevent ir-reversible renal failure (42).

The American Medical Association has alsosupported apheresis in use of treatment of GS

though it has not specified under what conditions(s). The American College of Physicians, how-ever, has called aph eresis an “investigational”therapy for GS, stating that studies to da te havefailed to demonstrate improved survival amongpat ients with th is disease receiving ap heresis (4).A more thorough review and assessment of theuse of aph eresis for GS was comp leted in early1983 by the Office of Health Technology Assess-ment (OHTA) in response to a Medicare coveragepolicy issue. The OH TA assessment reported thebeneficial effects of plasma exchange for somegroups of GS patients. However, probably be-

cause of the absen ce of prospective RCTs, OH TArecommended plasma exchange only be consid-ered stand ard therapy for “life threatening forms”of GS (94).




In a related area of renal disorders, rejectionof the donor kidney remains the major problem

in renal transplantation. Acting on the h ypothesis

that rejection is due in part to a circulating an-

tibody d irected against the vascular end othelium,

several groups have used intensive plasma ex-

change to treat renal allograft rejection. Scoville

Associates (108) has reported that apheresis is ap-parently effective in controlling approximately 50percent of acute rejection episodes, and that thegraft survival period has been lengthened whenapheresis is used in a combination therap y regi-men with steroids versus use of steroid therapyalone. The role of apheresis in the managementof acute renal transplant rejection (particularly inthose cases wh ich d o not respond to steroid th er-apy) has been called promising, though, morewell-controlled stud ies need to be u nd ertaken atthis point (30).

Blood Disorders

Another d isorder for w hich use of apheresis has

generated some initial response and promise has

been in treatment of patients with antibodies toFactor VI I. Aph eresis has been investigated as apotential therapy for patients w ith antibodies orinhibitors to Factor VIII dur ing the p ast 10 years.

Factor VIII is a substance in the blood involvedin hemostasis (i.e., the normal process of bloodclotting for control of bleeding). Patients with themost common type of hemophilia lack Factor VIII

and are at risk of developing Factor VIII an-

tibodies when given supplemental, exogenous Fac-tor VIII to help control bleeding episodes. It has

been estimated th at as many as 20 percent of such

patients may develop this condition. Factor VIIIinhibitors can also arise spontaneously in otherpa tients. This so-called idiopa thic or acquired in-hibitor to Factor VIII can occur in women in theirfirst year after giving birth, persons w ith rheu -matoid arthritis, the elderly, and persons su ffer-ing a variety of other disorders (57,146).

As par t of this case stud y, a primary literaturereview, analysis, and evaluation w ere und ertaken

for treatment of this disorder with ap heresis. Ninestudies were reviewed and both imm ediate andlong-term findings were tallied. For 16 of the 18patients at risk due to severe bleeding from sur-gery, the immediate clinical results were uniformly

successful. In all cases hemostasis was achieved,and the patient fully recovered from the acuteepisode. Nine patients were reported to have poorlong-term results, but several patients were re-ported to have achieved a permanent reductionin Factor VIII inhibitor antibodies without theneed for additional therapy. Importantly, though,

the overall quality of the research evidence w asfound to be poor: the studies were all pretrialclinical reports (generally of one patient), therewas n o agreed up on treatment, the goals of thestud ies differed, and , with so few patients, theissue of sample bias should not be discounted(146). The complete assessment of apheresis in the

treatment of antibodies to Factor VIII is presented

in appendix C.

Antibodies to Factor VIII are encountered in a

number of hematological (and nonhematological)disorders. Likewise, a host of hematological dis-

orders are thought to be related to a gone-awryimmune mechanism, and as a result, several blood

disorders have been treated with apheresis, in-

cluding thrombotic thrombocytopenic purpura,

hemolytic-uremic syndrome, idiopathic throm-

bocytopenic purpura, autoimmune hemolyt ic

anemia, and rhesus hemolytic disease.

Thrombotic thrombocytopenic purpura (TTP)is an interesting examp le of a disorder for w hichapheresis appears to be of benefit as a lifesavingmeasure although the rationale for its use is stillvery speculative. It is a condition involving th e

developm ent of diffuse, small blood clots and adeficiency of platelets. Its cause is unknown butmay be related to a d isordered immu ne mecha-nism acting directly on the platelets or on theblood vessels, or on both concurrently. Apheresishas been rep orted to h ave benefits in several cases,possibly by removing circulating immune com-plexes or an antiplatelet antibody. * Results of apheresis for TTP have been encouraging with upto 80 percent response rates reported in somestudies. The American College of Physicians’assessmen t (4) is typ ical of several reviews andof the research comm un ity (7,42,108,117,125,127,

144) in stating that “apheresis in conjunction with

*Because of TTP’s possible relation to immune complexes, thisdisorder is sometimes grouped under the immune-complex relateddisease category, and could logically be included in the next sec-tion’s discussion (“Immune-Complex Related Diseases”) as well.



36 q Health Technology Case Study 23: Tth Safety, Efficacy, and Cost Electiveness of Therapeutic Apheresis

exchange transfusions, corticosteroids and plateletinhibitors, appears to be efficacious and standardin the treatment of thrombotic thrombocytopenicpu rpu ra.” The American College of Physiciansnoted further that, “Despite the fact that trials in-dicating efficacy were u ncontrolled, the reductionsin mortality in patients with TTP compared to

those not receiving apheresis were so significantthat aph eresis appears to be beneficial.” Simon(128) has also claimed that selective use of apher-esis can also decrease morbidity, hospital stays,long-term chronic dialysis, and maintain a p ro-du ctive lifestyle for patients long er. NCH CT (92)condu cted an assessment of TTP for Med icarecoverage policy, and noted the reported beneficialeffects, but cau tioned th at the qu ality of researchwas plagued by the complete absence of controlledclinical trials to confirm these findings. (Somehave argu ed th at such trials are imp ossible giventhe sud den an d life-threatening intensity of the

disorder’s onset.) NCHCT, because of the life-threatening natu re of TTP, stated that th e use of apheresis (specifically, plasmapheresis and plasmaexchange) “seems justified when other conven-tional therap ies have failed.”

Hem olytic-uremic synd rome (HUS) is char-acterized by a d ecay of kidn ey function, destruc-tion of red cells, and a dramatically reduced levelof circulating platelets. It shares a number of features with TTP. In fact, HUS has been con-sidered by some clinicians to be a variant of TTP,this being su pp orted by overlapping clinical and

path ologic characteristics and the p ossibility of similar pr ecipitating events. There is no o bjectivemethod at present to d istinguish H US from TTP,although in the case of the former, the kidney istypically the main an d often only target organ,children are primarily affected, and the prognosisis generally mu ch better (71,146).

A primary literature review and assessment was

conducted by Wortman and Murt (85) for this

case study on the use of apheresis in the treatment

of HUS. Data from the eigh t commu nications that

have appeared in the literature during the past 3

years are p resented on a total of 11 patients, buteach case is described individually. Only one of the communications suggests that plasma ex-change has limited effectiveness on the d iseaseprocess (11). H ow ever, the au thors in th is article

add that the clinical benefit may have been com-prom ised because apheresis wa s performed d ur-ing a recurrent phase of the illness (which isrecognized as being associated with poor prog-nosis). The remaining seven stud ies are almostuniformly favorable in su ggesting that ap heresiscontributes to clinical improvement although

there is no explanation provided about whichmeasures are used to gauge th is imp rovement.Several authors ad d th e caveat that aph eresis beinitiated d uring th e early stages of the d isease inord er to realize its full benefit (132). Parries, etal. (106), caution th at ap heresis alone is associatedw ith comp lications (e.g., hep atitis) and that th eserisks should be weighed against the potential ben-efits of apheresis.

As might be expected w ith a total reporting of 11 pa tients, the research base is too small and in-complete to endorse aph eresis as a treatm ent for

HUS. Furthermore, the studies contain no com-parison groups, while treatment designs and out-come measures varied widely, further limiting theability to make an y conclusion or recomm enda-tion. A full discussion of this assessm ent is foundin append ix B.

Rhesus hemolyt ic disease (Rh disease) of thenew born is characterized by fetal anemia, jaun -dice, enlargement of the liver and spleen and gen-eral edema. Approximately 65 percent of un-treated cases result in stillbirth or infant mor tali-ty. The disease is caused by Rh antibodies pr o-du ced in m aternal blood w hich m ay cross the pla-

centa and destroy fetal red blood cells. Antibod-ies, directed against an Rh positive fetus, developin an Rh negative mother following a previouspregnan cy in w hich the fetus w as Rh positive orfollowing transfusion of Rh positive blood (108).

Murt (85) has reported that between 1968 and1981, 13 stud ies were pu blished on the effects of apheresis in the management of severe Rh disease.The quality of the research studies is quite poor:all 13 stud ies are observational, and all but oneare reports of individual case studies. The numberof patients in these studies ranges from 1 to 96

and the median is 3. Only 3 of the 13 studies havegiven plasma exchange an unfavorable review,and 2 of these stud ies are the initial pu blishedreports of the u se of aph eresis in treating p reg-nant w omen w ith Rh d isease (14,112).




There are a host of other autoimmune hema-

tological disorders treated by apheresis. Suchdisorders include autoimmune hemolytic anemiaand idiopathic thrombocytopenic purpura. Theyare caused by antibodies which characteristical-ly attack and lead to the d estruction of valuableblood components. These diseases have beentreated w ith some success with ap heresis, but thereports are anecdotal (42).

lmmune-Complex Related Diseases

In imm une-complex related diseases, antigen-antibody comp lexes can be d eposited in tissue an dproduce severe inflammation and tissue damage.Just as researchers and clinicians reasoned thatprotein p lasma substance removal could be ex-tended to antibody removal, circulating immu necomplexes began to be experimentally removedthrough apheresis methods.

Renal Disorders

This furth er extension to imm un e comp lexeswas p articularly notable in England and Australiawhere there was an initial interest by nephrologistsin the application of apheresis for rapidly pro-gressive glomerulonephritis (GN) (127). Char ac-

terized b y a rapid deterioration of renal function,

GN appears to arise from two mechanisms. The

first mechan ism stems from the dep osition of im-mune complexes which are formed in the circula-tion and subsequently lodge in the glomeruli

(small structures in the kidney which contain cap-illary blood vessels surrounded by a thin mem-brane which acts as a filter for the separation of urine). The second mechanism, the much rarer,arises wh en an an tibody is generated against thekidney, w hich sets in pr ocess a chain of inflam-matory events leading to GN. Plasma exchangefor rap idly progressive GN has been evaluated asa therapy mode with rather uncertain results(90,108). Several case studies have been published

reporting the clinical success of patients treated

with concurrent plasma exchange and immuno-

sup pressive drug therap y. However, there is some

speculation that similar results may b e obtainablewith immunosuppressive drug therapy alone (108,

128). Apheresis in rapidly progressive GN has also

been associated with a high degree of infectioncaused by a variety of unusual pathogens (42).

NCHCT was requested by HCFA in May 1981

to conduct an assessment of the safety and clinical

effectiveness of “membranous and proliferative

glomerulonephritides” for Medicare coverage and

reimbu rsement p olicy (38). Du e to bud getary and

staff cutb acks, that assessment was n ot issued u n-

til early 1983 by NCHCT’s successor organization,

the O ffice of H ealth Techn ology Assessment (28).

The OHTA assessment concluded that for rarer

types of GN (antibody related), it appeared that

plasma exchange “favorably affected” GN, and

“should be recomm ended as standard therapy” forthese conditions. How ever, for those m ore com-mon cases of GN associated with immune com-plex mechanisms, OHTA concluded that the roleof apheresis is “much less clear-cut and should beinvestigated further” (94).

Connective Tissue Disorders

The advocated clinical successes in GN led to

investigative and experimental usage of apheresis

in a wh ole host of connective tissue d iseases whichwere though t to be possibly related to imm unecomplex deposition in tissues and often correlatedwith levels of circulating immu ne comp lexes (127).

Syst emic lupus eryt hematosus (SLE) is a chron icand often fatal disease characterized by patholog-ical changes in the vascular system, man ifestedin skin rashes, fever, arthritis, and heart, lung,and kidney damage (108). Preliminary reviews in-dicate that apheresis has produced “striking short

term clinical improvement” in some patients withhigh levels of circulating immune complexesbefore treatment. However, other patients withSLE, but not high levels of circulating immunecomplexes before treatment, have also respondedto therapy. Study results have also been con-founded by poorly controlled immunosuppressiveand anti-inflammatory drug therapy accompany-ing aph eresis (117, 128). As w ith aph eresis in thetreatment of rapidly progressive GN, HCFA re-quested NCH CT in May 1981 to assess the safe-ty and clinical effectiveness of apheresis therapyfor SLE as a cand idate technology for Med icare

coverage and reimbursement. That assessment,now und er the aegis of OHTA, has not yet beencompleted (28). The American College of Physi-cians (4) and the American Society of Hematology(7) have both judged apheresis for SLE as “in-

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38 q Health Technology Case Study 23: The Safety r Efficacy, and Cost Effectiveness of Therapeutic Apheresis

vestigational” only, noting that no adequatelycontrolled scientific studies have established itsefficacy. Both gr oup s, how ever, cautiou sly allowfor the possibility of u se in critically ill SLE pa-tients who fail to respond to conventional dr ugtherapy.

Rheumatoid arthritis (RA ) is a chronic diseaseof the joints marked by inflammation and atrophyof the bones. In late stages, deformity and im-mobility develop. While it is unclear at p resentwhich p lasma factors are involved in RA (immun -oglobulins, immune complexes, lymphokines,etc.), several medical centers have reported ben-eficial effects of plasma exchan ge or r elated p ro-cedures: lymphapheresis and lymphoplasmapher-esis. Several apheresis protocols have beenreported. Clinical responses have been claimed inthe remission of symptoms that lasts severalmonths (117). Rothwell, et al. (118), however,

reported no statistically different clinical responsein a controlled stud y that had one group receive

plasma exchange and drug therapy while a second

group received drug therapy only.

Because RA affects approximatelys million to

7 million individuals in the United States, with

no known cure, the question of apheresis treat-

ment benefits has become a somewhat volatile

issue. Over the p ast 2 years, the Council on Scien-

tific Affairs of th e American M edical Association,

the A m er ican R heum at i sm A ssoc ia t ion , t heAmerican College of Physicians (who consulted

with th e American Society of Hematology and th eAmerican Society of Oncology, as well), and

NCHCT have all formally considered the evi-

den ce. All have concurred that ap heresis for treat-

ment of RA is an experimental therapy b ut h ave

sugges ted i t s poss ib l e use in se r ious , l i f e -

threatening complications of RA, such as vas-culitis, cryoglobulinemia, or hyperviscosity syn-drome (59,86). In a separate assessment, NCHCTexplicitly recommend ed apheresis in the m anage-men t of life-threaten ing rheumatoid vasculitis* asa treatment of last resort and possibly lifesavingintervention when more conventional therapies

have failed. The Center stated that such “pro-

“Rheumatoid vasculitis is marked by a destruction and necrosisof sections of the body, particularly toes and fingers and areas servedby small vessels that are inflamed.

cedu res are usually reserved for those patientswho have failed to respond to more conventionaltherapies and it is usually combined w ith them”(93).

There is also some current debate about theproper mix of apheresis therapy and drug therapy

for RA and about the relative effects of plasmaexchange and lymphocyte removal. Studies arestill needed to define the role of each therapy inthe management of severe RA. Wallace, et al.(139), have recently reported the results of adouble-blind, controlled study of lymphoplas-mapheresis versus sham apheresis in RA for 14patients. The results proved mixed. Whereas somemeasures of disease severity improved significant-ly in the treated group as compared with the con-trol group, others d id n ot. All reported benefitsof therapy w ere tempor ary (12).

Cutaneous vasculitis, an additional connectivetissue d isorder treated w ith therapeutic apheresis,is characterized by inflammation of the smallblood vessels of the skin. Temporary clinical re-sponses have been reported in the literature. Thereare no know n controlled stu dies (108).

Skin Disorders

Several dermatologic diseases which arethought to involve immune mechanisms have in-dicated a response to therapeutic apheresis.Pemphigus vulgaris is a rare d isorder character-ized by bubblelike lesions on the surface of the

skin. Remissions have been reported with ap her-esis, but there are no published clinical trials(2,108,144). Single cases of clinical resp onses toherpes gestationis, a subepidermal blistering con-dition of pregnancy, and psoriasis, a chronic,genetically determined dermatitis, have also beenreported (108).

Cancers

Therapeutic apheresis in the treatment of mu lti-ple myeloma w as discussed earlier in this chapter.Several reports have also described recent at-

tempts to treat various forms of other cancers withplasma exchange. Animal studies have suggestedthat the grow th of the tumors is related to d efi-ciencies in the imm un e p rocess (144). The ration-ale for apheresis is that the removal of immune




complexes or blocking factors might improve im-mu ne responsiveness to tumors. Preliminary re-sults have been mixed and further evaluation w illbe required . A refinement of plasma exchange,involving modification of plasma (by circulatingit through protein-A columns) has recently been

reported to prod uce benefits in several forms of cancer, including b reast cancer (117).

At the beginning of this century, hopes for de-veloping vaccines for treatment and specificdiagnostic tests for cancer were based on remark-able advances in immu nology and their successfulap plication to man y infectious d iseases. Early ef-forts to relate immu nology and cancer failed be-cause of a lack of understanding of the complex-ity of the imm un e response. In recent decades,how ever, investigations have d iscovered a prob-able role of the immu ne system in both the d e-velopment and spread of tumor cells (108). At

present, apheresis for cancer is experimental, butit could broaden the fundamental understanding

between malignancy and the immune response

(144).

Miscellaneous Disorders

Table 4 presents a list of diseases either believedto be of immunological origin or of unknowncause for w hich plasma exchange has been ex-perimentally employed as a therapy and positiveclinical responses reported. Typically, in eachdisease category, plasma exchange procedu res

have involved only a sm all sample group any-w here from 1 to 30 patients and there have beenno control or comparison groups against whichto measure treatment results. Evidence, then, is

Table 4.—Therapeutic Apheresis for Miscellaneousimmunological Diseases and Diseases of

Unknown Cause

Miscellaneous immunological diseases

Graves’ diseaseCrohn’s diseaseSevere asthmaInsulin-resistant diabetesScleroderma

Diseases of unknown cause

Hypertension (idiopathic only)Raynaud’s phenomenonIdiopathic pulmonary hemosiderosis

SOURCE: Adapted from Scoville Associates, 1981.

anecdotal and awaits additional research beforereliable conclusions can be dr aw n regard ing thepotential role of apheresis for these disorders(42,80,108,144).

Cell-ReIated Diseases

The u se of aph eresis (specifically cytaph eresis)therapy has been anecdotally reported to be quitebeneficial in the treatment of diseases involvingexcess or abnorm al blood cellular comp onents.While not common, certain clinical situations maybenefit from the removal and lowering of aplatelet coun t or w hite blood cell coun t in a pa-tient. Very high wh ite coun ts, such as in gran-

ulocytic leukemia, can cause immediate andsevere crises with cerebral hemorrhaging, and pos-sibly death. Emergency removal of white cells canbe lifesaving while chemotherapy is initiated,

although chronic treatment has generally failedto alter the outcome of the d iseases. Sickle celldisease (SCD) is characterized by red blood cells(RBCs) containing abnormal hemoglobin. The“sickling” of RBCs in capillaries impairs bloodflow and can produce severe complications. Ex-change transfusion (removal of RBCs followed byreplacement with normal RBCs) has been reportedto p rod uce ben eficial results in SCD crises. Also,long-term u se of platelet removal an d w hite cellremoval in the treatment of autoimmu ne d iseases,including multiple sclerosis and rheumatoid ar-thritis, have also been reported, an d research in

those areas continues.Although not for therapeutic purposes, cy-

tapheresis applied to healthy donors also has im-portant clinical app lications in th e p reparation of component concentrates. Many d iseases involvedecreased levels of white cells or platelets. Cancerchemotherapy, as well, often depresses bone mar-row p rodu ction of wh ite cells and platelets so thattransfusions of the deficient components are clin-ically beneficial. Recent refinements in blood sep-arator devices make it practical to collect largenumbers of platelets or white cells from a singledonor rather than pooling separate componentsfrom multiple donors. This is of considerable ben-efit in m inimizing the risk of donor/ recipient an-tigenic incompatibility and hepatitis transmission(117).



40 qHealth Technology Case Study 23: The Safety, Efficacy, and Cost Electiveness of Therapeutic Apheresis

CONCLUSIONS AND DIRECTIONS FOR RESEARCH

Clearly, a variety of diseases-often rare-havebeen treated by apheresis in circumstances whereconventional therapy has not been beneficial.There is a great deal of enthusiasm among re-searchers and clinicians w ho w ish to explore all

the possibilities for therapeutic apheresis. Medical journals are replete with anecdotal reports of ph ysicians’ trying ap heresis as a last resort in aw ide ran ge of diseases. These cases, how ever, donot p rovide a strong systematic base for recom-mend ing the widespread use of apheresis as amature and effective technology.

Aph eresis app ears to be a relatively safe pro-cedure, though it is not without at least short-termrisks. The long-term risks of removing usefulblood comp onents have been termed “worrisome”and are unclear at best (80). Apheresis device

equipment can also be termed effective in the sensethat the technology accomp lishes the intended re-moval of plasma and cells.

How ever, there have been very few w ell-con-trolled stud ies documen ting the efficacy of thetechnology in actually improving health (53).More sp ecifically, there h ave been few situat ionsin which isolated pathogenic proteins, antibodies,immune complexes, and blood cells were removedand unequivocal clinical results observed. The useof apheresis has been generally acknowledged asan effective treatment application for acute

therapy in a small group of relatively obscurediseases. These include acquired myastheniagravis, primary macroglobulinemia (Walden-strom’s), and hyperglobulinemias, including mul-tiple myeloma. There is certainly suggestive evi-dence, too, that therapeutic apheresis is successfulin arresting the disease process for some p atientsund er some disease conditions. Convincing proof of clinical efficacy, how ever , is still lacking in thewid er variety of diseases in wh ich this treatmentis being u sed.

Any interpretation of clinical results has been

further hampered by the lack of standardized ap-plication of this therapy. Criteria for patient selec-tion and treatment schedules for man y d isease ap-plications still need to be develop ed. The relativeroles of exchange, drugs, and supportive care needto be further d efined an d clarified.

The problem of standardized application of apheresis is not surprising in considering th at thescientific rationale for use of the technology totreat a specific disease category is sometimes veryweak. Because the disease-causing mechanisms re-

main largely u nknow n, speculation has n ecessari-ly determined the intensity of the ap heresis sched-ule, the volume exchanged, and whether thereshould be concomitant removal of cellular com-ponents with or without the addition of im-mu nosup pressive drugs. Each of these aspects of apheresis has been the subject of much discussionand disagreement (12).

Though some researchers say it is “too early”to do controlled trials because d octors have notyet d etermined the theoretically best treatmen tsto be tested, research in apheresis seems to be in

transition. In an effort to d ocument the value of therapeutic apheresis, large prospective random-ized trials have been organized for several diseaseapplications in which apheresis therapy has notbeen sh ow n to b e either clearly effective or inef-fective (2,12). Although some of this research isbeing done without direct government support,a substa ntial portion of exper imenta l and clinicaltrial work is being und ertaken w ith the help of the National Institutes of Health (NIH). Becauseof the high costs of these stud ies, it is not sur -prising—or unreasonable—that public moneyssupp ort such a significant n um ber of them. Table

5 presents a listing of major ongoing researchstudies.

In order to pr ecisely define what advan tages,if any, apheresis would have, controlled trialsneed to address the safety and efficacy issuesdiscussed in this chapter of present apheresistechnologies. Long-term studies will also beneeded to detect any additional unforeseen orunspecified questions of safety, as well as effec-tiveness. Importantly, future research must alsocompare the present treatment modalities withnew and emerging approaches such as plasma fil-

tration through specific affinity columns (with thereturn of the patient’s own plasma) or relatedscientific advan ces such as the u se of monoclinalantibodies (see “Future Technological Directions”section in ch. 2 for a discussion of these treatmentapp roaches). Many r esearchers and observers in




both the public and private sectors speculate that diseases (53). If the present applications of ther-

therapeutic apheresis as now applied w ill be re- apeutic apheresis are indeed in such a period of

placed over the next 10 years by either advances flux, great care must be taken to target research

in equipment-embodied apheresis technology or and clinical efforts into the most promising and

basic scientific research into th e causes of various beneficial technology-related developments.

Table 5.—Present Apheresis Research Activity

Location Principal investigator Disease indication

Major NIH Stud/as SUNY—Stony Brook . . . . . . . . . . . . . . . . . . . . . .Washington University. . . . . . . . . . . . . . . . . . . . .Cincinnati General Hospital . . . . . . . . . . . . . . . .Johns Hopkins University . . . . . . . . . . . . . . . . . .

NIADDK, NIH . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Walter Reed Army Medical Center . . . . . . . . . .

University of Cincinnati . . . . . . . . . . . . . . . . . . . .Massachusetts General . . . . . . . . . . . . . . . . . . . .NIADDK, NIH . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Rush-Presbyterian St. Lukes. . . . . . . . . . . . . . . .Cincinnati General Hospital . . . . . . . . . . . . . . . .Rush-Presbyterian St. Lukes. . . . . . . . . . . . . . . .George Washington University. . . . . . . . . . . . . .University of lowa. . . . . . . . . . . . . . . . . . . . . . . . .University of Pennsylvania . . . . . . . . . . . . . . . . .NIADDK, NIH . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Scripps Clinic and Research Foundation . . . . .Columbia University . . . . . . . . . . . . . . . . . . . . . . .Mayo Foundation . . . . . . . . . . . . . . . . . . . . . . . . .SUNY at Brooklyn. . . . . . . . . . . . . . . . . . . . . . . . .Columbia University. . . . . . . . . . . . . . . . . . . . . . .Boston Children’s Hospital. . . . . . . . . . . . . . . . .University of Utah Medical Center. . . . . . . . . . .Peter Bent Brigham Hospital . . . . . . . . . . . . . . .Johns Hopkins Hospital . . . . . . . . . . . . . . . . . . .Miami Veterans Medical Center. . . . . . . . . . . . .University of Rochester. . . . . . . . . . . . . . . . . . . .Cincinnati General Hospital . . . . . . . . . . . . . . . .Columbia University . . . . . . . . . . . . . . . . . . . . . . .

Johns Hopkins University . . . . . . . . . . . . . . . . . .NCI, NIH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .NCI, NIH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .University of Texas. . . . . . . . . . . . . . . . . . . . . . . .University of New Mexico, Albuquerque . . . . .Columbia University. . . . . . . . . . . . . . . . . . . . . . .Columbia University . . . . . . . . . . . . . . . . . . . . . . .Columbia University . . . . . . . . . . . . . . . . . . . . . . .Tufts University. . . . . . . . . . . . . . . . . . . . . . . . . . .Johns Hopkins University . . . . . . . . . . . . . . . . . .

Other major studies Rogosin Kidney Center . . . . . . . . . . . . . . . . . . . .Evanston Hospital (Ill.). . . . . . . . . . . . . . . . . . . . .Southwestern Medical School . . . . . . . . . . . . . .El Dorado Hospital . . . . . . . . . . . . . . . . . . . . . . . .Froedtert Memorial Lutheran Hospital . . . . . . .Kingston General Hospital, Ontario . . . . . . . .Toronto Western Hospital . . . . . . . . . . . . . . . . . .Froedtert Memorial Lutheran Hospital . . . . . . .Victoria Hospital, Ontario . . . . . . . . . . . . . . . . . .Hammersmith Hospital, London . . . . . . . . . . . .Canadian Red Cross (sponsor). . . . . . . . . . . . . .

Gorevic, PeterShonfeld, G.Stein, EvanKwiterovich, Peter

Balow, J. E.Johnson, John

Pollak, VictorCoggins, CecilKlippel, J. H.Lewis, EdmundKashvap, MotiLewis, EdmundLachin, JohnHunsicker, LawrenceSchumacher, H.Wilder, R. L.Vaughan, JohnJacobs, JerryBunch, Thomas W.Diamond, Herbert S.Chess, LeonardWeiner, HowardPetajan, JackWeiner, HowardMcKhann, GuyLian, EricMarder, VictorGlueck, CharlesEdelson, Richard

Moser, HugoStevenson, H. C.Schiffer, C. A.Tindall, RichardSimon, TobyGrossman, MarcJaffe, IsraeliResor, StanleyAgnello, VincentMoser, Hugo

Saal, StuartDau, PeterTindall, RichardGiordano, GeraldKhatri, BhupendraGiles, AlanCardella, CarlKaufman, H. MyronClark, WilliamLockwood, MartinRock, Gail

CryoglobulinemiaFamilial hypercholesterolemiaFamilial hypercholesterolemiaHypercholesterolemia, xanthomatosus,

atherosclerosisGoodpasture’s syndromeGoodpasture’s syndrome and rapidly progressive

glomerulonephritisGlomerulonephritisGlomerulonephritisSystemic lupus erythematosusSystemic lupus erythematosusSystemic lupus erythematosusLupus nephritisLupus nephritisLupus nephritisRheumatoid arthritisRheumatoid arthritisRheumatoid arthritisRheumatoid arthritisRheumatoid arthritisRheumatoid arthritisRheumatic diseaseMultiple sclerosisMultiple sclerosisMultiple sclerosisGuillain-Barré syndromeThrombotic thrombocytopenic purpuraIdiopathic thrombocytopenic purpuraLipoprotein metabolismPemphigus

Refsum’s diseaseCancerLeukemiaNeuromuscular disorderNeonatal adaptationPorphyria cutanea tardaConnective tissue disorderDermatomyositis, polymyositis, andImmune complex diseaseHunter’s syndrome

Myasthenia gravis

polyneuropathy

Myasthenia gravis, multiple sclerosisMyasthenia gravisMultiple sclerosisMultiple sclerosisRheumatoid arthritisRenal transplant rejectionRenal transplant rejectionLupus nephritisRapidly progressing glomerulonephritisTTP, ITP, Rhesus Iso-immunization

SOURCE: National Institutes of Health, 1982



4Cost Effectiveness andReimbursement Policy:

Issues and Evidence



,

4.

Cost Effectiveness and Reimbursement

Policy: Issues and Evidence

In add ition to the issues of health status or otherhealth outcome related effects (i.e., safety, ef-ficacy, and effectiveness) of apheresis, efficiencyissues must also be ad dressed. The cost of pro-viding apheresis therapy is a matter of almostuniversal concern in the available literature. Asspiraling health care costs continue to plaguemed ical care delivery in this country and else-wh ere, it is imp ortant to examine wh ether thereis imp rovement in the qu ality of life and w hichtherapies offer the greatest value for the resourcesinvested.

Because of the broad and pervasive influenceof third-party p ayment m echanisms on health caredelivery, any discussion of economic effects of thera peu tic ap heresis mu st also be closely tied toan examination of fund ing and reimbu rsementpolicies of both p rivate and government insuran ceprogram s. Reimbursement p olicies have profoundeffects on the adoption and use of medical tech-nologies, as well as the innovation process itself of medical procedures such as therapeutic apher-esis. Informed coverage decisions require infor-mation concerning medical technologies, that is

at least as detailed as that needed for theregulatory decisions of the Food and Dru g Ad-ministration (FDA) regarding d evice equipm ent.Whereas regulatory decisions tend to be of a “go”,“no go” n ature, reimbursemen t decisions are, orat least could be, more related to appropriate useof technologies, a much finer distinction (104).Appropriate use decisions would support the pro-vision of effective aph eresis therap y and efficient

COST EFFECTIVENESS

Two important m ethods u sed to assess the costsand benefits of therapeutic apheresis, and develop-ing comp arisons am ong effects, costs, and benefitsare cost-benefit analysis (CBA) and cost-effective-

care. That is, only proven treatment alternativeswou ld be considered for widespread clinical ap-plication and the lower cost treatment alternativewould not only be available but used (102,104).

Until recently, apheresis was rou tinely reim-bursed for by some third parties when prescribedby a p hysician. How ever, concerned abou t costsand estimates of expansion of use over the n ext5 years, third -party payers are now attem ptingto tailor their policies according to the principleof appropriate use—i.e., to pay for apheresiswh ere and w hen it is a proven an d efficient ther-apeutic method (80,117). Medical insurers are,however, far from a consensus on how, when,

and if they should cover apheresis (34,49).

The research and policy issues regarding the

costs and benefits of apheresis therapy, including

a discussion of third-party reimbursement, form

the substance of this chapter. It is a discussion that

initially examines the methods that can be used

in assessing the economic effects of therapeuticaph eresis. Currently, the most visible and poten-tially most useful of methods is cost-effectivenessanalysis (CEA). As CEA is not simply an econom-

ic technique, but rather a blend of economic andclinical information, it w ill serve to conceptu allyintegrate cost concerns with the assessment of safety and efficacy issues in chapter 3. An absenceof reliable estimat es of the efficacy an d safety of aph eresis treatment an d of its costs and savingsprohibits conclusive results, but gaps in presentknow ledge can be iden tified and directions forfuture research can be addressed.

ness analysis (CEA). CEA implies a comparativeanalysis of the costs and health effects of alter-native treatments. In a CEA, a comm on ou tcomeis specified (e.g., functional status) an d the costs

45



46 . Health Technology Case Study 23: The Safety, Efficacy, and Cost Effectiveness of Therapeutic Apheresis

of providing alternative treatments are compared .Treatment costs are typ ically specified in m on-etary terms. CBA, on the other hand, requires thatboth cost and benefits be assigned m onetary val-ues. A CBA exam ines the ratio of resources used(cost) to resources saved (benefits) wh en p articulartreatments or even d ifferent treatment r egimensor programs are employed (102, 104).

While CEA/ CBA can be thought of as an aidto synthesis of both health effects and economiceffects, the valu e of a CEA/ CBA lies mor e in theprocess of performing the analysis than in anynum erical results. There are a num ber of reasonsfor this, among the m ost important of wh ich areCEA/ CBA’s inabilities to adequately add ressethical issues and the u ncertainty of specifyingcomprehensively the costs and benefits of alter-native treatm ents. This is clearly the case withtherapeutic apheresis because there are no reliable

estimates of savings du e to treatment benefits thatare ava ilable or know n. In ad dition, factors otherthan those qu alified in a CEA/ CBA (e.g., social,ethical, or value influences) should be consideredin making a decision (12,98,102,104).

OTA, in its assessment of the methods of CEA/ CBA (98) developed 10 principles to guide the con-du ct, use or evaluation of CEA/ CBA stud ies (seetable 6). The Principles most relevan t to the assess-ment of therapeutic apheresis are that alternativemeans (technologies) to accomplish the stated ob-

jectives should be identified and subjected to anal-

yses; all foreseeable benefits/ effects shou ld be d e-fined and , if possible, mea sured , as should all ex-pected costs; present value discoun ting should beperformed ; sensitivity analyses should be con-du cted to show a range of possible outcome val-

Table 6.—Ten General Principles of Analysis(for CEA/CBA Methodology)

1. Define probiem2. State objectives3. identify alternatives4. Analyze benefits/effects5. Analyze costs6. Differentiate perspective of analysis7. Perform discounting8. Analyze uncertainties9. Address ethical issues

10. Interpret results

SOURCE: Office of Technology Assessment, 1980.

ues; and ethical issues (that have surfaced insignificant ways in therap eutic apher esis) shou ldbe addressed. The rigorous specification of datasources for quantitative analyses was another im-portant criterion for CBAS.

Potential costs and benefits can be assessed w ith

varying d egrees of comprehensiveness. Further,means for estimating them vary (102,104). Thus,in a CBA, the cost of a treatment p rocedu re in-cludes not only the direct costs of salaries of treat-ment providers an d supp ort staff, disposable, re-placement fluids, dru g therap ies, adm inistrativeand overhead costs, but also indirect costs suchas lost prod uctivity d ue to patient’s time m issedin work. Additionally, it should be noted that un-critical use of market prices can lead to large gapsbetween cost estimates and true costs. Illustrativeof this problem is the use of hospital charge datato reflect the costs of hospital care. A common

practice, this form of “pricing” ignores the knownidiosyncrasies of hosp ital accounting in w hichhospitals charge w ell above true marginal costsfor certain services and use the profits to subsidizeother services for which charges do not cover mar-ginal costs. For example, hospital pharmacycharges can vary from 10 to 1,000 percent of thetrue cost of dru gs depend ing on the frequency of their use, their level of cost, purpose, etc. (104).

In the case of apheresis therapy, replacementfluids such as albumin, saline solutions, and freshfrozen plasma are particularly vulnerable to suchpricing practices. For example, a recent survey by

Levy (74) of Los Angeles hospitals showed almostall paid $28 to $29 for one unit of albumin. Inturn, these hospitals charged the patient anywh ere from a low p rice of $90 to a h igh of $175per unit.

In condu cting a CBA or CEA one must decidewhich benefits to measure and how to measurethem, if measurement is at all possible. For ex-amp le, it has been argued that substantial savingsfrom reduced expenditures on d rugs, surgery, andhospitalization accrue from therapeutic apheresistreatments, although this will vary depending on

the differing lengths and intensity of the diseaseremission.

Unem ployment and lost produ ctivity could bereduced in the long-term as well. Limiting analyses



Ch. 4—Cost Effectiveness and Reimbursement Policy: Issues and Evidence q 47

to work-related measur es, however, may hav e theeffect of underestimating the potential benefits of aph eresis therap y to a significant nu mber of in-dividuals not cur rently in the w ork force—e.g.,the chron ically ill, the retired elderly, stud ents,full-time homemakers, etc. A further point is thatthe efficiency of apheresis may decline—as evi-denced by frequent u sage as a treatment of lastresort—with severity of impairment. In addition,savings on such items as redu ced expenditures forquack remedies need to be calculated. It is re-ported that rheu matoid ar thritis patients, for ex-amp le, spend over $1 billion a year on pu rportedremed ies ranging from the “night shade d iet, ”which p rohibits tomatoes, eggplant, and potatoes,to devices such as vibrators and drugs such asDMSO (dimethyl sulfoxide). Some arthritic suf-ferers even sit in uran ium mines in their searchfor relief (34). Other ben efits, such as th e sense

of well-being that aph eresis rep ortedly generatesin many p atients (108), may be more d ifficult toquantify.

Despite problems, wh en it is don e well, the u seof CEA/ CBA d oes aid the complete listing of ex-pected costs and benefits as well as the explicitconsideration of assumptions underlying them.Assum ing such specification is possible, such ana l-yses provide a better scientific basis to aid in mak-ing decisions. Given the current d ebate over therelative costs and benefits of apheresis, and theincreasing debate over reimbu rsement p olicy, suchinformation does indeed appear to be essential.

Estimating Costs

While no reliable estimates of savings due totreatment benefits are available or generallyknown (12), the present task of evaluatingtreatments can include the context of costs, forwh ich th ere have been several general estimates.There has additionally been a more specific studyconcerning the costs of reimbursing for apheresisof rheumatoid arth ritis patients und er the Medi-care program.

By almost any standard , the costs of providingthis therapy are a concern. It is the issue of coststhat has aroused the greatest controversy sur-round ing the technology and is the most obviousexplanation for the increasing scrutiny of apher-

esis by a variety of health care p rofessionals. Theconcerns over costs have focused not only on theprice of a single treatment session, but a lso thedramatically rising use of apheresis for therapeuticpurposes in recent years.

CalculationsThere are two dimensions (124) to expenditure

determination-price and quantity. Many tech-nologies become expensive because of high costeven wh en app lied to a small num ber of patients(e.g., end stage renal disease), while othersgenerate large expend itures because the p rocedu reis so extensively u sed even th ough the cost perpa tient is relatively low (e.g., routine in-hosp itallab tests). Apheresis represen ts an interesting com-bination of a technology which is, on the onehand, extremely expensive per patient, but issimultaneously of potential benefit to great num-

bers of patients.

Simp le cost pr ojections for therapeu tic apheresiscan be said to depend on three variables: the priceof each un it of service (cost per treatm ent), thequantity of services that would be used (treat-ments per patient), and the size of the populationpotentially benefiting from treatment (patientpopulations). By multiplying these variablestogether, an estimate of total expend itures canthen be determined.

Cost per Treatment

Estimates of the costs of individu al apheresistreatments are very much available, but varywidely according to individual author and anal-ysis from $400 to $1,200. (A mid point est imate,then, is $800 per treatm ent. ) An investment of $19,000 to $32,000 for a blood cell separator isthe initial cost here, and disposable sets producedby m anu facturers w ill vary betw een $40 and $90per treatment. (Membrane disposable prices maybe substantially higher—as much as $400-atfirst.) Space (overhead expense), trained staff, anda physician-director are also essential ($27 to

$300). Replacemen t fluid s (at an aver age volu meof 2.8 liters), such as albumin or fresh frozenplasma, make u p the rem ainder of the costs, run-ning $125 to $600 per treatment (the exception iscytapheresis, which usu ally d oes not require re-




placement proteins because volume loss is small)(2,8,12,22,34,42,108,117,75,125) .

Treatments per Patient

Most studies estimate the n um ber of treatmentsper p atient as averaging about 10 per year, though

a few estimate that n um ber to be as low ass andas high as 15 to 20 per year. As already discussed,apheresis protocols for various diseases will dif-fer d ramatically in n um ber and frequency of treat-men ts. Some a pp lications w ill entail single treat-ments for emergencies, while it is likely thatchronic diseases such as rheumatoid arthritis willgenerally require 15 to 20 treatmen ts, althoughmore th an 30 will be used in some cases (2,34,73,

108,42,117).

Patient Populations

The potential patient popu lation for aph eresiscan be app reciated in a nu mber of different ways.If the poten tial patient p opu lation is defined asthose persons w ith any of more than 75 diseasescurrently treated with apheresis, the potentialpopulation is significant. There are an estimated5 million to 7 million people w ith rheum atoid ar-thritis, 400,000 to 500,000 persons with multiplesclerosis, 400,000 to 500,000 persons with sys-temic lupus erythematosus, 100,000 myastheniagravis patients, and at least 50,000 to 60,000

others with one of the other diseases. However,man y patients in each disease category are pres-ently being treated satisfactorily with drugtherapy, and thus they may not now be consid-ered candidates for apheresis (though in somediseases, such as m ultiple sclerosis and Good-pasture’s syndrome, effective alternative therapyis very limited, so that virtually the entire patientpopulation could eventually become candidates

for apheresis). If apheresis is used only on patientswho have failed to respond to traditional formsof therapy, the p otential total patient popu lationis redu ced to abou t 5 percent. of its original size,and estimates place this population at from325,000 to 427,000 (22,34,73,80,117,125). Thesemust be considered conservative estimates because

they limit the potential candidate population tothose patients wh o hav e reached a severely debili-tating or life-threatening state in these d iseasestates. If apheresis therapy replaces other therapymodes in routine maintenance programs for vari-ous d isorders, the patient popu lation w ould bemuch higher (117).

Results

Hav ing determined estimates for each of theseseveral variables, and multiplying these variablestogether, total cost estimates for apheresis therapy

per year can be projected to range from $650 mil-lion to $7.69 billion, with a m idp oint estima te of $3.01 billion (see table 7). Imp ortan tly, these p m-

jections are simple cost calculat ions t hat carryw ith t hem a num ber of methodological caveats.

Caveats

For one, there are no cost calculations of ac-comp anyin g hospitalization, ancillary services oressential adjuvant therapies, such as immunosup-pressive dru gs, which wou ld increase cost esti-mates. Secondly, there is no determination hereof “adoption share, ” a yearly measure of marketpenetration, defined as the p roportion of eligiblecandidates for w hich treatment was ind icated andon which it would have actually been performed.Calculation of the adoption share requires fairlyaccurate p rocedural use d ata, as well as project-ing wh at the diffusion rate for the procedure is

Table 7.—Estimating Costs of Apheresis Therapy

High estimate Midpoint Low estimate

Costs per treatment . . . . . . . . . . . . . . $1,200 $400Treatments per year . . . . . . . . . . . . . . 15 10 5

Patient population . . . . . . . . . . . . . . . 427,000 376,000 325,000Total costs . . . . . . . . . . . . . . . . . . . . $7.69 billion $3.01 billion $650 million

SOURCE: Off Ice of Technology Assessment, 1983.




and w ill be. * Pred iction of adop tion share is oneof the most d ifficult tasks, but one of the m ostimportant for p redicting future costs. The adop -tion share subsequ ently allows for the d iscount-

ing back of future costs over a determined p atient

care time horizon, and the accum ulation of a p res-ent value.

Currently, apheresis is performed on only se-lected patients. Unfortunately, no accurate dataexists on national figures, with estimates placingthe number of procedures performed at from80,000 to 200,000 per year (22,34,73,80,117).These estimates, if accur ate, would mean that,using O TA treatm ent estima tes (see table 7), cur -rent national expenditures on apheresis range from$3.2 million to $240 million. According toSchweitzer and Foxman (124), however, if oneassum es availability of reimbursement for th istherapy, then one must also assume expansion of

availability of service, and utilization would in-crease over time to essentially the point where allwho could derive benefit from treatment woulddo so. The imp ortan ce of reimbu rsem ent policiescovering apheresis becomes apparent, then, if suchpolicies push the ad option share to 100 percent.Given present reimbursement policies (see sectionon “Third-Party Reimbursement”), this representsan extreme estimate but is useful for cost pu rposeshere.

The economic and cost implications of a deci-sion by a third-party payer to reimburse for

apheresis is a last but crucial caveat to costestimates. As Schweitzer and Foxman (124) fur -

ther poin t out, if med ical services were not link ed

to one another, and criteria determining appro-

priateness or need for a service were unam-

biguous, the relationship between reimbursement

q The classical pattern of diffusion has been the ascending logisticcurve, which indicates that the proportion of adopters for a newtechnology rises with time according to an S-shaped pattern. Thispattern is appropriate for technologies for which continued ascendan-cy is likely over the immediate horizon, and for which subsequenthigh utilization can be expected. For many applications of apheresis,however, the pattern is probably more complex. Warner (141) hasproposed a three-stage “desperation-reaction” model of medical dif-

fusion, in which initial enthusiasm is followed in the second stageby an adjustment, followed subsequently by informed decisions.The informed decisions could represent mature, high use (as in ac-cepted innovation) or zero use (for an unacceptable innovation).Furthermore, disapproval of reimbursernent could occur at any pointin this process (19).

and expend iture would be a simple one. Underthese conditions, one wou ld simp ly identify thequantity and price of the service in question priorto a change in the reimbursement policy, andassume tha t these expend itures would be shiftedto the new payer. How ever, both the deman d forand the supply of medical care are price sensitive.

A decision to reimburse, by lowering the net priceto consumers and raising it to those who producemed ical care—ph ysicians an d hosp itals—will,therefore, have a tend ency to increase the qu an-tity of the service consumed . In ad dition, priceeffects will arise involving n ot only th e service inquestion, but other services which are either sub-stitutes for or complements to it. Failure to fullyapp reciate these qu antity and price effects con-tributed to the serious und erestimate of the End-Stage Renal Dialysis p rogram in 1972 (113).

Cost StudiesOnly one known stud y, prepared u nder con-

tract to the National Center for Health CareTechn ology (NCH CT) in 1981, has systematically

examined the costs of apheresis. The study only

estimated savings, if any, anticipated as a result

of the disapproval of coverage for a medical pro-

cedure. The study was carried out following

NCHCT’s recomm end ation to the H ealth Care Fi-

nancing Administration (HCFA) not to reimburse

for therapeutic apheresis in the treatment of rheumatoid arthritis. The cost projections, by

most sensibilities, were considered startling. Thestudy used a Wallace, et al. (140), estimate thatas m any as 700,000 Americans m ight be candi-da tes for ap heresis at a first-year cost of $40,000per patient and $18,000 per patient each year

thereafter. This implied a cost of up to $28 billion

in the first year. If 5 to 10 percent of the nearly

1 million Medicare-eligible patients with rheuma-

toid arthritis were to be given ap heresis, it wou ld

cost between $2 billion and $4 billion (124).

NCHCT noted that these were gross cost projec-

tions, and could be modified by projected sav-

ings from reduced expenditures for hospitalized

bed rest, medication, and joint surgery. Mainte-nance of, or return to, a productive lifestyle would

also have to be considered (as noted previously

in this section) if apheresis were shown to be ef-fective (107) 0



50 qHealth Technology Case study 23: The Safety r Efficacy, and Cost Effectiveness of Therapeutic Apheresis

The NCHCT study of potential costs, by com-parison, casts OTA cost estimates as conservative,both from the standp oint of potential patient pop -ulation and cost per treatment estimates. Th eNCHCT study, however, has been criticized forusage of “inflated” estimates pertaining to p oten-tial patient population. More widely accepted

figures come from Max Hamburger, in concur-rence with the Am erican Society for Ap heresis(49), who estimates the potential RA patient pop-ulation at less than 70,000, or about 10 percentof NCH CT estimates.

THIRD-PARTY REIMBURSEMENT

Reimbursement p olicies by third parties, likeother aspects of therapeutic apheresis, has beenthe su bject of some d ebate because of the com-

peting factors of cost and therapeutic prom ise thatthis case stud y has variously discussed. The de-velopment of most of these policies has been re-cent, and there would ap pear to be the ground-work for an even more intensified period of evaluation, debate, and formulation of thesepolicies in the near future. The following reviewelaborates on these developments and issues.

Federal Policies

The Federal Government has been substantiallyinvolved in the funding of apheresis through

research sup por t (see ch. 3); benefit program s suchas Med icare, Medicaid, m ilitary, and Veterans’Adm inistration hospitals; and employee insurancepackages such a s the Dep artmen t of Defense’sCivilian H ealth and Medical Program of the Uni-formed Services (CHAMPUS) and the FederalEmployee Health Benefit Plans.

Medicare*

Although the cost of apheresis has focused at-tention on reimbursement, cost information hasnot been explicitly or directly considered in

Regardless of which estimate is selected, the ef-fect of reimbursement policy on potential directexpenditure estimates is clear from both stud ies.Furthermore, as alluded to earlier, the expenditureimplications of a reimbursement decision are in-tertwined with the technology’s diffusion, produc-ing direct and indirect effects, some of which may

be wide-reaching. The magnitude of the direct costestimates alone suggests that the procedure’s safe-ty and efficacy should be closely scrutinized be-cause of the potential cost of possibly prematurediffusion.

Medicare coverage determinations. The legis-latively mandated practice of paying u sual andcustomary fees does not easily accommodate such

analyses. Instead, Med icare coverage d etermina-tions have relied on safety and efficacy criteriain an effort to “sketch the boundaries of acceptedgood med ical practice” (98).

Formal Federal policies for reimbursement of apheresis under its Medicare program have de-veloped almost completely over just the past fewyears, probably reflecting the fact that HCFA pro-cedur es for mak ing coverage decisions wer e highlyinformal un til early 1980. The staff of the Officeof Coverage Policy, often with assistance fromthe Health Stand ards and Qua lity Bureau , wou ldreview th e issue, consult experts in the field w ithwh om they w ere acquainted, and come to a deci-sion (104). Three or fou r regional office in qu iries

concerning coverage positions on apheresis sur-

faced d uring that p eriod, bu t no national instruc-

tions were issued.

Although a formal agreement between HCFA

and the Public Health Service had existed since

around 1966, a somewhat more formal, syste-

matic, and credible assessment process involving

a panel of physicians within HCFA and from

NCHCT was established in early 1980. When

q On Apr . 20, 1983, Pub lic Law 98-21 provided for extensivechanges in Medicare reimbursement policies for hospital-based care.Under the statute, whose provisions will be ph ased in over 3 years,hospitals will receive a flat fee per patient, set prospectively, on thebasis of patient diagnosis in one or more of 467 diagnosis-related

groups (DRGs). It is unclear at this point how the DRG-based pay-ment system will affect the adoption and u se of apheresis. Whatis certain, however, is that information on the effectiveness of thistreatment will be even more important as physicians and patientface increasingly scarce resources.




HCFA decided that a pr ocedu re involved a qu es-tion of national importance, a request for a tech-nology assessment w as sent to N CHCT. Usuallysuch a request asked NCHCT to determine thesafety and efficacy of a particular technology andto recommend whether HCFA should reimburse(103,104). Because the nu mber of questions about

coverage of apheresis increased substantially be-ginning in 1979-80 (56), HCFA, on the ad vice of NCHCT, issued its first national instructions on

apheresis in Au gust 1981. Effective September 15

of that year, HCFA announced the coverage of

therapeutic apheresis for the following indications

(52):

1.

2.

3.

plasma exchange for acquired myastheniagravis;leukapheresis in the treatment of leukemia;andplasmap heresis in the treatment of primarymacroglobulinemia (Waldenstrom) and hy-

perglobulinemias, including multiple mye-loma.

The HCFA policy statement wen t on to say that

apheresis should b e denied for other indications,

but that information on claims for wh at seems to

be other nonexperimental uses should be p rovidedto HCFA’S central office (53).

Even before the August policy release-in Mayof 1981—H CFA requested th at N CHCT evaluatethe safety and clinical effectiveness of apheresisfor the treatment of (38):

1.2.

3.

4.

5.

6.

Goodpasture’s syndrome;systemic lupus erythematosus;membranous and proliferative glomerulo-nephritides;mu ltiple sclerosis;potentially life-threatening complications of rheumatic diseases (rheumatoid arthritis, sys-temic lupu s erythem atosus, polymyositis/ derm atomyositis, and progressive systemicsclerosis); andthrombotic thrombocytopenic purpura(TTP).

NCHCT issued formal assessments on the indi-cations of multiple sclerosis, rheumatoid arthritis,rheumatoid vasculitis, and TTP. Two other in-dications— Goodpasture’s syndrome and mem-

branous proliferative glomerulonephritides-wereevalua ted in ear ly 1983 by the Center’s organ iza-tional su ccessor, the O ffice of H ealth TechnologyAssessment (OHTA) (28). (NCHCT and OHTAassessments are discussed in ch. 3.) HCFA has yetto implem ent instru ctions on any of these six cat-egories for national coverage policies.

Although Medicare’s national coverage is rel-atively new , it is not un likely that man y hospitalapheresis treatments for Medicare patients withcovered and noncovered disease indications havebeen performed an d reimbu rsed w ithout officialsanction of HCFA. Because Professional Stand -ards Review Organ izations d o only a limited jobof surveillance, because descriptions in the lineitem billings are very general, and because newprocedu res often do not have a p rocedure codenum ber, the identity of Medicare reimbursementsfor ap heresis therapies may h ave been concealed(104,117).

Medicare provides coverage for ap heresis re-gardless of whether or not it is performed at ahospital (108). It has been reported , however, that

indepen dent, freestanding settings are less likely

to receive reimbursement at this time, fueling

speculation that HCFA hopes to control the use

of apheresis by limiting reimbursement to hos-

pital-based therapy (73). There is no known in-

tention by HCFA to implement such a regulation

at this time or in the near future.

Medicaid

Medicaid provides medical assistance to low-income individuals. Treatment costs are shared

by the States and the Federal Government, Each

participating State must provide certain basic

health services, but the States have a great deal

of leeway concerning specific coverage (102).

Med i-Cal (California M edicaid), for example, will

approve payment only for apheresis conductedin the treatment of certain diseases, including

myasthen ia gravis, lup us, and Good pastu re’s syn-

drome. Treatment of such disorders as rheuma-

toid arthritis and multiple sclerosis, on the other

hand, are at present considered investigationaland are thus not covered (108). As of August

1982, M ed i-Cal was in the midst of a review of all its apheresis coverage policies, and was ex-




pected to formulate a new policy statement con-cerning its coverage policies (58).

Veterans’ Administration (VA) and Departm entof Defense (DOD)

The extent of VA and DOD involvement in theuse of apheresis is reflected in a hosp ital and bloodbank survey by Scoville Associates (108). Thatsurvey revealed that 30 VA and military hospitalsperformed therapeutic apheresis, on 260 patients,and a total number of 1,350 procedures. Nobreakdown of usage by disease, or whether usewas for clinical or research purposes, is available.

Und er DOD’s CHAM PUS program , the use of apheresis in the treatment of any condition p riorto August 1981 was considered investigational andnot a CHAMPUS benefit. Since then, however,the CHAMPUS program h as taken the basic Med-icare policy and expanded i t somewhat.

CHAMPUS now extends coverage to use of theprocedu re as a “last resort treatment of certainmed ical conditions. ” The specified indications are(8):

1. myasthenia gravis during a life-threateningcrisis;

2. anti-basement membrane antibody nephritis(i.e., as a result of Goodpasture’s syndrome);

3. life-threatening imm un e comp lex vasculitis;4. hyperviscosity of the blood associated with

multiple myeloma, Waldenstrom’s macro-globulinemia, and hypergam maglobulinemia

purpura; and5. TTP.

Private Sector Policies

Like their Federal counterparts, private insurershistorically reimbursed on a routine basis for bothapheresis procedures and replacement fluids, buthave recently begun to examine apheresis pro-cedures more closely and issue explicit policystatements concerning coverage. In March of 1981, Blue Shield of California approved payment

for therapeutic plasma exchange and lymph-

apheresis in the treatment of severe cases of rheumatoid arthritis if there are acute life-threatening complications or if conventional drugtherapy has failed (80,117).

At present coverage under Blue Cross insuranceprograms varies greatly from State to State. Forexample, the Southern California, Texas, andSouth Carolina Blue Cross org anizations generallyfollow the Med icare gu idelines and w ill normal-ly app rove paymen t for aph eresis. Illinois BlueCross ind icated th at their reimbursement schedu le

depend s on the disease being treated and w hatother therapies have been tried, but that ingeneral, they w ill app rove m ost requests. Massa-chusetts Blue Cross covers ap heresis for 14 d if-ferent disease indications. The Greater New York Blue Cross, on the other hand, does not coverapheresis therapy u nd er any of their plans (61,

79,108).

The N ational Blue Cross/ Blue Shield Associa-tion issued a policy statemen t in May 1982 as aguideline to local Blue Cross/ Blue Shield plans.

That policy recommends coverage—in hospitalsettings only-of nine d isease categories includ ingsevere my asthen ia gravis and leu kem ia (34). TheN ational Blue C ross-Blue Shield Association p ol-icy d oes not necessarily man date acceptance andimplementation by individual plans, however,and is subject to a possible future review at anappropriate time (16).

Many private insurance companies, too, includ-ing Pacific Mutua l and Prud ential, provide cov-erage for apheresis regardless of wh ether or not

it is performed at a hospital. As with Federalpolicies, uniform private third-party coverage ispivotal to the future development of the pro-cedure, particularly in freestanding and commer-cial settings. The growth of commercial centershas been slowed in some States by the fact thatsome insurance organizations do not p rovide ben-efit paym ents for aph eresis p rocedu res performedoutside the hospital. FDA has yet to establishlicensing procedu res for apheresis centers, andmany private insurers have indicated a reluctanceto provide reimbu rsement for therapy und er un-controlled conditions, which could lead to p ossi-

ble treatment overuse and abuse. There appearsto be less overall concern, though, in the case of private p ayers, about future restrictions on reim-bursement for apheresis treatment (108).



Ch. 4–Cost Effectiveness and Reimbursement Policy: Issues and Evidence q 53

CONCLUSIONS

Acknowledgment of apheresis as a safe and ef-fective treatment application, as an acute therapyin a sm all group of relatively uncomm on d iseases,is reflected in present Medicare reimbursementpolicy. Suggestive evidence of the safety and ef-ficacy of apheresis in a host of other disorders hasalso forced a flurry of reimbursement policy re-views and formulations among both governmentand private party insurers.

Reimbursement policies to the present have re-vealed an increasingly cautious an d explicit ap -proach to coverage of apheresis for almost alldisease indications, and understandably so.Aph eresis is still not a proven cure for any dis-order. It may need to be d one repeated ly for cer-tain d isease cond itions, at a cost of up to $1,200or more each time. Total cost estimates potentially

run into the billions of dollars. Nevertheless, bytreating certain disease complications, apheresishas reportedly lessened suffering and helped pro-long lives. Reliable estimates of these benefits haveyet to be determined and quan tified. As a result,cost-benefit ratios and CEAS have not yet beenconducted.

It should be reemphasized that the formationof cost-benefit ratios and CEAS shou ld not be con-sidered only economic tools. This point is notnegated by the fact that CEA/ CBA is describedas an efficiency-based technique. Measurement of

the efficiency of therapeutic apheresis will dependas much on output as on resources used to pro-du ce the output. One of the critical outpu t or out-come measures that can be addressed by CEA/ CBA is the effect of aph eresis on health sta tus orother health outcome related effects. Any CEA/ CBA that attempts to analyze such ou tcomes foran evaluation of therapeutic aph eresis w ill onlybe as comp rehensive and valid as the data on theefficacy and safety of apheresis. Thus, health out-come related CEA/ CBAs for apheresis are de-pendent on the existence of an adequate efficacyand safety information base. The statu s of such

information for many disease indications forwh ich therap eutic aph eresis has been used, how-ever, is inadequate. As a result, it may be ex-ceedingly difficult to demonstrate therapeutic

apheresis a cost-effective technology for whichthird-party payment is justified.

Medical insurers are presently far from a con-sensus on which disease indications should be

covered, probably stemming from a less than con-sistent scrutiny of the evidence on safety and ef-ficacy. A wid ening of Medicare and private in-surer coverage of therapeutic apheresis for specificlife-threatening complications (e.g., rheumatoidvasculitis) is probable in the n ear futu re. But directcost estimates and the potential cost of possiblypremature diffusion alone make it unlikely andunwise that third-party payers will support anybroad extension of benefits for apheresis treatmentuntil more valid data is generated. Until evidenceis available, therapeutic apheresis will largely beviewed as an experimental techniqu e, not to be

considered as a p art of routine care. In light of such a situation, present research and clinical trialsbeing carried out assum e even greater imp ortance.It will be several years, though, before all theresults are in.

Lastly, a significant (but still speculative) fac-tor amidst the cost and reimbursement policy de-bate is the potential cost redu ctions of new apher-esis equipment and treatment modalities. Thepresent trend tow ards p lasma p erfusion (moreselective removaI of undesirable plasma fractions)offers the possibility of eliminating the need for

replacement fluids wh ich could reduce the p resentcost per treatment by 20 to 50 percent. Staffingcharges are presently based on a large proportionof acute treatments w hich are usu ally performedon an in-patient basis, often at the patient’s bed-side. Some observers pred ict the futu re growthin apheresis to involve increases in maintenancetherapies wh ich could be p erformed on an out-patient basis, with reduced involvement of hos-pital staff (74,108).

On the other hand, there seems to be a trend

toward in-hospital use in areas such as Washing-

ton, D.C. In that region, after the Red Cross started d oing therapeutic aph eresis in March 1978,

only one of the first 16 months’ 106 procedures

was done in a hospital. But from July 1980 to

98-822 0 - 83 - 5 : QL 3




April 1981, nearly five out of six were. Future tivities for freestanding, independent commercial

decisions regarding treatment settings will no clinics, reimbursement policies, and whether

doub t depend on a nu mber of factors such as hos- apheresis is administered largely for reasons of

pital charges, regulation and standard setting ac- acute or maintenance therapy in specific disorders.



5.Implications for Policy

In summary, the confluence of technological

advances in apheresis equipment and recent scien-

tific research linking many chronic disease con-ditions to immunological dysfunction has served

to expand dramatically the number of apheresis

procedures in the pasts to 10 years. Therapeutic

apheresis has exhibited many of the classic fea-

tures that have come to characterize the hopes,

concerns, and fears about medical technologies

over the last three decades.

Utilization and diffusion of therapeutic apher-

esis seems to have closely followed Warner’s (141)“desperation-reaction” model. Initial rapid diffu-

sion h as occurred in th e absence of safety and ef-

ficacy evidence. The rapid diffu sion is du e in partto a lack of a suitable alternative technology, in

part to claims —some of them dramatic—of thetechnology’s beneficial effects, and in part to

desperation on the part of patients and of pro-

viders responsible for treatment. In chronic and

life-threatening situations, apheresis has found its

broadest and most frequent application.

Most recently, however, the lack of well-vali-

dated clinical evidence has influenced provider

behavior. Ambiguous results have given rise to

physician caution, while lack of evidence and high

costs have provok ed increased regulation by med-ical insurers, possibly slowing diffusion. Best

estimates are that utilization and diffusion have

plateaued, at least for the present. The future of

therapeutic apheresis seems predictable in that in-creases or declines in u se will be pred icated onnew ly ava ilable eviden ce (35,95).

Several recurring issues in need of further studyand resolution have run through the examinationof therapeutic apheresis. One issue, given the cur-rent state of this technology and many unan-swered questions about patient criteria for use,

is wh at constitutes the ap prop riate timing of in-tervention in the course of a d isease and w hetherthe procedu re to be followed in performing ther-apeutic apheresis is adequately standardized. Suchquestions are basic in the development of the tech-

nology, and research to address them is necessary,as it forms a foundation for the conduct of well-

controlled testing an d clinical trials. The Ap heresisPanel of the American Medical Association’sCouncil of Medical and Scientific Affairs hasrecently discussed the idea of a national apheresisregistry that wou ld track use and form a know l-edge base for development of well-controlled stud-ies (32). On a smaller scale, the American RedCross has requ ested its regional blood services toregister all apheresis patients at the onset of treat-ment and report treatment methods and resultsup on comp letion (1.21).

A second issue, wh ich ar ises w here conditions

of use have been sufficiently standardized, is thelack of well-designed research studies and the needfor such undertak ings. There have been at leasttwo obstacles preventing the accumulation of valid evidence of safety and efficacy: the ethicsof providing sham apheresis or conventional ther-apy for control group patients, and the high costsof such trials. Long hours of sham apheresis pro-cedures, while possibly inflicting on control grouppatients some of the same side effects of apheresisas treatment group patients, has led to questionsof the ethical implications of such trials. Fur ther-more, in life-threatening or severely debilitating

situations, doctors feel they cannot ethically denyapheresis therapy to control group patients.

The obstacle of costs of well-designed studieshas been partially offset by a r ecent infusion of Government and foundation funding. Shouldcosts continu e to be a p roblem, one alternativemight be to have third-party payers, includingMedicare, selectively reimburse for therap euticapheresis in return for clinical data. If im-plemented prop erly, this alternative could su b-stantially increase the quality of informationavailable for public and private reimbursement

coverage d ecisions. Evidence of the techn ology’scost effectiveness could result in yielding substan-tial bud getary sav ings. Even if the results of suchtrials were d isapp ointing, they could lead the w ayto u nexpected ad vances in research (47).

57




Because of the promise of apheresis for certaindisease complications, this technology would ap-pear to be a particularly choice candidate for sucha policy course. In such conditions as Good-pasture’s syndrome, for example, effective alter-native therapies are very limited a nd the d iseaseis frequently fatal. Because apheresis has been

claimed effective, selective reimbu rsem ent couldbe of great utility from both r esearch an d clinicalstandpoints.

There would be problems in implementing thisalterna tive (see e.g., 104), prim arily concerningthe legal and ethical implications of selectivelyreimbursing for health care. It seems clear, how-ever, that third-party payers could use this ap-proach to encourage less costly and more effec-tive forms of treatment. In the case of Medicare,too, elements of the Public Health Service couldbe involved in developing research protocols and

in interpreting research evidence from the result-ing experiments.

A recent pr ecedent exists for third-party payerpar ticipation in clinical trial fun ding for aph eresis.Five Midw estern State or local Blue Goss/ BlueShield grou ps and other third-party payers haveagreed to reimburse five centers involved in a ran-dom ized clinical trial of apheresis for mu ltiplesclerosis. Both the investigational procedure anda sham p rocedure are covered. Medicare and theState Medicaid groups, on the other hand, are notparticipating, but administrative and other re-

search costs of the trial are being funded througha National Institutes of Health grant (97).

The Arthritis Foundation and the National Mul-tiple Sclerosis Society are also sponsoring ameeting (to be held in July 1983) at which theyhope to develop proposals for third-party payerparticipation in funding other clinical trials.Representatives of both private and public in-surers will be participating (97).

A third issue is the possibly transitional natu reof this technology. Some m ajor new hard ware d e-

velopments are now undergoing clinical tests.These use adsorption colum ns and membranesthat work like molecular sieves. When a specificfraction w hose removal is desired can be iden tifed,an ad sorption column containing an antibody tothat fraction can remove it from the plasma as

it passes through . Another method, resemblinghemod ialysis, passes the blood across a m embranewith a specific antibody attached to it. A thirdtechnique u ses a m embrane filter to remove frac-tions of a specific molecular weight (80).

These advances in equipment may, in the

course of the next decade, be reinforced or evenovershadowed by advances in basic biomedicalresearch or in emerging parallel developmentssuch as biotechnology. The National Cancer In-stitute, and the N ational Heart, Lung, and BloodInstitute, for example, are curr ently sup portingstrategies for the separation of complex blood pro-teins. Advanced separation technologies couldmake it possible to index most human proteins.Once proteins are displayed and distinguishedfrom one a nother, investigators might then teaseout individual functions and relate them to theDNA code. Other activities could include the

detection of abnorm al protein patterns in diseasestates (e.g., leukemia), and the corresponding pro-duction of preventive or neutralizing elements(e.g., monoclinal antibodies) to these noxious ordamaging processes (53,60).

In the final analysis, such a state of scientificand technological flux has important policy im-plications. Therapeutic apheresis, as a medical in-tervention, falls into a category of medical tech-nologies classically referred to as half-waytechnologies (133). These are generally treatmentsdirected at correcting the effects of a disease orpalliating them. It has been pointed out and il-lustrated repeatedly in the literature and researchcommunity that such measures are less satisfac-tory and more costly than so-called definitivetechnologies, which effectively prevent or controla d isease or cond ition (e.g., poliomyelitis vaccine).As Robbins (116) and n um erous others have as-serted, “where alternatives exist, resources shouldbe directed so as to encourage the developmentof definitive technologies as opposed to half-w aymeasu res.” To the extent that su ch alternativescan be identified, considerable attention shouldbe given to the possibility of devoting resources

to their development. Indeed, one of the critical,ongoing p olicy issues in m edicine is how to es-tablish the m ost rational and p rodu ctive balancebetween developm ent and supp ort of half-waytechnologies and that of basic research towarddefinitive technologies.



Appendixes



Appendix A.— Health Program Advisory Committeeand Acknowledgments

HEALTH PROGRAM ADVISORY COMMITTEE

Sidn ey S. Lee, Chair

Michael Reese Hospital and Medical Center

Stuart H. Altman*Florence Heller SchoolBrandeis University

Carroll L. EstesDep artment of Social and Behavioral SciencesSchool of NursingUniversity of California, San Francisco

Rashi FeinDepartment of Social Medicine and Health PolicyHarvard Medical School

Melvin A. GlasserHealth Security Action Coun cil-Committee for National Health Insurance

Patricia KingGeorgetown Law

Joyce C. Lashof

Center

School of Public HealthUniversity of California, Berkeley

Margaret MahoneyThe Commonwealth Fund

Frederick MostellerDepartment of Health Policy and ManagementSchool of Public HealthHarvard University

Mitchell Rabkin*Beth Israel HospitalBoston, Mass.

Doro thy P. RiceDep artment of Social and Behavioral SciencesSchool of Nursin gUniversity of California, San Francisco

Richard K. RiegelmanGeorge Washington UniversitySchool of Medicine

Walter L. RobbMedical Systems OperationsGeneral ElectricMilwaukee, Wis.

Frederick C. Robbin sInstitute of Medicine

Rosemary StevensDepartment of History and Sociology ScienceUniversity of Pennsylvania

q Until April 1983.

61




ACKNOWLEDGMENTS

The development of this case study was greatly aided by the advice and review of a number of people inaddition to the Ad visory Panel for the assessment of Medical Technology an d Costs of the Medicare care Programand th e Health Program Advisory Panel. The case study director and OTA staff wou ld like to express their ap-preciation especially to the following individuals:

Cheryl Anderson, Advocacy International, Ltd.Jack M . Anth ony, Travenol Laboratories, Inc.Thomas Asher, Immunogenetics, Inc.Robert Berenson, Washington, D.C.Eugene Berkm an, Tufts New England

Medical CenterGary F. Brown, Seattle, Wash.Meredith F. Buco, Blue Cross/Blue Shield

AssociationMaria Ch arest, Arthur D . Little, Inc.,

Cambridge, Mass.Arthur A. Ciarkowski, Food an d

Drug Administration

Vincent Ciuryla, E. I. du Pent de Nemours & Co.,

Inc.P. P. Clymer, Office of Technology AssessmentRobert M. Collins, Cobe Laboratories, Inc.Dennis Cotter, Office of Health Technology

AssessmentW. Palmer Dearing, Blue Cross/Blue Shield

AssociationVincent T. DeVita, Jr., National Cancer InstituteAllen J. Douma, American Medical AssociationFrances Edmondson, Travenol Laboratories, Inc.Lenny Friedman, American Red CrossW. Bradfo rd G ary, Travenol Laboratories, Inc.Murray Goldstein, National Institute of

Neurological and Communicative Disorders

and StrokeMax I. Hamburger, State University of New York at Stony Brook

Steven Heyse, National Institute of Arth ritis,Diabetes, and Digestive and Kidney D isease

Terry Hollis, Blue Cross/Blue Shield of Massachusetts

Douglas W. Huestis, University of ArizonaJohn Verrier Jones, Dalhou sie University,

Nova Scotia, Canad aRichard Land field, Goodell, Landfield, Becker,

Green & Martingale, Washington, D.C.Claude Lenfant, National Heart, Lung, and

Blood InstituteJoshu a Levy, Immu nogenetics, Inc.L. M. Magner, E. I. du Pent de Nemours & Co.,

Inc.

Guy M. McKhann, Johns H opkins H ospitalDonald Myers, RMR Health and Hospital

Consultants, Inc.Terri Louise Nally, American Chemical SocietyNan Newell, Office of Technology AssessmentRobert K. Oldham, National Cancer InstituteRobert W. Reilly, American Blood Resources

AssociationJ. Gerald Sandier, American Red CrossPhillip s L. Scoville, Scoville Associates,

Greenville, S. C.Ira D. Singer, Project Hope

Glenda Sweeney, American Red CrossGarry Vibert, Parker-Hannifin Corp.

Donald Young, Health Care FinancingAdministration



Appendix B. —Apheresis for Hemolytic-Uremic Syndrome

Prepared for OTA by: Paul M. Wortman, Ph. D.Hillary Murt, M.H.S.A.

In collaboration with: Bruce Friedman, M.D.

The most prominent feature of hemolytic-uremicsynd rome (HUS) is renal microangiopathy, which ischaracterized by endothelial damage in glomerularcapillaries and renal arterioles. The event wh ich ini-t iates this endothelial damage is un known althoughsome authors have suggested that end otoxin is a primecandidate (71). The damaged endothelial cells becomeswollen, leading to renal ischemia and decay of kidneyfunction and two secondary hematologic events—redcell destruction (hemolytic anemia) and a dramatical-ly redu ced level of circulating platelets (thromb o-cytopenia). The former results from mechanical dam-age to red cells passing through the dam aged vessels.

The reduced platelet count results not only fromtrauma but also localized intravascular coagulation(and platelet consumption) occurring in the damagedvessels.

An alternative and m ore recent hyp othesis citesdecreased formation of PGI 2, (prostacyclin) as theprecipitating event leading to the full-blown clinical

manifestation of the syndrome (instead of a toxic agentsuch as end otoxin). The find ing of PG1 2 deficiency inadults and children with HUS supports this concept(11). In th is case, the loss o f PGI 2, caus es localizedplatelet aggregation in renal vessels and vascularobstruction. Traumatic red cell destruction (hemolyticanemia) is a corollary of the development of the

microthrombi which partly occlude the vascularlumens (84).

Finally, Seger, et al. (126), have suggested that HUS

is a polyetiologic syndrome with neuraminidase be-ing the culprit agent in some cases, particularly among

children suspected of having pneumococcal infections,as this agent can produce lesions in all three cellsystems (red blood cells, platelets, and endothelialcells).

The hemolytic-uremic syndrome shares a numberof features, including vascular endothelial damage,with thrombotic thrombocytopenic purpura (TTP). Infact, HUS has b een considered b y some clinicians tobe a variant of TTP, this being su pp orted by similar

overlapping clinical and pathologic characteristics andthe possibility of similar precipitating events. Thereis no objective method at pr esent to distinguish HUSfrom TTP, although in the case of the former, the kid -ney is typically the main and often only target organ,

children are p rimarily affected, and the p rognosis isgenerally mu ch better (71). These au thors b elieve,how ever, that a clinical diagnosis of one or th e otherconditions must be made because the treatment dif-fers and in HUS, depends on the man agement of thecomplications associated w ith ren al failure.

Plasma exchange (PE) was first administered as atherap y for TTP in 1959 by Ruben stein and others(84). Rapid and sustained recovery was observed aftertwo exchange transfusions with fresh whole blood toan n-year-old patient.

Taft and Baldwin (132) noted that centers whichhave experience with five or more p atients diagnosed

with TTP and treated with PE are reporting survivalrates in the 60- to 80-percent range. Plasm a exchan geis now being ad vocated as a p otential therapy fortreating HUS because of the su spected etiologicalsimilarity between the syndrome and TTP. Apheresisis viewed as being potentially helpful in removing atoxic agent (e.g., end otoxin, neu ramin idase) or replac-ing a missing factor, possibly a physiological inhibitorof platelet aggregation. In the latter case, Beattie, etal. (11), and Misiani, et al. (84), have both suggestedthat PE using norm al plasma replaces a missing fac-tor needed for stimulating PGI 2 production b y vascularendothelium.

Specification of TreatmentOnly eight reports (including two letters to the editor

and one abstract) have been published in the Englishmed ical literature on th e effectiveness of p lasma ex-change in the management of HUS. These eight com-munications account for 11 patients diagnosed withHUS ranging in ages from 1½ to 59 years who weretreated as an ancillary therapy with corticosteroids,antiplatelet drugs, or heparin. * Moreover, in seven

q Beattie, et al. (11), report on a 3%-year-old boy diagnosed with HUS.The patient was initially treated with aspinn and dipyrimadale (S mg/kg/day)and his condition gradually improved. Plasma exchange was not initiateduntil 10 days later when the patient was readmitted to the hospital with recur-rent symptoms of HUS. The authors do not indicate whether any drug therapywas administered during the second episode, so it is assumed that PE wasthe only therapy administered. The article by Taft and Baldwin (132) focusesprimarily on the treatment of patients diagnosed with TTP. They only brief-ly mentioned two patients with HUS who were treated with apheresis anddo not provide full case histories.

63



App. B—Apheresis for Hemoly tic-Uremic Sy ndrome q 65

Table B-1 .—Apheresis Experience Among Patients Diagnosed With Hemolytic-Uremic Syndrome

Range of plasma Range ofStudy exchanges plasma volumereference Number of Age range performed removed per Types of replacementnumber patients of patients per episode exchange fluids used

1 3½ yrs. 2 1,000 ml Fresh frozen plasma1 : : : : : : : : : : : : : 2 7 yrs. 3 Unknown Whole blood5 . . . . . . . . . . . . . 2 54-56 yrs. 1 3,000 ml Fresh frozen plasma

6 . . . . . . . . . . . . . 1 21 yrs. 5 3,000 ml Fresh frozen plasma andnormal saline

7 . . . . . . . . . . . . . 2 19-22 mo. 1,500 ml-2,350 ml Whole blood8 . . . . . . . . . . . . . 1 8 yrs. 8 1,500 ml Albumin, fresh frozen plasma9 . . . . . . . . . . . . . 2 2-7 yrs. 1-6 27 ml/kg-89 ml/kg Whole blood, fresh

frozen plasma10 . . . . . . . . . . . . . 1 37 yrs. 4 Unknown Unknown


tients und ergoing PE were children, who have smallerblood volum es. Table B-1 also shows th at whole b loodand fresh frozen plasma are the two m ost common re-placement fluids used in the process of plasma ex-change for patients with HUS. Human serum album inwas used as a replacement fluid in only one case andthe authors noted that there was no im provement afterthree exchanges, suggesting that no circulating agent

perpetuated the condition. Plasma exchange was thenperformed with fresh frozen plasma, which was fol-lowed b y a promp t recovery in th e platelet count (131).

The ab sence of explicit and detailed p rotocols forperforming p lasma exchange p oses a major problemin the evalu ation of the effectiveness of aph eresistherapy. However, given the rare occurrence of H USin the popu lation, it comes as no su rprise that notenough information has been accumulated on the useof plasma exchange to develop such protocols.

Misiani, et al. (84), suggest that at the present timeit is impossible to define individual PE requirementssince both the patient’s and donor’s plasma m ay dif-fer with respect to the plasma factor (e.g., PGI 2) con-centrations. Those authors recommend apheresing afull volume at the initial exchange, followed by one-half the initial amount daily until full hematologicremission is obtained . The literature on TTP, on theother han d, is considerab ly more extensive and con-sequen tly, a set of treatment gu idelines or p rotocolshas recently been proposed b y Taft and Baldwin (132).They have developed a clinical scoring system (in-cluding necrologic evaluation) to evaluate the day-to-day severity of the disease, which maybe used to de-termine the frequency of PE. Relying on five clinicalcriteria (i.e., platelet count, serum LDH, totalbilirubin, creatinine, and necrologic status) a score is

calculated to determine whether therapy should becontinued. Since several investigators have suggestedthat H US is a variant of TTP, it is conceivable th at

such a scoring system modified slightly to take accountof the clinical manifestations specific to HUS could beused to determine the appropriate frequency and vol-ume of PE.

Outcome Measures

A recurring critical issue in any attempt to analyzethe effectiveness of a medical innovation is the select-ing of appropriate endpoints for evaluating the suc-cess or failure of the innovation. In m any instan ces,outcome measures are either lacking, not specified, or

ill-defined in the written reports. For example, onestudy of HUS reports that the patient “showed im-provement” after the PE was initiated, without defin-ing p recisely wh at imp rovement m eans (135).

It appears that on, the whole, nonspecification of outcome measures is less of a problem when evaluatingthe effectiveness of plasma exchange for patients withHUS. While it is noteworthy that none of the eightstudies provide a discussion that specifically focuseson the kind s of outcome measures that should b e usedto evaluate apheresis for HUS, there does appear tobe some consensu s in the literature on the array of clinical indicators that are reported pre- and post-PE.

Table B-2 shows, for example, that all eight studiesreported whether or not their patients und erwentchronic dialysis and their mortality experience. How-

ever, the length of followup during which mortalitydata w ere collected varies across studies, wh ich maylimit the usefulness of directly comparing mortalityrates, Furthermore, seven of the eight studies reportedcreatinine or BUN levels (i.e., indicators of renal in-

sufficiency) and six studies indicated platelet counts.All six indicators displayed in table B-2 should be con-

sidered to b e objective outcome measu res. That is tosay, none of th ese measures is likely to be influen ced



66 qHealth Technology Case Study 23: The Safety, Efficacy, and Cost Effectiveness of Therapeutic Apheresis

Table B-2.—Variability in Effectiveness of Plasma Exchange Therapy for Hemolytic-Uremic Syndrome as Expressedin Selected Outcome Measures (all outcome measures relate to past plasma exchange period)

Outcome measures

Patients with Patients forPatients with Patients with Patients with eventual decline whom chronic

Study increment in eventual remission of in serum creatinine dialysis wasreference Number of platelet decline neurologic or BUN (renal initiatednumber patients count in serum LDH signs improvement) or continued Mortality

1/1NA2/21/1NA1/1

2121/1

NANA2/2NA

NANA

2/2NA

NA1/1NA

NA

NANA

NANA

0/11/11/21/10/21/12121/1

1/10/11/20/12/20/10/20/1

0/10/11/20/12/20/10/20/0

NA-Not available.


by expectations of th e ph ysician or patient concern-ing the efficacy of treating HUS with apheresis.

These measures clearly represent en dpoints th at areevaluated at different times during a given episode of

HUS. It may, in fact, be convenient to make a distinc-tion between the more general measures of healthstatus relating to HUS (e.g., chronic dialysis, mortali-

ty), which represent the sum total of many influencesand the more sensitive and specific hematologic, bio-chemical, and clinical signs and symptom s (e.g., plate-let count, creatinine, BUN, serum LDH levels, an dneurological status) that often occur rapidly follow-ing plasma exchange. The former may be called ‘long-term” outcomes, whereas the latter may be termed “im-mediate” outcomes.

When an outcome m easure such as m ortality is usedto evaluate the effectiveness of apheresis therapy forHUS, the benefits of apheresis may b e substantially

understated. Plasma exchange may, for instance, bringabout a temporary improvement in the patient’s clin-ical status, but other intervening factors may ultimate-ly cause the p atient’s death. Most clinicians, however,would probably agree that the ultimate objective of apheresis therapy is to increase the likelihood of sur-vival, which suggests that survival (or mortality) is animportant outcome measure of the efficacy of apheresisand should not be disregarded.

The need for chronic dialysis, on the other hand,may be a more app ropriate outcome measure for deter-mining the u ltimate success of plasma exchange in thetreatmen t of H US, since renal failure is a m ajor ele-men t of the syndrome. Chronic dialysis was deem ed

necessary for 4 of the 11 patients listed in table B-2(two of whom later died) which represents a 36-percentfailure rate w hen d ialysis is used as the sole measureof the effectiveness of PE therapy.

Finally, changes in hematologic and biochemical pa-rameters such as platelet count, serum LDH, cre-atinine, and BUN levels may also be used to evaluatethe effectiveness of apheresis therapy. The difficulty

with u sing these measures, however, is that patientsmay show im provement in one or all of those param-eters yet still require long-term dialysis (e.g., patientsin studies 1 and 5). In short, the “immediate” outcomemeasures may be necessary but insufficient indicators

of the efficacy of plasma exchange. Perhaps th esemeasures and the end points of chronic dialysis andmortality could be combined in some way as co-meas-ures. The problem of combining multiple evaluationcriteria and assessing the significance of the results isa difficult one. For example, researchers may chooseto assign different weights to each outcome measurewhich would lead to disagreement and perhaps a lack

of consensus on the effectiveness of PE in treating

HUS.

Patient Selection

In seven of the eight studies, PE therapy was ini-tiated when patients diagnosed with HUS did not re-spond to either hemodialysis or peritoneal dialysis orother conventional therapies including corticosteroids,antiplatelet drugs, or heparin. In other words, apher-esis was performed on these patients as a last resorttherapy when there were no other effective alternativetherapies and death was the likely outcome. Since onlythe “worst cases” of HUS appear to be selected forapheresis therapy, it is possible that the effectiveness

of plasma therapy is underestimated, depending onwh ich ou tcome m easure is used. If PE is initiated inthe later stages of the disease (i.e., when end-stagerenal disease is inevitable), the beneficial effects of



App. B—Apheresis for Hemolyt ic-Uremic Syndrome q 67

apheresis maybe dramatically reduced if chronic dial-ysis is the end poin t used for evaluating th e effec-tiveness of the treatment.

Evaluation of the Evidence

The eight communicat ions that have app eared in theliterature during the past 3 years describing the effec-tiveness of apheresis in treating patients with HUSpresent data on a total of 11 patients, but each caseis described in dividually. Only one of the commu nica-tions suggests that PE has lim ited effectiveness on th edisease process (11). However, the authors in this ar-ticle add that the clinical benefit may h ave been com-

promised b ecause PE was performed d uring a recur-rent ph ase of the illness which is recognized as bein g

associated with poor prognosis. The remainin g sevenstudies are almost uniformly favorable in suggestingthat apheresis contributes to clinical improvement,although there is no explanation provided about which

measures are used to gauge th is improvement. Severalauthors add th e caveat that PE be initiated du ring theearly stages of the d isease in order to realize its fullbenefit (132). Parries, et al. (106), caution that PE aloneis associated with complications (e.g., hepatitis) andthat these risks should be weighed against the poten-

tial benefits of apheresis.What can be said about the “scientific soundness”

of the data on w hich the conclusion th at PE is ef-ficacious is based? Scientific soundness is defined here

as the adequ acy and the credibility of the available in-formation for reaching a consensus. First, in the caseof evaluating the use of PE therapy for treating HUS,it is quite clear that the newn ess of this particular ap-plication of the techniq ue is associated w ith a smalland incomplete research base. With only 11 patients,there is insufficient data on wh ich to make a recom-mendation to endorse this procedure. Second, the cred-

ibility of the evidence is open to question because of the q uality of research used in all eight stud ies; these

case studies do not include any comparison groups.The m ajor problem with the case-study app roach (and

other pretrial studies) is that they are subject to a varie-ty of competing alternative explanations for the ob-served effects of the therapy. Interpreting the evidencebecomes even more problematic when the potential af-fects of apheresis therapy are confounded by othertherapies that are used concomitantly with p lasma ex-

change. Apheresis was the single therapy used in on lytwo case studies; one patient completely recovered andthe other patient underwent chronic dialysis because

of continued deterioration of renal function (11,106).

Finally, it is unclear as to which criteria (e.g., out-come measures) should be used in evaluating the ef-fectiveness of the therapy. There are too few cases todetermine w hether there is high concordance betweenthe “immediate” outcomes (e.g., platelet counts, LDH,

creatinine, and BUN levels) and the “long-term” out-comes (e.g., chronic dialysis, mortality). If th esemeasures turn out to b e discordant, some method w illhave to be developed to combine these multip le evalu-ative criteria in order to arrive at the recommendation.



Appendix C.— Apheresis for Inhibitors to Factor Vlll

Prepared for OTA by: Paul M. Wortman, Ph. D.Hillary Murt, M.H.S.A.

In collaboration with: Bruce Friedman, M.D.

Factor Vlll Antibodies

Apheresis, and more specifically, plasma exchange(PE), has been investigated as a potential therapy for

patients with antibodies or inhibitors to Factor VIIIdu ring th e past 10 years. Factor VIII is essential toachieve hemostasis (i.e., permit normal blood clotting

and end bleeding). For that reason, patients with classichem ophilia have been particularly at risk from com-plications associated with the development of FactorVIII antibodies. It has been estimated th at as many as20 percent of such patients may develop this condi-tion. Factor VIII inhibitors can also arise spontaneous-

ly in other patients. This so-called idiopathic or ac-

quired inhibitor to Factor VIII can occur in women intheir first year after childbirth, persons with rheuma-

toid arthritis, the elderly, and persons suffering a varie-ty of other disorders.

The major concern in these situations has been toreturn Factor VIII to normal or effective levels. Treat-

ment typically involved immediate and continueddoses of human Factor VIII concentrate. This treat-ment often failed since it did not remove existing an-tibodies in the blood and frequently app eared to stim-ulate the produ ction of more antibod ies. To deal withthese complications a variety of alternative treatmentshas been investigated. One of these has involved theuse of apheresis with or without Factor VIII. The fol-lowing sections summarize the available scientific re-search reporting on the use of PE in treating patientswith antibod ies to Factor VIII.

Literature Reviews

Twenty articles were located and retrieved from aMEDLARS search of the research literature. Four of these articles did not d eal specifically with cases in-volving Factor VIII, five were in a foreign language(two in Russian, two in German, and one in Hun -garian), one article w as a d up licate copy of anoth er,and one contained the same case information asanother by the same authors. Of the foreign languagearticles, the tw o in Russian were excluded , the one inHungarian also was published in English and that ar-

ticle was included in our review; the two German stud-ies were read. One of the German articles did n ot deal

with Factor VIII and th e other presented a very brief case draw n from 210 patients an d also was n ot in-cluded in this review.

There remain ed nin e articles to review after thevarious exclusions were made. The articles were allcase studies in volving from on e to six patients. Fivestudies reported treating a single patient; two had tw opatients; one had three, and another had six. Of the18 patients in these nine studies, 10 had classichemophilia, seven idiopathic Factor VIII antibodies,

and one had von Willebrand’s disease. The patientsgenerally faced a life-threatening situation. Thirteenhad severe bleeding an d three requ ired or were recov-ering from surgery. The p atients ranged in age from3 to 77 and generally had either low levels of FactorVIII or high levels of Factor VIII inh ibitor reportedprior to treatment.

68



App. C—Apheresis for Inhibit ors to Factor VIII q 69

Specification of Treatment

Although apheresis was employed in all of thesestudies, the actual definition or specification of treat-ment varies widely from one report to another (seetable C-1). First, the nu mb er of PEs vanes wid ely from

just 1 (109,143) to 15 (129). The modal number of PEswas three (occurrin g in six of the 18 patien ts) withanother four receiving two exchanges. The volum e of plasma actually exchanged also differed widely from

one study to the next, ranging from 500 to 6,000 m lper exchange. The replacement fluid also varied. Al-though in seven studies fresh frozen plasma was used,other fluids included albumin, gelatin, plasma protein,and saline (or plasma expander). It should be notedthat in most patients wh o were severely compromisedfresh frozen plasma was used. The treatment alsovaried in d uration , lasting from 1 day to 6 weeks.

Perhaps most troublesome in determining the ap-propriate treatment regimen is the use of immu nosup-pressants such as azathioprine and cyclophosph amide

in conjunction with apheresis. Five of the eight studiesused one of them simultaneously with PE and two hadtried it before using PE. Nevertheless, there is a great

difference of opinion on the value of such therapydespite its confounding with apheresis. One study(129) claims that “immunosuppression has not beenshow n to be effective and may well interfere withwou nd h ealing and in crease susceptibility to infection. ”However, another study (111) concludes that “a com-bination of specific immun e supp ression and inten-

sive . . . (apheresis) . . . may be the best form of treatment in patients with acquired idiopathic factorVIII inhibitors and life-threatening bleeding.” Theresolution of these conflicting claims and the separa-tion of the two treatments (PE and immunosuppres-sion) poses some difficulties in so few stud ies.

The study by Pintado, et al. (111), contains the bestdiscussion of possible alternative treatments. In thatstudy one elderly patient with idiopathic or acquired

Factor VIII inhibitor was given six plasma exchangesover a 2-week period. These researchers reviewed theprevious literature and concluded that “spontaneousremission of the immune response” (i.e., terminationof production of Factor VIII antibodies) was “unlike-ly.” Instead, they feel that the remission was due tothe combined use of immunosuppressants and “anti-genic load” (i.e., human Factor VIII concentrate).

Treatment with Factor VIII concentrate poses an ad-ditional problem in determinin g the efficacy of apher-esis. As noted in th e introd uction, Factor VIII sup -plementation is viewed as the p rimary treatment w ithapheresis an adjun ct to improve its efficiency. The u seof Factor VIII was, in fact, reported in all nine studiesencompassing 16 of the 18 patients treated. However,in one study (37) involving two patients, this treat-ment was evidently discontinued just prior to apheresisbecause of a rise in inhibitor level in one patient and

an ad verse reaction (to a porcine derivative) in theoth er. Similarly, in th e stud y by Pille r, et al. (109),one of three patients was treated with Factor VIII con-centrate just prior to apheresis. While the inhibitorlevel w as red uced fr om 1.3 to 0.5, p/m l, the goal of this study was its complete neutralization and an in-

crease in Factor VIII. In the remaining two patients(who were not in a life-threatening situation) apheresisusing Factor VIII-free solutions was tried in an attemptto prevent the “rapid increase” in inhibitor activity.In both cases there was a “less rapid” return of inhibitoractivity to its previous level (and, in one case, a “con-siderably higher” level). The au thors conclude that in-hibitor levels can be lowered through “repeated . . .(aph eresis) . . . at intervals of about one month. ”

The Piller, et al. (109), stud y did not employ im-munosuppressants concurrently in conjunction withapheresis (although one patient received prior treat-ment with azathioprine and Factor VIII with cyclo-phosphamide “without success”). If the hypothesis of Pintado, et al. (111), is correct, then antibodies would

continue to be produced requiring regular PE. As noted

Table C-2.—Effectiveness of Apheresis for Factor Vlll Inhibitors

Immediate Followup

Factor Vlll Factor VlllStudy reference number Hemostasis inhibitor (µ/ml) inhibitor (µ/ml)

1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . — 1.2 0.82 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . yes 36 83 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . yes 1-8 0-14 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . — O-4.8 0-17

5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ye s —o6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . yes — o

7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ye s 12 08 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ye s —

9 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ye s 0-1 5-47SOURCE: Office of Technology Assessment, 1983.

98-822 0 - 83 - 6 : QL 3



70 q Health TechnoIogy Case Study 23: The Safety, Efficacy, and Cost Effectiveness of Therapeutic Apheresis

th is is exactly the con clusion of Piller, et al. (109).Moreover, the two studies with the greatest numberof PEs did not use immunosuppressants. In the studyby Slocombe, et al. (129), noted above, one of the twopatients received 15 PEs exchanges along with vary-ing d oses of Factor VIII. Similarly, Cobcroft, et al.(23), performed nine apheresis treatments on a patient(who had previously had unsuccessful imm unother-

apy). One can only speculate on wh ether as man y ex-changes would have been required had immunosup-

pressants been employed concurrently. In both studies,how ever, there is little justification provided for ad-ditional exchanges beyond the first two.

In sum mary, the m odal regimen in the research s tud-ies involved two or three aph eresis treatments in con-

junction with both immunosuppressants (typicallycyclophosphamide) and Factor VIII concentrate (fromhumans). Two hypotheses seem tenable from thesestudies. First, immunosuppressants may stop the pro-duction of antibodies as Pintado, et al. (111), claim,with the apheresis quickly removing existing anti-bodies. And second, apheresis using Factor VIII-free

solutions such as gelatin or saline may slow the returnof the inhibitor activity as Piller, et al. (109), main-tain. The two treatment therapies are clearly not in -depend ent and could b e combined. At present thereis a need for more systematic research on the most ap-propriate treatment for patients presenting with Fac-tor VIII antibodies.

Results of Treatment

The results of the treatment just described in the ninestudies reviewed are presented in table C-2. Both short-term or immediate results and long-term findings are

ind icated. For 16 of the 18 patients at risk du e to severebleeding or surgery the immediate clinical results wereun iformly successful. In all cases hemostasis wasachieved and the patient fully recovered from the acuteepisode. One should note, of course, that cases of clin-ical failures are much less likely to be su bmitted or ac-

cepted for publication.The measures of Factor VIII inhibitor (in ~/ml) and

Factor VIII (in percent normal) are not consistentlyreported in the text. Where possible this informationwas recorded or in terpolated from tables and figures.These figures indicate a less than consistent pattern of results. In almost half the patients (i.e., 8 of 18) theinhib itor level falls below 2 @ml at followup; wh ilein 9 of the patients reported, the inhibitor level is 8µ/ml or greater. The inhibitor data for one patient(129) were not available, but were probably very lowgiven the Factor VIII level of 75 percent.

Eight of the nine patients with poor long-term resultsare from just two stud ies (109,143). The Piller, et a l.,study d iffered from all the others in that its sole ob-

jective, as noted earlier, was the long-term reductionin the Factor VIII inh ibitor level. This stud y did n otemploy Factor VIII therapy along with immunosup-pressants in the two failed cases (although one hadreceived them earlier). It should b e noted that short-

term control was achieved and the authors concludethat one could “treat severe hemorrhages immediate-ly by on ly admin istering Factor VIII or by combiningone . . . (apheresis) . . . run with replacement ther-apy.”

The oth er six patients, one-third of the total fromall of the stud ies, with poor long-term or “second aryrise” in the inhibitor level, were treated by Wensley,et al. (143). In this case, apheresis combined withhuman Factor VIII concentrate produced an initial low-ering of the inhib itor level to permit hemostasis andhealing. The authors recommend this combined ther-

apy as a better alternative to using “significant quan-tities” of Factor VIII alone.

As noted in the previous section, the impact of im-mun osuppressants should be considered. Neither of these two studies reported the concurrent administra-tion of immunosuppressants to patients. On the otherhand , five of the six patients treated with immu nosup-

pressants h ad followu p in hibitor levels of 1 @ml orless.

Evaluation of the Evidence

In conclusion, it is important to ask wh at one caninfer from these nin e studies. To do this, it is usefulto consider the qu ality of the research evidence pro-vided. A numb er of points should be considered inreaching an overall assessment.

First, the studies are all pretrial clinical reports gen-

erally of one patien t (i.e., the five articles). There wereno clinical trials comparing a num ber of p atients sys-tematically treated b y a n umb er of well-defined ther-apies. In fact, other th an referen ces to some p rior treat-ment regimen there is no comparative informationavailable.

Second, as an earlier section noted, there is noagreed upon treatment for patients with inhibitors toFactor VIII. While apheresis is used and endorsed in

all nine stud ies, the treatment is m ore comp lex thanthat. Other concurrent therapies are described withvarying results and the number of PEs also differedfrom stud y to study. While a num ber of possible hy-potheses were examined, the eviden ce is far from con-



App. C—Apheresis for Inhibitors to Factor VIII q 71

elusive on what is the best method to treat this con-dition.

Third, the goals of the studies also differed. Mostinvolved acute, life-threatening situations, usuallyepisodes of severe bleeding. In those cases, short-termresolution of the problem was sought and generallyachieved. In a few other stud ies, longer term solutions

to the an ti-Factor VIII were attempted with varyingresults. Here too, there are possible treatment com-binations that need to be further investigated.

Finally, with so few patients in so few studies onemu st consider the issue of sample bias. It would onlytake a few reports of a few p atients with differing ornegative results to alter one’s notion of the efficacy of apheresis in this situation. For this reason the evidencecan only be viewed as preliminary and provocative.It is far from persuasive.

Apheresis in combination with other therapy is onlyan emerging technology for treating patients with Fac-tor VIII antibodies. There is a n eed for m ore carefulstudy an d sp ecification of the treatment and its effects

—both of immediate and longer duration. There area num ber of quest ions that need to be answ ered beforeits efficacy is established . If, as is likely, apheresis con-tinues to be employed in life-threatening situations,then p hysicians should b e encouraged to un dertakemore systematic study of th e treatment. This could in-clude a number of therapeutic alternatives syste-matically applied to a series of patients, perhaps in acontrolled trial.

In conclusion, it should b e noted th at some experts

believe all the treatment combinations described aboveare not effective. In particular, PE is viewed as astopgap measure, at best, because (as the literature in-dicates) the antibod y titer rapidly increases post ex-change. For these reasons current interest has focusedon b ypassing the b lockade of the Factor VIII inhibitor

by administering new agents that contain a mixtureof clotting factors, including activated Factor VIII.Given th e availability of these new agents, such treat-ment m ay be the th erapy of choice for patients withhigh titers of Factor VIII antibod ies.



Appendix D. —Apheresis in Guillain-Barre Syndrome

Prepared for OTA by: Richard K. Riegelman, M. D., Ph. D.

Introduction

Guillain-Barré syndrome (GBS) (65,119,148) is an

acute polyneuropathy. It begins in a restricted area of the bod y, most often distally, and then sp reads orascends to in volve many mu scle groups. The rate and

extent of progression vary wid ely. Man y patients re-cover spon taneously with out life-threatening p rogres-sion. Some become severely paralyzed within a fewdays wh ile in others the disease worsens slowly andinsidiously over a period of several days or evenweeks. The extent of paralysis varies widely. Sensoryand autonomic nervous system involvement can alsooccur. In the most severely involved individuals, con-trol of blood p ressure and b reathing mayb e affected

requiring a respirator and in tensive care management.Progression of weakness usually ceases less than 4weeks after onset. Spontaneous recovery usuallybegins within 2 to 4 weeks after progression stops.Recovery is usually gradual, but abrupt spontaneousrecovery has been documented.

With current intensive care management under themost ideal conditions the mortality can be reduced to5 percent or less. Prognosis for complete recovery isgood, with about 85 percent of patients restored tonormal function. The remaining usually have onlymild residual deficits.

The etiology of GBS remains un know n. Cases havebeen associated with injection of foreign protein, cat

scratches, dog bites, transfusions, and immu nizations,including rabies vaccine and the widely p ublicized as-

sociation with the 1976 influenza vaccine program.Rumpl, et al. (119), have summarized the evidence

as of 1981 for an immunologic mechanism as follows:Experimental allergic neuritis has shown striking sim-

ilarity with the disease in humans. The immune patho-genesis of GBS was further supported b y the finding of complement fixing antibodies, of precipitating anti-bodies against trypsinized wh ite matter extracts and of myelinotoxin serum antibodies of the IgM class in pa-tients with GBS. Cellular hypersensitization to periph-eral nervous antigen presented by circulating immuno-blasts and lymphocytes supported the role of cellularmechanisms in pathogenesis.The rationale for the use of plasma exchange (PE)

in GBS is based on the presence of serum antibodies

which can be removed by PE.

Brettle, et al. (15), first repo rted th e su ccessful useof PE in acute G BS in 1978. An abrup t and dramatic

improvement was seen in this case. This report waspublished shortly after Hughes, et al. (63), reporteda poor response to steroids in a controlled clinical trialof acute GBS. With evidence against the use of steroidsestablished in a controlled clinical trial and withevidence of a dramatic improvement with plasma ex-change, many centers throughout the world began toexperiment w ith and report their results of PE therapy.

The existing literature includes m any case reportsand sm all series of cases in wh ich apheresis or morespecifically PE was used in the treatment of acute GBS.

In reviewing this literature one m ust app reciate sev-eral factors repeatedly emphasized b y the auth ors andcritics.

1.

2.

3.

4.

5.

As an experimental therapy initial use of the ther-apy was not standardized. The timing, quanti-ty, duration, and type of PE varied considerably.

In some patients the therapy was used concur-rently with steroid treatment and in others after

steroids had failed. Some p atients were treatedafter extended respirator and intensive care ther-apy while others were treated in an effort to avoidthe need for such care.The m easures of assessment of outcome also var-ied en ormously. Some in vestigators reported ob -vious and at times dramatic clinical improve-ments while others reported changes in nerve con-duction tests and immunological changes which

preceeded or were unassociated with a clinicalresponse.The reported stud ies are all case reports withoutany concurrent control group s, blin din g, ran-domization, or other techniq ues u sed in con-trolled clinical trials.The documentation of adverse effects was notsystematic and m ay have been biased by the tend-ency to report successful uses of a n ew th erapy.The natu ral history of acute GBS with its tend en-

cy for spontaneou s and occasionally abrup t im-provement makes the interpretation of therapyrelated results more difficult.

Despite these difficulties much has been learned fromthe initial studies and reports on the use of PE in GBS.The following section summarizes the reported evi-dence on efficacy.

72



App. D—Apheresis in Guil!ain Barré Syndrome • 73

Efficacy

The reported individual cases repeatedly refer tostriking or dramatic change which occur within min-utes to hours after plasma exchange.

One report (134) stated: “the improvement after theexchanges was so abrupt and striking that it induced

us to believe that the plasma exchanges were essen-tially responsible for this development. Particularly inour case with ventilator insufficiency and bulbarpalsy, which worsened day by d ay, the course of thedisease seemed to have been reversed by plasma ex-change indu cing an im med iate amelioration. The re-sponse was qu icker in those nerves which had deterio-rated the latest, which is in accordance with clinicalexperience in cases of spontaneous recovery.”

Other cases of dramatic improvements after plasma

exchange includes the following:Littlewood and Bajada (77) report: “On day 8 of our

patient’s illness respiratory vital capacity fell to 1.41and was accomplished by complete ophthalmoplegia

and iridopligia. A dram atic imp rovement in vital ca-pacity followed the first session and was subsequent-ly m aintain ed.” Similarly, Corachan, et al. (27), report

a case of: “ . . . dramatic imp rovement after . . .(apheres is) . . . “ Levy, et al. (76), report that “clinicalimprovement was dramatic” in a patient with chronicrelapsing d isease.

Not all in vestigators have rep orted success. Cook,et al. (26), reported a series of five patients only oneof whom had a “significant clinical improvement. ”Maisey and Olczak (78) reported two patients whofailed to respon d to PE. Gross, et al. (45), have argu edthat Maisey’s use of 1.5 liters per day of plasma ex-change was “small compared w ith those used by other

operators for the same disease and in other diseaseprocesses.” They fu rther argue that one wou ld n ot ex-

pect all cases to respond . They w rite: “Cases of inflam-matory polyneuropathy probably constitute a hetero-geneous group and it wou ld be surprising if every pa-tient proved to benefit from plasma exchange.”

Several larger series have also b een recently re-ported . Rump l, et al. (119), reported eight cases of suc-cessful treatment with PE. They report: “Recovery wasabrupt in all cases after the first PEs. Improvement wasmore marked, w hen . . . (aph eresis) . . . was per-formed on three successive days with plasma ex-chan ges of 2.0-3.01 each . . . . Recovery s eeme d tobe delayed in cases when plasma exchanges were re-

duced to 0.5-1.51 each and were spread over severaldays or weeks, even when the nu mb er of plasma ex-changes w as increased.”

Durward, et al. (33), reported their experience withsix cases all of wh om im proved to som e degree after

PE. They conclude “Ou r experience to d ate (11 in-cidents in six patients) is of recovery beginning or ac-celerating immediately after plasma exchange . . . .We started exchanges fairly early-usually about oneweek after onset —and exchanged more than 10—1 oneach occasion (except in case 3). ”

Dau , et al. (31), report on 13 patien ts with acute

GBS who underwent 2 to 3 weeks of PE with 4 or 5exchan ges of 4 liters. Seven p atients, all of whom were

still progressing or stable “stopped p rogressing on th eday of the first . . . (apheresis) . . . and had discerni-ble clinical improvement within 48 hours.” Among theother patients two continued progressing, three werealready slowly imp roving and aph eresis “did n ot seemto accelerate recovery.” In these pat ients apheresis wasstarted “relatively late after disease onset .“ In the lastpatient there was progressive deterioration. The reportconcluded that factors associated with a good ou tcomewere:

1. Institution of apheresis early in the course of theillness.

2. Normal evoked muscle action potential.3. Little electromyographic evidence of denervation.4. Age less th an 50 years.Schooneman, et al.’s (123), series of 10 patients with

acute GBS is the only reported series in which no p a-tients received steroids and in which a control groupwas attempted. In add ition, the auth ors performed ex-

tensive neurological testing before and after each ex-change. Respiratory impairment was assessed by clin-ical examination and blood gas determinations.

In 9 of their 10 cases patients showed improvementwithin 24 hours after the first exchange. The authorsbelieve that “the p rogressive phase of the d isease washalted.” They term their results “spectacular.” In com-

paring their 10 patients to 258 historical control pa-tients with G BS they conclude that aph eresis appeared

to shorten the d uration of paralysis, reduce the n eedfor tracheotomy, and shorten the hospital course.They did not dem onstrate reduced m ortality since onepatient died in each group. They also did not demon-strate or claim that these patients represented com-parable study and control groups.

Safety

Plasma exchange carries inherent risks in all pa-tients. Samtleben, et al. (120), reporting on 100 con-secutive PE procedures, observed allergic reactions to

albumen in 10 percent, hypocalcemic symptoms in 6 percent, and vasovagal reactions in 5 percent. Otherside effects have included massive extracorporeal bloodclotting, hypercoagulation states with vascular throm-bosis, hemorrhagic tendencies, changes in serum lipid



74 q Health Technology Case Study 23: The Efficacy, and Cost Effectiveness of Therapeutic Apheresis

fractions, cardiac arrhythmias, and pulm onary emb oli(93).

Rum pl, et al. (119), reported that in their experien ce

with plasma exchange for GBS, cardiovascular prob-lems, coagulation difficulties, and allergic reactionsmade it necessary to interrupt PE and influenced the

amount of exchanged plasma.Patients with severe GBS may have an u nstab le

autonomic nervous system p redisposing them to prob-lems with blood pressure control and cardiac ar-rhythmias. The n eed to perform the p rocedure onrespirator dependent patients may further complicate

PE.In light of these consid erations M ayr, et al. (81),

who have successfully used PEs in GBS, conclude:“The considerable risks and high technical require-men ts may limit this therapy to th e severe course of Guillain-Barré syndrome.”

Need for Controlled Clinical Trials

A controlled trial is not a trial of a treatment. It isa trial of a specific means of administering a therapy;thus it requires agreement on the timing, extent, and

duration of therapy.The performance of a controlled clinical trial should

be preceded b y enough research to establish an agreedupon method for administering the therapy. In addi-tion, before going to the expense of a well-performedcontrolled clinical trial, it is important that preliminaryevidence exists of the effectiveness and additional ben-efit of the treatment. These two prerequisites to a con-trolled clinical trial have b een ad equately fulfilled bythe existing literature.

Despite the controversy in the reported literature

over the efficacy and safety of PE in GBS, both th eadvocates and th e skeptics appear to agree on the needfor controlled clinical trials. A sampling of their com-ments should demonstrate this point.

Irvine and Tibbles (64) in their report of an ap-parently successful treatment with exchange transfu-sions conclud e: “In the futu re it will be important todocum ent failu res as well as success to place this treat-men t in its proper p erspective. It is likely that theorganization of a prospective controlled trial of th iscostly form of m anagemen t will b e necessary. ”

Du ring 1981 a series of letters appeared in the British Medical Journalreporting dramatic improvement, evi-dence of subtle response, and cases without measurable

improvement. All three reports agreed on the need fora controlled trial. The group (78) reporting no responsewrote: “If anecdotal reports are relied on, publicationbias ensures that apparently successful results dom-inate the literature. ” The group (62) reporting success

wrote: “ . . . a controlled trial of plasma exchange isnecessary in acute inflammatory polyradiculoneuro-pathy before its value can be assessed. Since patientswith this condition begin to improve after a variabletime after the onset of symptoms and usually recover

completely, it is not surprising that each new treat-ment has been hailed with enthusiasm on the basis of anecdotal reports.” The group (33) reporting subtlerespon ses concurred , stating: ‘These d ata only re-emp hasize the n eed for a controlled clinical trial,especially in the early phase, in order to delineate therole of plasma exchange in acute Guillain-Barré syn-

drome.”In their advocacy of their forthcoming controlled

clinical trial Asbury, et al. (10), wrote in the October1980 issue of Neurology that apheresis of “an acutelyill patient with respiratory depression and autonomicinstability is not a benign procedure. Until this studyis completed anecdotal reports of the efficacyof . . . (aphere sis) . . . in the Gu illain-Barre syndrom eshould be interpreted with caution. At present, it isno t poss ib l e to s t a t e the the rapeu t i c ro l ethat . . . (aph eresis) . . . plays for this disease,”

Controlled Clinical Trials in Progress

In December 1980, the National Institute of Neuro-logical and Communicative Disorders and Strokefun ded a 3-year mu ltiple site cooperative stud y of apheresis treatment of acute GBS (87).

The primary stud y question is: Does apheresis ef-fect a significant beneficial change in the early course

of severely ill patients with GBS? Secondary studyquestions include the following:

1.

2 .

3 .

Are there clinical, epidemiologic, laboratory, orelectrodiagnostic factors associated with a goodoutcome of GBS? If so, how does apheresis in-teract with these factors?Is there a subgroup of patients with GBS forwhom apheresis can be expected to be of valueand a subgroup for whom it cannot?Can aph eresis reduce the incidence of long-termcomplications (assessed at 6 months) in the 15 to20 percent of GBS patients destined to have somelasting deficits?

The stu dy uses gen erally accepted criteria for thediagnosis of GBS. Patients must be within 30 days of onset of definitive neuropathic symptoms. They mu st

require a walker or sup port to walk 5 meters or bemore severely affected. Steroid treatment is not givento study patients. The quantity and timing of the PEare consistent with that reported for successful usesof PE in GBS.



App. D—Apheresis in Guillain Barré Syndrome q 75

The study protocol provides standard m ethods forassuring randomization, informed consent, termina-tion, monitoring of followup, and statistical analysis.

The study is designed to include about 240 patients.This nu mb er is adeq uate to provide an 80-percentchance of demonstrating a statistically significant im-provement if apheresis actually provides a 50-percentimprovement over conventional therapy. As of July

1, 1982, 102 patients had been enrolled in the study.An interim analysis of the data is planned wh en ap-

proximately 120 patients have been entered into th estudy. The interim analysis is designed to determinewhether the study should continue. This analysis willconsider the following three possibilities:

1.

2 .

3 .

The evidence is overwhelming that the apheresispatients are doing better, and if the study w ereto continue with little or no advantage to the ex-change protocol over the second half of the study,a statistically significant difference would stillexist.the exchange protocol patients are doing w orseor no better than the other p atients and continua-

tion of the stud y could not, even w ith an extremereverse of results in the second half, demonstratea beneficial effect of apheresis.Neither extreme exists.

The end points considered in this analys is wil l be m eas-ures of clinical improvement 4 weeks after entry intothe study as w ell as time spent on a respirator. If theinterim report reaches conclusion 1 or 2, the study w illbe stopped and presumably the results released andreported. Otherwise the study will continue and theresul ts presumably w il l not be released b y the N at ionalInstitutes of Health (NIH ).

The NIH study appears to be adequately designedto answer the basic questions regarding efficacy of

apheresis. The results should largely determinewhether evidence exists for moving PE from an ex-perimental status to that of a conventional therapy for

A second randomized controlled clinical trial is cur-rently underway in Great Britain (87). This study also

includes p at ients wh o require supp ort to walk 5 metersor who are more severely affected. The findings onthe first 19 randomized patients were reported in May1982. A “decided trend in favor of plasma exchangewas noted at 4 weeks after random ization wh ich didnot reach statistical significance. ”

NIH will not currently release preliminary resultsof the American study. The interim analysis shouldbe completed by early 1983, but unless the results of the interim analysis clearly answer the efficacy ques-tion, a full report may not be available until 1984.

Conclusions

1 .

2.

3.

4.

5.

Case reports and small-scale, mostly uncontrolledtrials provided suggestive evidence that plasma ex-change may b e efficacious for som e patients w ithacute GBS.Because of the low mortality and good prognosisfor most patients with Gu illain-Barré synd rome, the

safety of the p rocedure an d ind ications for its useshould be delineated prior to nonexperimental useof plasma exchange in G BS.

The conditions for use of plasma exchange in acuteGuillain-Barré syndrome have been sufficientlystandardized to enable a controlled clinical trial of the procedure.The potential cost saving and potential for short-ened disabi l i ty make wel l -des igned control led s tud-ies of this therapy important.Controlled studies of the efficacy, safety, and in-dications for plasm a exchan ge in acute GBS are cur-rent ly in progress. These s tudies should be adeq uateto provide data which address the essential clinical

qu estions. Until the results of these stud ies areavailable, the use of plasma exchange in GBS shouldbe considered an experimental procedure.

acute GBS.



Appendix F.— American Red Cross Bibliography

This appendix contains a Therapeutic Apheresis Bibliography that was compiled by theAmerican Red Cross and is distributed to American Red Cross regional blood services to facilitateaccess to current information on therapeutic aph eresis by specific disease categories.

The b ibliography is d ivided in to two sections. The first section contains 1,241 citation s thatcomprised the ap heresis literature as of May 1982. Th e second section is a supplement that adds778 referen ces through January 1983 to the original list.

References in b oth sections are listed by reverse chronological order an d grouped by sp ecificdisease categories. Some articles may b e cited in m ore than one category if their content w ar-rants multiple listings. Texts, symposia, and review articles (sec. XVII) may also contain infor-mation p ertinent to specific diseases, but some of these sum mary pu blications may n ot be listedby disease category.

77



ARC Blood ServicesBibliographyTPB XVII-2

“First Annual Apheresis Symposium: Current Concepts and Future Tren@.”Published Proceedings. Chicagot American Red Cross Blood Services, 1979.

%eukapheresia and Donor Safety W orkshop.n June 4, 1979. Bethesda, MD: Bureauof Bidogics.

“Pheresis A Vital Blood Service.n Workshop for American Red Cross PheresisStaff. Washington, DC: American Red Cross Blood Services, 1979.

Gddrmn 3M, Lowenthal R M (edsh ‘Leukocytes Separation Collection andTransfusion.” Londom Academic Press, 1975.

AMERICAN RED CROSSBLOOD SERVICES

Therapeutic Phereais Bibliography

Sqplement No. 2

hmlary 1983



References



preferences q 765

154.

Care Financing Administration, Department of Health an d Hu man Services, Baltimore, Md. ,

memorandum on “Medicare Coverage Instruc-tions on Pheresis, ” to Director, National Centerfor Health Care Technology, Department of Health and Human Services, Rockvil le , Md. ,Mar. 11, 1981.

Young, D. A., Office of Coverage Policy, Bureau

of Program Policy, Health Care Financing Ad-ministration, Department of Health and Human

Services, Baltimore, Md. , memorandum on“Plasmapheres is - Memorandum of August 25,1980” to Associate Director for Medical andScientific Evaluation, National Center for HealthCare Technology, Department of Health and

Hu man Services, Rockville, Md. , Oct. 24, 1980.

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