Benefit-And-Cost Analysis of Medical Interventions: The Case of Cimetidine and Peptic Ulcer Disease
September 1981
NTIS order #PB82-118910 LIBRARY OFFICE OF TECHNOLOGY ASSESSMENT CASE STUDY #11
THE IMPLICATIONS OF COST-EFFECTIVENESS ANALYSIS OF MEDICAL TECHNOLOGY
SEPTEMBER 1981
BACKGROUND PAPER #2: CASE STUDIES OF MEDICAL TECHNOLOGIES
CASE STUDY #n: BENEFIT-AND-COST ANALYSIS OF MEDICAL INTERVENTIONS: THE CASE OF CIMETIDINE AND PEPTIC ULCER DISEASE
Harvey V. Fineberg, M. D., Ph. D. Associate Professor and Laurie A. Pearlman, A. B. Research Analyst
Harvard School of Public Health, Boston, Mass.
OTA Background Papers are documents that contain information believed to be useful to various parties. The information under-girds formal OTA assessments or is an outcome of internal exploratory planning and evaluation. The material is usually not of immediate policy interest such as is contained in an OTA Report or Technical Memorandum, nor does it present options for Congress to consider.
CONGRESS OF THE UNITED STATES Office of Technology Assessment Washington D C 20510 Library of Congress Catalog Card Number 80-600161
For sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, D.C. 20402 Foreword
This case study is one of 17 studies comprising Background Paper #2 for OTA’s assessment, The implications of Cost-Effectiveness A Analysis of Medical Technology. That assessment analyzes the feasibility, implications, and value of using cost-effec- tiveness and cost-benefit analysis (CEA/CBA) in health care decisionmaking. The ma- jor, policy-oriented report of the assessment was published in August 1980. In addition to Background Paper #2, there are four other background papers being published in conjunction with the assessment: 1 ) a document which addresses methodological issues and reviews the CEA/CBA literature, published in September 1980; 2 ) a case study of the efficacy and cost-effectiveness of psychotherapy, published in October 1980; 3 ) a case study of four-common diagnostic X-ray procedures, to be published in summer 198 1; and 4 ) a review of international experience in managing medical tech- nology, published in October 1980. Another related report was published in September of 1979: A Review of Selected Federal Vaccine and Immunization Policies. The case studies in Background Paper #2: Case Studies of Medical Technologies a r-e being published individually. They were commissioned by OTA both to provide information on the specific technologies and to gain lessons that could be applied to the broader policy aspects of the use of CEA/CBA. Several of the studies were specifi- cally requested by the Senate Committee on Finance. Drafts of each case study were reviewed by OTA staff; by members of the ad- visory panel to the overall assessment, chaired by Dr. John Hogness; by members of the Health Program Advisory Committee, chaired by Dr. Frederick Robbins; and by numerous other experts i n clinical medicine, health policy, Government, and econom- ics. We are grateful for their assistance. However, responsibility for the case studies re- mains with the authors.
Director
Ill Advisory Panel on The Implications of Cost-Effectiveness Analysis of Medical Technology
John R. Hogness, Panel Chairman President, Association of Academic Health Centers
Stuart H. Altman Sheldon Leonard Dean Manager Florence Heller SChool Regulatory Affairs Brandeis University General Electric Co.
Barbara J. McNeil Department of Radiology Peter Bent Brigham Hospital
Robert H. Moser Executive Vice President American College of Physicians
Frederick Mosteller Chairman Department of Biostatistics Harvard University
Robert M. Sigmond Advisor on Hospital Affairs Blue Cross and Blue Shield Associations
Jane Sisk Willems VA Scholar Veterans Administration OTA Staff for Background Paper #2
Joyce C. Lashof, Assistant Director, OTA Health and Life Sciences Division
H. David Banta, Health Program Manager
Clyde J. Behney, Project Director Kerry Britten Kemp, * Editor Virginia Cwalina, Research Assistant Shirley Ann Gayheart, Secretary Nancy L. Kenney, Secretary Martha Finney, * Assistant Editor
Other Contributing Staff
Bryan R. Luce Lawrence Miike Michael A. Riddiough Leonard Saxe Chester Strobe]*
OTA Publishing Staff
John C. Holmes, Publishing Officer John Bergling Kathie S. Boss Debra M. Datcher Joe Henson
● OTA contract personnel. Preface
This case study is one of 17 that comprise ● examples with sufficient evaluable litera- Background Paper #2 to the OTA project on the ture. lmplications of Cost-Effectiveness Analysis of On the basis of these criteria and recommen- Medical Technology.* The overall project was dations by panel members and other experts, requested by the Senate Committee on Labor OTA staff selected the other case studies. These and Human Resources. In all, 19 case studies of 16 plus the respiratory therapy case study re- technological applications were commissioned quested by the Finance Committee make up the as part of that project. Three of the 19 were spe- 17 studies in this background paper. cifically requested by the Senate Committee on Finance: psychotherapy, which was issued sepa- All case studies were commissioned by OTA rately as Background Paper #3; diagnostic X- and performed under contract by experts in aca- ray, which will be issued as Background Paper demia. They are authored studies. OTA sub- #.5; and respiratory therapies, which will be in- jected each case study to an extensive review cluded as part of this series. The other 16 case process. Initial drafts of cases were reviewed by studies were selected by OTA staff. OTA staff and by members of the advisory panel to the project. Comments were provided In order to select those 16 case studies, OTA, to authors, along with OTA’s suggestions for in consultation with the advisory panel to the revisions. Subsequent drafts were sent by OTA overall project, developed a set of selection to numerous experts for review and comment. criteria. Those criteria were designed to ensure Each case was seen by at least 20, and some by that as a group the case studies would provide: 40 or more, outside reviewers. These reviewers ● examples of types of technologies by func- were from relevant Government agencies, pro- tion (preventive, diagnostic, therapeutic, fessional societies, consumer and public interest and rehabilitative); groups, medical practice, and academic med- ● examples of types of technologies by physi- icine. Academicians such as economists and de- cal nature (drugs, devices, and procedures); cision analysts also reviewed the cases. In all, ● examples of technologies in different stages over 400 separate individuals or organizations of development and diffusion (new, emerg- reviewed one or more case studies. Although all
ing, and established); these reviewers cannot be acknowledged indi- ● examples from different areas of medicine vidually, OTA is very grateful for their com- (such as general medical practice, pedi- ments and advice. In addition, the authors of atrics, radiology, and surgery); the case studies themselves often sent drafts to ● examples addressing medical problems that reviewers and incorporated their comments. are important because of their high fre- quency or significant impacts (such as Cost ); ● examples of technologies with associated high costs either because of high volume (for low-cost technologies) or high individ- ual costs; ● examples that could provide informative material relating to the broader policy and methodological issues of cost-effectiveness or cost-benefit analysis (CEA/CBA); and tive. The reader is encouraged to read this study in the context of the overall assessment’s objec- tives in order to gain a feeling for the potential role that CEA/CBA can or cannot play in health care and to better understand the difficulties and complexities involved in applying CEA/CBA to specific medical technologies.
The case studies were selected and designed to The 17 case studies comprising Background fulfill two functions. The first, and primary, Paper #2 (short titles) and their authors are: purpose was to provide OTA with specific in- formation that could be used in formulating Artificial Heart: Deborah P. Lubeck and John P. general conclusions regarding the feasibility and Bunker implications of applying CEA/CBA in health Automated Multichannel Chemistry Analyzers: care. By examining the 19 cases as a group and Milton C. Weinstein and Laurie A. Pearlman looking for common problems or strengths in Bone Marrow Transplants: Stuart O. Schweitz- the techniques of CEA/CBA, OTA was able to er and C. C. Scalzi better analyze the potential contribution that Breast Cancer Surgery: Karen Schachter and these techniques might make to the management Duncan Neuhauser of medical technologies and health care costs Cardiac Radionuclide Imaging: William B. and quality. The second function of the cases Stason and Eric Fortess was to provide useful information on the spe- Cervical Cancer Screening: Bryan R. Luce cific technologies covered. However, this was not the major intent of the cases, and Colon Cancer Screening: David M. Eddy”’ CT Scanning: Judith L. Wagner Elective Hysterectomy: Carol Korenbrot, Ann B. Flood, Michael Higgins,” Noralou ROOS, and John P. Bunker End-Stage Renal Disease: Richard A. Rettig Gastrointestinal Endoscopy: Jonathan A. Show- stack and Steven A. Schroeder Neonatal Intensive Care: Peter Budetti, Peggy McManus, Nancy Barrand, and Lu Ann Heinen Nurse Practitioners: Lauren LeRoy and Sharon Some of the case studies are formal CEAS or Solkowitz CBAs; most are not. Some are primarily con- Orthopedic Joint Prosthetic Implants: Judith D. cerned with analysis of costs; others are more Bentkover and Philip G. Drew concerned with analysis of efficacy or effec- Periodontal Disease Interventions: Richard M. tiveness. Some, such as the study on end-stage Scheffler and Sheldon Rovin renal disease, examine the role that formal Selected Respiratory Therapies: Richard M. analysis of costs and benefits can play in policy Scheffler and Morgan Delaney formulation. Others, such as the one on breast cancer surgery, illustrate how influences other These studies will be available for sale by the than costs can determine the patterns of use of a Superintendent of Documents, U.S. Govern- technology. In other words, each looks at eval- ment Printing Office, Washington, D.C. 20402. uation of the costs and the benefits of medical Call OTA’s Publishing Office (224-8996) for technologies from a slightly different perspec- availability and ordering information. Case Study #11 Benefit-and-Cost Analysis of Medical Interventions: The Case of Cimetidine and Peptic Ulcer Disease
Harvey V. Fineberg, M. D., Ph.D. Associate Professor and Laurie A. Pearlman, A.B. Research Analyst
Harvard School of Public Health Boston, Mass.
AUTHORS’ ACKNOWLEDGMENTS
A number of people aided us at various stages in the preparation of this report. For their valuable advice, we would like to thank Dr. Morton I, Grossman, Center for Ulcer Research and Education, Veterans Administration Center, Los Angeles; Dr. Thomas P. Al my, Dartmouth Medical School; Dr. Marvin H. Sleisenger, VA Hospital Medical Service, San Francisco; Dr. Benjamin A. Barnes, Center for the Analysis of Health Practices, Harvard School of Public Health; Dr. Janet Elashoff, Center for Ulcer Research and Education, VA Center, LOS Angeles; Dr. Morton Paterson, Smith- Kline Corp.; Dr. Morris Olitsky, Robinson Associates, Inc.; Dr. George von Haunal- ter, Dr. Virginia Chandler, Stanford Research Institute; Dr. Richard Monson, Har- vard School of Public Health; and Dr. Murray C. Wylie, University of Michigan School of Public Health. Dr. Grossman also kindly shared with us a manuscript in press. Several researchers described to us their work in progress. We are especially grateful to Dr. Wylie and to Dr. ]ohn F. Geweke of the University of Wisconsin De- partment of Economics. We thank Dr. Leighton Read of the Center for the Analysis of Health Practices for introducing us to useful literature on ulcer disease. We also appreciate the cooperation of Mr. Charles Dennison, Mr. Donald Green- berg, and Ms. Ethel Black of the National Center for Health Statistics, who promptly responded to our numerous requests for information. Dr. Joan Standard of the Food and Drug Administration was also very helpful. By naming people who have advised and assisted us, we do not mean to shift responsibility for any errors or misinterpretations that may appear in this case study. Contents
Page Table No. Page Summary ...... 3 8. NCHS and CPHA Data on Number of Introduction ...... 3 Selected Surgical Procedures in the The Benefit-and-Cost Model for Medical United States, 1966-78...... 22 Interventions. ..,...... 3 9. Components and Measures of Components Peptic Ulcer Disease...... 4 in a Benefit-and-Cost Analysis of Cimetidine. 26 Cimetidine...... 4 10. Short-Term, Double-Blind, Placebo- The Benefit-and-Cost Model Applied to Controlled Studies of Cimetidine: Effect on Cimetidine...... 5 Duodenal Ulcer Healing ...... 29 Review of Benefit-and-Cost Analyses of 11. Short-Term, Double-Blind, Placebo- Cimetidine...... 6 Controlled Studies of Cimetidine: Effect on Suggestions for Further Research ...... 6 Gastric Ulcer Healing ...... 31
Introduction ...... 6 12< Short-Term, Double-Blind, Placebo- The Benefit-and-Cost Model for Medical Controlled Studies of Cimetidine: Effect on Interventions ...... 7 Duodenal Ulcer Pain Relief ...... 32 Peptic Ulcer Disease ...... 10 13 Short-Term, Double-Blind, Placebo- Definition and Etiology ...... 10 Controlled Studies of Cimetidine: Effect on Symptoms and Diagnosis ...... 11 Gastric Ulcer Pain Relief...... 33 Treatment and Natural History ...... 11 14. Controlled Trials of Maintenance Epidemiologic Patterns ...... 13 Cimetidine in Peptic Ulcer...... 36 Cost of Illness ...... 18 15. Results of Treatment With Two Hypothetical Summary ...... 22 Subpopulations of Ulcer Patients: Type A Cimetidine ...... 23 More Resistant to Treatment and Prone Physiologic Rationale and Development . . . . . 23 to Relapse Than Type B...... 37 Diffusion ...... 24 16. Short-Term, Double-Blind, Placebo- The Benefit-and-Cost Model Applied to Controlled Studies of Cimetidine: Effect on Cimetidine ...... 25 Antacid Consumption...... 40 Elements in the Analysis ...... 25 17. Number of Selected Surgical Procedures in Clinical Effects ...... 26 the United States, 1966-78 ...... 41 Health System Effects ...... 39 18. Proportion of Patients With First-Listed Outcome ...... 46 Diagnosis of Ulcer Disease Having Surgery, Summary ...... 48 1966-78 ...... 43 Review of Benefit-and-CostAnalyses of 19. Number and Rate of All and Selected Cimetidine ...... 49 Abdominal Surgical Procedures in the Available Analyses ...... 49 United States, 1970-78...... 43 The Study by Robinson Associates, Inc...... 49 20. Percentage Cost Savings Estimated From Guidelines for Review of Health Care Robinson Associates Study ...... 56 Cost Analyses ...... 57 Suggestions for Further Research...... 58 References ...... 59 LIST OF FIGURES LIST OF TABLES Table No. Page Figure No. PageL 1. Selected Contemporary Interventions l. Benefit-and-Cost Model for Medical Used in Peptic Ulcer Disease ...... 7 Interventions ...... 8 2. Number of Deaths in the United States With 2. Number of Deaths in the United States With Ulcer Disease as the Primary Cause, 1960-79. 15 Ulcer Disease as the Primary Cause, 1966-79. . 15 3. Mortality Rates in the United States for 3. U.S. Hospital Discharges With Ulcer Disease Deaths Due to Ulcer Disease, 1953-78 ...... 16 Diagnoses, All Sites, 1966-78 ...... 17 4. Number of U.S. Hospital Discharges With 4. Paradigm Decision Tree: Cimetidine and Ulcer Disease Diagnoses, 1966-78 ...... 16 Alternative lntervention Strategies ...... 26 5. Ulcer Disease in the United States According 5. NCHS Data on Number of Selected Surgical to the Health Interview Survey, NCHS . . . . . 17 Procedures in the United States, 1966-78. ,... 42 6. Costs of Ulcer Disease in 1975 as Estimated 6. CPHA Data on Number of Selected Surgical by NCDD and SRI ...... 19 Procedures in the United States, 1966-78. . . . . 42 7. Costs of Ulcer Disease in 1975 and 1977 7. Number of Deaths in the United States as Estimated by SRI...... 22 From Ulcer Disease, 1976-79 ...... 46 Case Study #11: Benefit= and-Cost Analysis of Medical Interventions: The Case of Cimetidine and Peptic Ulcer Disease
Harvey V. Fineberg, M. D., Ph. D. Associate Professor and Laurie A. Pearlman, A.B. Research Analyst
Harvard School of Public Health Boston, Mass.
SUMMARY
Introduction population may be defined in terms of diagnos- tic category, a clinical sign or symptom, a risk This case study presents a conceptual model factor, or a complication of disease. for assessing the benefits and costs of medical technology, and uses this model as a framework The model posits two principal classes of ef- for analyzing the benefits and costs of cimeti- fects: clinical effects and health system effects. dine in the treatment of peptic ulcer disease. The specific components of each depend on the population and intervention of interest. Clinical The body of the study is organized into three effects and health system effects interact and major parts: 1) a description of the benefit-and- lead to an outcome, expressed in terms of health cost model; 2) a selective description of clinical status and resource costs. features, epidemiologic patterns, and costs of peptic ulcer disease; and 3) a review of the de- The components of the model apply to both velopment, dissemination, health benefits, and cost-effectiveness analyses (CEAs) and benefit- resource costs of cimetidine. The study ends cost analyses (BCAs), but the two analytic ap- with a critique of one major analysis of cimeti- proaches have distinct purposes and measure dine’s costs and benefits and some suggestions some components in different ways. The model for further research. can also serve as a basis for identifying the structural components of a decision analysis The Benefit-and-Cost Model for that compares alternative medical interven- Medical Interventions tions. The benefit-and-cost model stresses that an The model and a set of guidelines for review evaluation of medical technology must apply to of health care benefit-and-cost analyses are used an identifiable patient population and a specific to organize and guide our discussion of the costs health intervention. An intervention may have a and benefits of cimetidine in peptic ulcer diagnostic or a therapeutic purpose. A patient disease. 4 ● Background Paper #.2: Case Studies of Medical Technlologies
Peptic Ulcer Disease We estimate that the costs of ulcer disease in 1975 were approximatel $2 billion. Just under Ulcers probably have multiple causes, but y half of this total was due to health care expend- gastric acid and pepsin appear to be necessar y itures (direct costs), and the remainder was due ingredients. Epigastric pain (pain in the upper to productivity losses from morbidit and mor- middle abdomen) is often a prominent symptom y tality (indirect costs). Our estimate is based on a of peptic ulcers, but the clinical presentation is review of two independent analyses of the costs variable. Furthermore, typical ulcer symptoms of ulcer disease, one by the National Commis- may be caused by conditions other than ulcers. sion on Digestive Diseases (NCDD) and the A definite diagnosis requires direct visualization other by the Stanford Research Institute (SRI). by endoscopy or radiographic imaging of the The NCDD and SRI estimates of the total costs ulcer. Specific treatments of ulcer disease are of ulcer disease in 1975, $1.3 billion and $2.6 directed at reducing the presence or effects of billion, respectively, differ by approximatel gastric acid. y $1.3 billion. The NCDD and SRI estimates of di-
Ulcer disease is a chronic condition with rect costs differ by approximately $400 million, spontaneous remissions and recurrences. Rates a difference that reflects differences in the two of complications and mortality from ulcers are studies’ methods and differences in their detailed relatively low, Excessive mortality appears to be assumptions and procedures. Their indirect cost
present only in the first year or so following estimates differ by approximately $900 million, diagnosis. Little reliable information exists a difference that reflects differences in the
about the natural history of ulcer disease in the studies’ projected morbidity losses. SRI’S in- general population. direct cost estimate, the higher one, is based on data from the Health Interview Survey, which is Peptic ulcer is a common condition that af- an inflated indicator of disease-specific morbidi- fects millions of Americans at some time during ty. In both the NCDD and SRI studies, esti- their lives. The best available epidemiologic mated indirect costs are based on a rather low evidence suggests that about 250,000 Americans discount rate—2.5 percent. Use of a smaller dis- develop new peptic ulcers each year. New duo- count rate increases the present value of future denal ulcers are more than four times as com- earnings, thereby increasing apparent costs of mon as new gastric ulcers. Some studies have illness due to morbidity and premature death. found that the incidence of duodenal ulcer rises gradually with age; others have found that it re- In addition to estimating costs for 1975, SRI mains fairly constant above age 35. Above age projected an estimate of peptic ulcer costs in 40, the incidence of gastric ulcer appears to rise 1977. Because of unwarranted assumptions of growth in the morbidity of ulcer disease and use more dramatically than the incidence of duo- denal ulcer. Duodenal and gastric ulcers are epi- of more expensive resources, the problem of demiologically distinct. Several lines of clinical overestimated costs is compounded for 1977. and epidemiologic evidence suggest that over the past 20 years the occurrence of new ulcers Cimetidine has declined, or ulcer disease is generally less Cimetidine represents a new class of hista- severe than it was at one time, or both. mine antagonists, called H2-receptor antago- nists, which block stimulation of gastric acid The basis for some estimates of the costs of secretion. The product was developed after ex- ulcer disease and the benefits of treatment is the tensive research by the Smith Kline & French Health Interview Survey of the National Center pharmaceutical firm and is marketed under the for Health Statistics (NCHS). Results of the registered brand name Tagamet®. Health Interview Survey, based on self-reported conditions in a household survey, however, ap- The Food and Drug Administration (FDA) pear to overestimate the occurrence and conse- approved the use of cimetidine for up to 8 weeks quences of ulcer disease. by patients with duodenal ulcer disease or hy- persecretory conditions such as Zollinger-Elli- duodenal ulcer. Cimetidine plus a moderate son syndrome in August 1977. Use of cimetidine amount of antacid. costs no more than a thera- spread rapidly. Since March of 1978, the drug peutically equivalent course of intense antacid has been prescribed in approximately 60 percent therapy. Experts now differ in their recommen- of ambulatory visits for ulcer disease each dations for initial therapy of duodenal ulcer, month. In 1978, a conservatively estimated 1.5 some favoring cimetidine and others antacids. A million to 2 million U.S. ambulatory patients reasonable approach is to select therapy based with ulcers and other symptoms of gastric acid- on each individual patient’s preferences and ity were treated with cimetidine. Worldwide personality. sales to hospitals and pharmacies in 1979 prob- ably exceeded $400 million. Compared to placebo, maintenance treatment with cimetidine for as long as 1 year signifi- The Benefit- and-Cost Model cantly reduces the chance of ulcer recurrence Applied to Cimetidine during the treatment period. Once cimetidine treatment is discontinued, patients appear to Organized according to the benefit-and-cost relapse at the same rate as they would have model presented earlier, this part of the case without maintenance treatment. We are aware study describes available information about the of no controlled trials comparing maintenance effects of cimetidine. It deals separately with cimetidine to treatments other than placebo. cimetidine’s clinical effects, its health system ef- There is little empirical evidence either that fects, and its potential impact on outcome. cimetidine prevents future complications of ulcer disease or that cessation of cimetidine pro- Numerous controlled studies of patients with motes complications. At present, FDA is consid- duodenal ulcer confirm that cimetidine pro- ering approval of cimetidine for use longer than motes healing and provides faster and more 8 weeks in patients with duodenal ulcers who complete pain relief than placebo. Less con- are at high risk for surgery. clusive evidence suggests the drug may be more effective than placebo for patients with gastric In European trials, but not in U.S. studies, ulcer. An intense antacid program appears to be cimetidine-treated patients tend to consume less about as effective as cimetidine for patients with antacid than placebo-treated patients. Very lim- duodenal ulcers, but more evidence of this is ited empirical data are currently available on still needed. Clinical studies have also shown the possible effects of cimetidine on use of other that relief of symptoms is not a reliable indi- medication, on diagnostic tests, and on physi- cator of healing. In general, European studies cian visits. There are several studies under way have found more favorable results with cimeti- that may shed light on these matters. dine than have U.S. trials. Data from NCHS show that in 1978, the first Cimetidine used for up to 2 months appears full calendar year after cimetidine was intro- to be a relatively safe drug. Most known side ef- duced in the United States, there was an unex- fects are minor or reversible; however, recently pectedly sharp decline in the rates of surgery for reported changes in the bacterial flora of the ulcer disease. This drop occurred against a stomach and endocrinologic effects may be background of falling rates of surgery and hos- more significant. Available studies of mainte- pitalization for ulcer disease over the previous nance cimetidine for periods up to 1 year do not decade. Although other explanations of the alter the current assessment of the drug’s rela- large drop in surgery for ulcer disease in 1978 tive safety. As is the case with any new drug, are possible, the widespread use of cimetidine possible long-term consequences of cimetidine’s may have been a contributing factor. use are not known. There is little evidence of any effect of cime- Compared to an intense course of antacids, tidine on mortality from ulcer disease. In one cimetidine is about equally effective and more short-term trial and one maintenance study, pa- risky, but less troublesome to patients with tients treated with cimetidine lost significantly fewer days of work than patients taking pla- methods used to compute average percentage ef- cebo, but no controlled study has compared fects due to cimetidine. We question some of the work loss among patients receiving different ef- assumptions and methods used in each of these fective treatments. areas. Aside from the fundamental issue of pos- sible inaccuracy in the physician estimates, we Review of Benefit- and-Cost Analyses believe the Robinson Associates study over- of Cimetidine states expected savings by twofold to threefold. Potential bias introduced by the selection of Several analyses of the resource cost implica- physician informants would increase the magni- tions of cimetidine have been undertaken in the tude of the overestimate. past few years. One major study, by Robinson Associates, Inc., estimated that if cimetidine Despite our criticisms of the study by Robin- had been used in 80 percent of duodenal ulcer son Associates, available data and analyses sup- patients, 1977 cost; for duodenal ulcer disease in port the belief that cimetidine currently saves the United States would have been reduced by more health resources than it costs. Whether $645 million. This conclusion rests on subjective further studies will affirm this conclusion or estimates provided by selected physician experts new developments will alter cimetidine’s cost of the clinical and health system effects of effectiveness are empirical questions for the cimetidine, and on independent estimates of the future. costs of duodenal ulcer disease based in part on the costs of peptic ulcer disease in 1977 pro- Suggestions for Further Research jected by SRI. If the object of analysis is to help inform clini- Our critical review of the Robinson Associ- cians and health policy decisionmakers about ates study focuses on the following five areas: the efficient use of resources in the care of pa- 1) the accuracy of the clinical and health system tients with ulcer disease, then the most helpful effects projected by their physician experts, approach would be to do a CEA of alternative 2) the relation between a percentage reduction in interventions oriented to particular groups of health services devoted to ulcer disease and sav- patients, comparing incremental clinical bene- ings in health resources, 3) the accuracy of the fits to marginal resource costs. Rather than enu- estimated total costs of all duodenal ulcer dis- merate the resource and health implications for ease used as a baseline for percentage savings, a cross-section of the population in a single 4) the applicability of projected percentage ef- year, the analysis might equally or more useful- fects to the total population of patients with ly focus on a cohort of patients and project ef- duodenal ulcer disease, and 5) the validity of the fects over their lifetimes.
INTRODUCTION
This case study has both a specific and a gen- dine and ulcer disease as an application of the eral objective. The specific objective is to assess general model for benefit-and-cost evaluation. ’ available evidence about the benefits and costs Peptic ulcer is a logical choice for this kind of of cimetidine, a recently introduced pharma- evaluation for several reasons. As a diagnostic ceutical agent, in the treatment of peptic ulcer category, it comprises several anatomically and disease. The general objective is to present an epidemiologically distinct entities, but these are approach to the evaluation of medical technol- sufficiently related to make peptic ulcer a valid ogy that emphasize:; salient features of both the diagnosis. This common medical problem has a patient population and the medical intervention of interest. The specific purpose serves the ‘We use the term “benetit-dnd-c(wt analysl~ ‘ t[) enc[)m pass both general one —we present our analysis of cimeti- cc)st-ettect iveness and C(WI -bend it (or bend It -cost I analyses. Case Study #11 Benefit-and-Cost Analysis of Medical lnterventions: The Case of Cimetidine and Peptic Ulcer Disease ● 7
highly variable clinical course and an evolving or analyze one in detail. We elected the latter pattern of clinical expression and occurrence. course, believing it would produce a more These features help demonstrate that a careful coherent exposition of the general model. assessment of a disease can be as important to We selected cimetidine for several reasons. the evaluation of technology as is a comprehen- First, it is a recent innovation that was dissemi- sive understanding of the technology itself. nated rapidly. Second, as a chemical entity, the Our selection of cimetidine emerged gradual- drug cimetidine does not evolve technically (un- ly. Initially, we wanted to use an assessment of like, for example, endoscopy) and its effects are peptic ulcer disease as a backdrop for reviewing relatively independent of the skill of the clini- the costs and benefits of a number of diagnostic cian (unlike, for example, surgery’s). Since there tests and therapeutic interventions such as those are fewer such complications related to the tech- listed in table 1. (In addition to these contem- nology, we can appreciate more readily the porary interventions, the variety of clinical ap- complexity introduced by features of the dis- proaches to ulcer disease over the past century ease. Finally, the clinical effects of cimetidine constitutes a rich history for anyone interested have been studied extensively, and its costs and in the progress and byways of medical science benefits have been and continue to be formally (85).) It soon became evident that we could assessed. either review several interventions superficially The body of this case study is organized into three main parts. First, we present a brief Table 1 .—Selected Contemporary Interventions Used in Peptic Ulcer Diseasea description of a general benefit-and-cost model —.- .— — for evaluating medical interventions. Second, Diagnostic interventions we describe pertinent clinical and epidemiologic Imaging features of peptic ulcer disease, and summarize ● Air-barium, double-contrast radiographic studies ● Fiberoptic endoscopy several cost-of-illness studies of the disease. Physiologic function tests Third, we review the development, dissemina- ● Gastric secretory testing tion, health benefits, and resource costs of Therapeutic interventions cimetidine. As a framework for the analysis of Medical cimetidine, we use the general benefit-and-cost ● Antacids ● Anticholinergics model for evaluating medical interventions and ● Cimetidine a set of questions provided in a section of this Surgical case study entitled “Guidelines for Review of ● Partial gastrectomy ● Truncal vagotomy, with antrectomy or drainage Health Care Benefit-and-Cost Analyses. ” We procedure offer a critique of one major analysis of cimeti- ● Highly selective vagotomy dine’s costs and benefits and end with sugges- .— —. aDeSCrlptlOnS of Some of these lnterv~nt;ons are prov!ded later lri~h Is st Udy tions for further research.
THE BENEFIT-AND-COST MODEL FOR MEDICAL INTERVENTIONS
Every assessment of the benefits and costs of fects on the clinical well-being of patients and medical care should apply to an identifiable pa- on other components of the health system. tient population and a specific health interven- These relations and interactions are summarized tion. The ultimate objective of a benefit-and- in the benefit-and-cost model shown in figure 1. cost assessment is to measure the effects that a specific intervention has on the health outcome The principal components of the model are as of those patients and on resource consumption. follows: 1) population, 2) intervention, 3) clin- Implicit in this objective is a societal perspec- ical effects, 4) health system effects, and 5) out- tive. The health and resource outcomes result come. The population may be delineated in from the intervention’s direct and induced ef- terms of a particular diagnosis or pathologic en- ● 8 Background Paper #2: Case Studies of Medical Technologies
Figure 1 .—Benefit-and-Cost Model for Medical Interventions
tity (e.g., peptic ulcer), a risk factor (e.g., The general framework of the model applies cigarette smoking), a clinical sign or symptom to any intervention and patient population. The (e.g., dyspepsia), or a complication of disease detailed components under clinical and health (e.g., gastrointestinal hemorrhage). Interven- system effects, however, will vary with the par- tions are of two broad types: tests, which are ticular disease and intervention being consid- meant to produce information about the clinical ered. Thus, for example, if we were analyzing status of the patient; and treatments, which are an intervention that might affect chronic disease intended to alter the development or course of in the elderly (e.g., a prevention or treatment disease. 2 Clinical effects include any physical or for senile dementia), we would want to consider psychological changes that may alter the health nursing home use explicit] y under health system status of the patient; these effects may be short effects. In general, the components identified for or long term. Health system effects include all clinical effects and for health system effects changes in the methods and means of medical should be: pertinent to the disease and interven- care that are consequent to the initial interven- tion; complete, in that all important effects are tion. The health outcome is reflected in mortali- considered; and mutually exclusive, so that a ty and morbidity, i.e., in the length and quality single effect is not counted twice. They should of life. The resource outcome, resource costs also be components for which readily available and savings, pertains to net effects on social and accurate measures can be obtained. The va- resource consumption. lidity and feasibility of a cost-effectiveness or a benefit-cost evaluation depend on the extent to ‘The distinction between tests and treatments is useful analyti- cally, but not absolute, since, albeit rarely, a therapeutic trial may which the analytic components conform to these also have a diagnostic intent. criteria. According to the model, an intervention itself Consider two interventions, endoscopy and may alter a patient’s clinical status, effect cimetidine, and the population of patients with changes in the health system, and consume re- duodenal ulcer. Both interventions are used in sources. Clinical effects include both the ad- some patients with duodenal ulcer; each is used vantages and risks of care. The direct clinical ef- independently of the other in some patients with fects of a test are typically limited to side effects duodenal ulcer; and both interventions are also and complications, but a test can also alter clini- used, singly or together, in some patients cal status by inducing changes in the health sys- without duodenal ulcer. Moreover, neither in- tem, primarily by altering the choice of therapy. tervention is used in some patients with duo- A treatment is intended to have direct clinical denal ulcer. Compound these partial overlaps effects, but can also alter subsequent use of with additional interventions, add variations in diagnostic procedures (a health system effect) the particular populations for which data are by changing the course of the disease. available, and the magnitude of the problem begins to become apparent. Clinical effects and health system effects can interact in both directions. As illustrated in the The benefit-and-cost framework outlined here model, interactions among the various health is applicable to both BCA, or cost-benefit anal- system components may also occur. Changes in ysis (CBA), and CEA. A BCA assesses the net a patient’s clinical status are likely to alter the value of an intervention by summing all effects future course of medical care for the patient; on a common scale. Typically, both resource and shifts in the medication, hospitalization, expenditures and health outcome effects are surgery, or other care given to the patient are assigned monetary values. A variety of means likely to affect clinical status. to measure the resource value of health benefits have been proposed; the most widely used is ex- Although the model is premised on the appli- pected productivity loss based on discounted cation of a particular intervention for a par- future earnings at the age of death or disability ticular disease, health system effects may not be (31,89). Thus, a BCA converts decreased deaths limited to the target disease entity. For ex- and disabilities into increases in productivity, ample, if an intervention reduces the number of and treats them as the indirect benefits of a physician visits for a particular disease, it could health intervention. These indirect benefits are alter the number of diagnostic tests and amount added to any direct savings in health resource of medication employed for other disease consumption (the direct benefits) to yield a net problems. value. Health outcome typically includes mortality In the cost-effectiveness approach, the aim is measures, such as number of deaths, age-ad- to measure the efficiency with which an inter- justed death rates, or years of life lost. It also in- vention achieves health benefits. The questions cludes morbidity measures, such as quality-of- addressed in CEA are: 1) What is the most effi- life or health-status indexes. Morbidity and cient way to achieve a particular health benefit? mortality may also be combined into a unitary or 2) Given specified available resources, what measure, such as quality-adjusted life years intervention strategy offers the greatest gain in (152) or another multiattribute utility scale (87). health benefit? Answering these questions re- As indicated in the model, morbidity and mor- quires the commensuration of different types of tality also have direct implications for pro- benefits, such as morbidity and mortality, but ductivity and hence for social resource con- permits benefits to be measured in their own, sumption. nonmonetary terms. A cost-effectiveness ap- The benefit-and-cost model for a particular proach is more likely than a benefit-cost ap- population and intervention suggests the com- proach to preserve a sense of intangible health plexity of undertaking a comprehensive assess- care benefits, which in the latter are typically ment of either all uses of a single intervention or noted and left unassessed. Although CEA may all interventions for a particular population. be more suitable for comparing alternative in- terventions for a particular disease, however, ditions) and effectiveness (effects under average BCA is necessary for comparing health care conditions) noted in reports from OTA (112). with other socially desirable uses of resources. Any benefit-and-cost analysis encounters nu- merous conceptual and practical difficulties. If one chooses to develop a decision analysis These range from the presence of uncertainty comparing the use of a particular intervention and the lack of reliable information to questions with its alternatives, the benefit-and-cost model of measurement and methods of aggregation can serve as a useful basis for identifying perti- over persons and time, to value judgments. Sys- nent structural components: chance events (e.g., tematic reviews of methodologic issues in CEA important results of the principal and subse- and BCA in health have been presented by other quent interventions), choices (e.g., use of other authors (149,151). health system components), and outcomes (e.g., net benefits and costs). The decision-analytic Following descriptions of peptic ulcer disease approach is a prescriptive model for choosing and cimetidine in the next two parts of this case among alternative treatment strategies. Even if study, we present an analysis of the costs and technically correct in all assumptions and com- benefits of cimetidine in peptic ulcer disease, putations, a decision analysis does not neces- using the general benefit-and-cost model de- sarily predict the management strategies em- scribed above. Later in the case study, we pre- ployed by physicians. In estimating the cost ef- sent a set of guidelines in the form of questions fectiveness of a given intervention, it is equally, to be used in reviewing benefit-and-cost anal- if not more, important to apply a descriptive yses in health care. These guidelines presume model (i. e., to base estimates on changes in familiarity with the basic assumptions and ap- management strategy that occur in practice). proaches in BCA and CEA. We believe they are The distinction between prescriptive and de- helpful for review of benefit-and-cost analyses scriptive assessment is analogous to the differen- of cimetidine such as that presented in the next tiation between efficacy (effects under ideal con- to the last part of this case study.
PEPTIC ULCER DISEASE
Definition and Etiology likelihood of developing duodenal ulcer. These factors include sex, age, blood type, a few A peptic ulcer is a crater that extends through diseases, and habits such as smoking and drink- the full thickness of the mucosa (mucous mem- ing coffee. Despite the popular notion of the brane) of the stomach or duodenum (the first or “high anxiety, ulcer-prone person, ” psy- proximal portion of the small intestine). The chological stress and personality factors have pathologic appearance of benign gastric not been shown conclusively to be related to the (stomach) and duodenal ulcers is similar; both development of ulcers, are believed to be related to too much stomach acid and pepsin for the level of mucosal The gastrointestinal tract is a continuous resistance (82) .3 Although the presence of organ, and there is a continuum in the anatomic stomach acid is necessary for ulcers to develop, location of ulcers in the stomach and duo- the level of acid is often normal in patients with denum. For unknown reasons, peptic ulcers ulcer disease; these patients presumably have show a predilection for areas at or near rnucosal impaired tissue resistance. Sturdevant and junctions (81). Since gastric and duodenal ulcers Walsh (140) list 17 factors other than excessive appear to differ in generic and other features, gastric acidity that may predict increased there are reasons to consider them separately in —..— clinical and epidemiologic studies. Often, how- ‘l)(’p\tn\ ,Ir(’ dIgw[ IL’(’ (,n.ynlc~ th.lt .lre .1[ tlve onlv in the prc\- ever, they are considered together, and the situ- t,n( t’ ()1
per year for men and 1.5 per year for women population at large. However, the previously (105). In the same study, physicians reported cited survey of Massachusetts physicians (105) the incidence of gastric ulcer per 1,000 persons also found that approximately 10 percent of age 25 and over to be approximately 0.35 per male physicians age 65 through 74 at some time year. had duodenal ulcer. The current level is a matter Different epidemiologic studies have found of conjecture, because the lifelong prevalence varying patterns of age-specific incidence of rate of ulcers ultimately depends on age-specific duodenal and gastric ulcer. In general, the in- incidence rates, and these rates appear to be cidence of duodenal ulcer appears to rise grad- declining, ually with age or to remain essentially constant Ulcer disease appears to have been occurring above age 35, and the incidence of gastric ulcer less frequently or less severely, or both, over the appears to rise more dramatically above age 40. past 20 years. This conclusion derives from sev- Bonnevie (18) found the age-specific incidence eral lines of clinical and epidemiologic evidence. rate of duodenal ulcer to increase gradually in These include overall declines in rates of mor- both sexes to a maximum of 3 per 1,000 inhabi- tality and hospitalization due to ulcer disease, tants between age 75 to 79. Gastric ulcer showed and, especially, several age-cohort analyses of a more dramatic rise in incidence above age 40, the incidence and mortality of ulcer disease. peaking at a level of about 1 per 1,000 for men age 60 to 64 and for women above age 70 (19). Susser (141,142) deduced from age-specific Among Massachusetts physicians surveyed in mortality rates between 1900 and 1960 that the late 1960’s, the incidence of duodenal ulcer there was a decrease in risk of ulcer disease in in both sexes appeared to increase up to age 25 each successive age cohort, producing a rise in to 34, and then to remain fairly constant; gastric the mean age of patients. This decline was cor- ulcer in male physicians continued rising to a roborated by a cohort analysis conducted by peak at age 65 to 74 (105). Fry’s review of his Monson and MacMahon in their survey of Mas- patient experience showed duodenal ulcers sachusetts physicians (105). Monson and Mac- reaching their peak incidence in both sexes in Mahon found the age-specific risk of developing the decade 1930-39 and gastric ulcers reaching ulcer disease among physicians born between their peak some 20 years later in the decade 1922 and 1932 to be much lower than the rate 1950-59 (57). for those born in the preceding 20 years. A study of British physicians found a 40-percent The aforementioned incidence figures are sub- decrease in the incidence of duodenal ulcer stantially lower than the rates found in recent disease between 1947 and 1965 (103). household interview surveys conducted by NCHS (35,36). After we review evidence con- U.S. mortality from ulcer disease has declined cerning the prevalence and changes in the oc- steadily since the early 1960’s (see table 2 and currence of ulcer disease during the past 20 fig. 2). The age-adjusted mortality rate dropped years, we will discuss NCHS’s Health Interview by two-thirds in 1977 from its 1962 peak level Case Study #11 Benefit-and-Cost Analysis of Medical Interventions: The Case of Cimetidine and Peptic Ulcer Disease ● 15
Table 2.–Number of Deaths in the United States With Ulcer Disease as the Primary Cause, 1960-79 — Peptic, site Year Gastric Duodenal unspecified Gastrojejunal Total 1960 ...... 5,707 5,653 — 322 11,682 1963 ...... 6,330 5,831 — 244 12,405 1966 ...... , ...... 5,599 4,722 — 197 10,518 1968 ...... 3,829 4,413 1,218 721 10,181 1969 ...... 3,719 4,381 1,212 798 10,110 1970 ...... 3,502 3,916 1,189 739 9,346 1971 ...... 3,385 3,680 1,055 700 8,820 1972 ...... 3,274 3,510 1,132 756 8,672 1973 ...... 3,289 3,385 1,014 765 8,453 1974 ..., ...... 3,050 3,048 971 751 7,820 1975 ...... 2,900 2,920 923 710 7,453 1976 ...... 2,834 2,686 908 698 7,126 1977 ...... 2,669 2,452 779 662 6,562 1978 ...... — — — — 5,550’ 1979 ...... — — — — 5,560b aprellmtnary flgure5, extrapolated from a10-PercentsamPle bprehmlnary~gure5 extrapolated froma IO percent sampleoverthe first 6monthsof 1979 SOURCE National Center for Health Statlsttcs, D!vlslonof Vital Statlstlcs, Hyattsvflle, Md
Figure 2.— Deaths in the United States With Ulcer (see table 3), Hospitalizations for ulcer disease Disease as the Primary Cause, 1966-79 have also declined steadily in both the United States (see table 4 and fig. 3) and Great Britain (21). The drop in U.S. hospitalizations appears mainly due to a fall in admissions for duodenal ulcer, whereas the drop in Great Britain is due more to declining admissions for gastric ulcer. Mendeloff (104) reported a sO- percent decline in the number of diagnoses of duodenal ulcer between 1960 and 1972 among an apparently constant population in the U.S. armed forces. Data from a large U.S. manufacturing company showed a 56-percent drop in episodes of disabil- ity due to duodenal ulcer and a 68-percent drop in episodes of disability due to gastric ulcer be- tween 1960 and 1970 among male employees (3). 6,000 Some of these trends might be explained by the advent of a dramatic and continuing im- 5,000 t provement in the prevention and care for ulcer disease during the past 20 years, but no likely candidate representing this can be found (21). 1965 1970 1975 1980 The data are consistent with a shift in the spec- Year trum of ulcer disease toward less severe forms, a possibility posited by Mendeloff (104). Such a Note: 1978 and 1979 figures are preliminary. shift may accompany what appears to be the
SOURCE Based on data from the National Center for Health Stat{ stfcs, DIvI- simplest explanation: Ulcers are occurring less slon of V!tal Statlstlcs Hyatt svllle Md frequently than they did previously. The rea- 16Ž Background Paper #2 Case Studies of Medical Technologies
Table 3.—Mortality Rates in the United States sons for the apparently declining incidence and for Deaths Due to Ulcer Disease 1953-78 severity of ulcers are matters for speculation, —— Age-ad lusted rate per b Year 100,000————— populatation— Crude rate The data on ulcer disease from the Health In- 1953 ...... 5.1 terview Survey of NCHS warrant separate con- 1958 ...... 5.3 sideration for three reasons. First, the Health ln- 1960 ...... 5.2 1961 ...... 5.2 terview Survey data are gathered in a unique 1962 ...... 5.4 manner; they are based on self-reported condi- 1963 ...... 5.2 tions in household interviews. Second, es- 1964 ...... 4.6 1965 ...... 4.3 timates of disease incidence and consequences 1966 ...... 4.2 obtained from Health Interview Survey data are 1967 ...... 3.9 substantially greater than those obtained from 1968 ...... 3.7 1969 ...... 3.6 other sources, including other NCHS sources 1970 ...... 3.2 and epidemiologic studies such as those de- 1971 ...... 3.0 scribed above; also, estimates from the Health 1972 ...... 2.9 1973 ...... 2.7 Interview Survey show little change between the 1974 ...... 2.4 years 1968 and 1975. Finally, the survey data 1975 ...... 2.2 deserve special attention, because they are used 1976 ...... 2.1 1977 ...... 1.8 to estimate some of the costs and benefits of 1978 ...... — treatment for ulcer disease that we review later aRates~hown lncludegastrlc, duodenal, andpeptlc ulcer (siteunspeclfled) in this case study. bAdJusted to 1940 population, the standard population used by the National Center for Health Statlstlcs Household surveys of chronic digestive SOURCE National Center for Health Statlstlcs, Dlvlslon of Vital Statlstlcs, Hyattsvdle, Md diseases in the United States were conducted in
Table 4.—Number of U.S. Hospital Discharges With Ulcer Disease Diagnoses, 1966-78
Peptic, site a Year Gastric ——-..—Duodenal unspecified .Subtotal—————Gastrojejunal— —------Totalb -.. Ulcer as first-listed diagnosis 1966 ...... 166,100 345,200 — 511,300 14,700 526,000 1970 ...... 89,200 273,500 68,300 431,000 7,400 438,400 1971 ...... 94,100 251,400 68,600 414,100 6,600 420,700 1972 ...... 99,300 241,400 81,200 421,900 7,400 429,300 1973 ...... 102,900 227,100 68,100 398,100 7,200 405,300 1974 ...... 101,500 239,800 75,300 416,600 8,700 425,300 1975 ...... 101,500 224,100 77,000 402,600 9,100 411,700 1976 ...... 103,400 194,000 81,100 378,500 6,900 385,400 1978 ...... 105,100 166,300 81,900 353,300 7,200 360,500 Ulcer as a listed diagnosis 1966 ...... 223,800 464,300 — 688,100 17,500 705,600 1970 ...... 127,200 384,200 108,900 620,300 9,100 629,400 1971 ...... 137,200 358,600 110,800 606,600 9,100 615,700 1972 ...... 147,300 362,300 131,800 631,400 9,500 640,900 1973 ...... 149,800 339,900 123,700 613,400 9,600 623,000 1974 ...... 156,400 360,200 136,100 652,700 11,200 663,900 1975 ...... 158,400 336,200 150,300 644,900 12,400 657,300 1976 ...... 160,700 302,300 158,300 621,300 10,700 632,000 1977 ...... 173,000 285,900 159,300 618,200 8,700 626,900 1978 ...... 165,400 279,400 184,600 629,400 10,800 640,200 — afncludes gastric, duodenal, and peptic ulcer (Site unspecified) blncludes gastric, duodenal, pept(c (site unspecified), and 9aStr0Je]LInal ulcer SOURCE. National Center for Health Slatistlcs, National Hospital Discharge Survey, Hyattsvllle. Md Case Study #11: Benefit-and-Cost Analysis of Medical Interventions, The Case of Cimetidine and Peptic Ulcer Disease ● 17
Figure 3.—U.S. Hospital Discharges With Ulcer Table 5.—Ulcer Disease in the United States Disease Diagnoses, All Sites, 1966.78 According to the Health Interview Survey, NCHSa
750 Measure 1968 1975 1978 Number of conditions (in 000’s) 3,360 3,955 3,778 Prevalence per 1,000 personsb. 17.2 18.9 17.7 Incidence per 1,000 personsc. 3.0 2.9 – 700 Ever hospitalized for ulcer disease...... 40.60/0 38.30/0 — Ever had surgery for ulcer disease...... 6.90/o 8.1% — 650 Currently under M.D. care. . . . . 61.1 0/0 65.40/o — M.D. visits in past 12 months: 0...... 32.4% 36.1% — 1 17.1% 17.8% — 600 2 to 4 : : : : : : : : : : : : : : : : : : : : 23.70/o 26.30/0 — 5 or more...... 18.20/o 15.80/o — Unknown ...... 4.60/0 4.00/0 — Number of bed-disability daysd: 550 0...... 74.5 74.5 — 1 to 3, ., ...... , . . — 7.4 – 4 to 7 ...., ...... — 5.2 – 8 to 14 ...... 4.9 4.4 — 500 15 to 30 ...... 3.6 3.6 – 31 or more...... 3.4 2.2 –
alnClude~ ~astrlc duodenal, pep~lc (site unspeclfled), and 9astrolelunal utcer bcondltlon repor~ed as hav(ng been present at some time durln9 the Year Prior 450 to Interview con set reported as wlthln year prior to lntervlew dA bed.dlsablllty day IS a day In which a person StayS In bed for all or most of the day because of ulcer SOURCE National Center for Health Stat! stlcs, Dwislon of Health Interwew 400 Statlstlcs, Hyattsvllle, Md
350 year reported in the NCHS National Ambula- tory Medical Care Survey (34). In contrast to other epidemiologic evidence for the declining incidence of ulcers, the Health Interview Survey 1965 1970 1975 results show little change, with even a slightly Year increased prevalence between 1968 and 1975.
SOURCE Based on data from the National Center for Health Statistics, Na- These discrepancies may derive from several Iional Hospital Discharge Survey Hyattsville Md sources. Most likely, more people report having ulcers in the Health Interview Survey than ac- by NCHS 1968 and 1975 (35,36). The surveys tually have them. Some individuals without consisted of questions asked at a sample of medical training may think of any stomach households designed to represent the civilian, trouble as “ulcers” and use the specific medical noninstitutionalized U.S. population. Selected term more broadly than is clinically correct. In Health Interview Survey results pertaining to 1975, more than 36 percent of the people who ulcer disease are summarized in table 5. The reported having ulcers in the previous year did projected incidence of new ulcers based on the not see a doctor for that reason. (The propor- Health Interview Survey, approximately tion with newly reported ulcers who were self- 600,000 cases per year, is more than double that diagnosed is not given. ) Many of those who did based on other epidemiologic evidence de- see a doctor may have been treated on the basis scribed earlier. People interviewed at home of symptoms without a definite diagnosis. The reported approximately 7 million physician Health Interview Survey may be an accurate visits for ulcers in 1975, nearly triple the 2.5 summary of what the noninstitutionalized pub- million physician visits for ulcer disease that lic reports, but that is not the same as an ac- 18 ● Background Paper #2: Case Studies of Medical Technologies
curate epidemiologic assessment of a disease Call (128), These investigators defined an problem. episode of duodenal ulcer illness as a 6-month
period beginning with the date of diagnosis of Cost of Illness duodenal ulcer. They assessed the cost of treat- ing episodes of duodenal ulcer disease for Studies of the cost of peptic ulcer disease are nonhospitalized patients treated at the Palo Alto among the earliest efforts by economists to Medical Clinic in 1964 (35 patients) and in 1971 assess the costs of individual diseases (14). (27 patients). In constant dollar terms, th Beginning with the very first studies, a basic e overall cost of treating ambulator patients distinction was drawn between direct costs y with duodenal ulcer declined slightl (but not (health system expenditures to prevent, diag- y significantly) between 1964 and 1971. The nose, and treat the disease) and indirect costs average number of physician visits per patient (economic losses due to morbidity and mortali- during the defined 6-month episode of illness fell ty). Most economic studies measure the indirect from 4.7 in 1964 to 3.8 in 1971. The average costs of illness in terms of loss of productivit y number of X-rays also declined slightly. These due to disabilit from disease and loss of future y decreases were nearly offset by increased productivit due to premature death. y expenditures for drugs. The same basic categories of direct and in- Patient-specific studies are very useful for direct costs continue to be used in contemporary many purposes, but they are not intended to economic analyses of the cost of illness (31,114). provide a cross-sectional view of all costs for all Most researchers take an aggregate approach to patients with ulcer disease in a given time measuring direct costs of disease, using data period. Providin such a view is the aim of from third-part payers, NCHS, and other hos- g y studies that take an aggregate approach to es- pital and physician surveys, and estimating timating direct costs of disease. total expenditures for a given disease population in a given time period, usually 1 year; we will In two recent studies of the cost of ulcer return to these methods shortly. First, however, disease discussed below, the indirect costs of we will mention patient-specific alternatives to ulcer disease were measured by using the measuring direct costs of illness. “human capital” approach of estimating losses in productivity attributable to the disease. A One alternative is to trace over time expend- number of philosophical objections have been itures for a cohort of patients with a particular raised to the “human capital/lost productivity” disease. As far as we know, no such studies of ulcer disease have been published, but at least approach to valuing lives, e.g., productivity measures omit consideration of pain and suffer- one study now under way at the Universit of y ing. Alternative methods for valuing life, such Wisconsin may produce useful information of as a “willingness-to-pay” approach, have been this sort (58). We comment on this stud by y used (1), but not as often as the human capital Weisbrod and Geweke in our discussion of approach. Over the past 20 years, the sophis- cimetidine. Such cohort studies have the ad- tication of lost productivit estimates has in- vantage of being patient-specific and may show y creased considerably, and now may include the relationships between interventions and expend- discountin of future earnings, the adjustment itures at one point in time and subsequent clin- g of future earnings for productivit gains, ad- ical courses and health expenditures. Cohort y justments for labor force participating rates, cost studies thus could complement other re- and calculation of productivit loss for people search, possibly as a part of longitudinal studies y performing unpaid housework (31), In addition of the clinical course of disease. to the sophistication of analysis, a second major A second patient-specific approach is to study difference between recent studies of the cost of the cost of treating episodes of illness. Duodenal ulcer disease and the earliest studies 20 years ulcer disease was one of eight medical condi- ago is the greater amount of information now tions studied in this way by Scitovsky and Mc- available about the prevalence, distribution, and health consequences of the disease. As Table 6.—Costs of Ulcer Disease in 1975 as discussed in the previous section of this case Estimated by NCDD and SRI study, however, uncertainty about the evolving (millions of dollars) epidemiology of ulcer disease is a major source Approximate of discrepancies in contemporary estimates of NCDD SRI midpoint the cost of the disease. estimates estimates estimates Direct costs One of the two recent analyses of the cost of Hospitalization . . . . . $501 $ 803 $652 Physician visits . . . . . 123 240 182 ulcer disease that we will now discuss was Drugs ...... 100 undertaken as part of the NCDD assessment of Nursing home care . . 102a 11 108a the socioeconomic impact of digestive diseases Other professional 1 3 } (4). The other analysis was prepared at SRI Subtotal ...... $726 $1,157 $942 under contract with Smith Kline & French Lab- Indirect costs b oratories by Von Haunalter and Chandler Mortality...... $369 $ 357 $ 369c Morbidity ...... 179d 1,116 648 (146). Both the NCDD and SRI studies es- Subtotal ...... 548 1,473 1,017 timated the cost of ulcer disease in 1975, and we focus primarily on those figures. In addition, Total ...... $1,274 $2,630 $1,959 the SRI study projected estimates for 1977; these aT’hl~ ~um represents tfle total for drugs, nursing homes, and other PrOfeSS~Onal costs Figures were not broken down further served as the basis for a major cost-effectiveness bFuture earnings discounted at 25 Percent cThe fllgher NcDD figure IS adopted for reasons explalned In the text study of cimetidine (the study by Robinson dThls figure ,s imputed from Information supplled In the NCDD rePort
Associates (121)) that is reviewed in another SOURCES NCL)D estimates: T P Almy, et al , “Report of the Workgroup on the Socloeconomlc Impact of Dlgestlve Diseases of the Subcommittee part of this case study. on Epldemlology and Impact. ” In Report to fhe Congress of the Urr/fed .Sf.sfes of fhe Nat/ona/ Comm/ss/on on Llges(we Diseases, The costs of peptic ulcer disease in 1975, as 1979 (4) SRI estimates: G Von Haunalter and V V Chandler, Cost of U/cer estimated by NCDD and SRI, are summarized D/sease In Me Un/fed Sfafes, 1977 (146) in table 6. The total cost (direct and indirect) estimated by NCDD is approximately $1.3 table 6). In addition, SRI’s estimates of direct billion; the estimate by SRI is approximately costs for hospital and physician services are $2.6 billion.6 Table 6 also shows a “midpoint notably higher than NCDD’s (see table 6). estimate” of approximately $2 billion. We Closer examination of the sources of these believe $2 billion to be a defensible overall cost discrepanices in direct cost estimates reveals estimate, for reasons we shall explain. Peptic variation in the two studies’ analytic methods, ulcers accounted for less than 1 percent of total as well as shortcomings in data needed for such costs of all illness in 1975 (114), and, according cost estimates. to NCDD figures, health system expenditures Medical care costs attributable to a particular for ulcer were approximately 9 percent of health , disease may be estimated in two ways: 1) by a expenditures for all digestive diseases in 1975. “top-down” approach that begins with total ex- Of the total $2 billion costs for ulcer disease, penses for all disease and imputes to a particular just under half are attributed to health system disease the proportion of costs equal to the pro- costs (direct costs); the rest are attributed to lost portion of total units of service used by patients productivity due to premature mortality and to who have the disease; or 2) by a “bottom-up” morbidity (indirect costs). approach that prices and sums the units of serv- A comparison of the NCDD and SRI esti- ice consumed by patients who have a particular mates by cost category reveals that the discrep- disease. Each approach has its strong points, ancy between them is largely due to differences and ideally, the two would corroborate each in the indirect costs attributed to morbidity (see other. In general, the top-down approach is simpler; by definition, the sum of all top-down ‘Smith Kllne & French markets c]metlcilne. estimates for each disease equals the total *Peptic ulcer cilsease was t~n ly IIne 01 n umert~u~ digestive expenditures for all disease. Theoretically, the diseases t(~r which NCDt) dcvelt~ped cost estimates. The auth(lrs (~t the NCDD rep(~rt ( 4 ) +tate c]ea r] v that they c(~n>i (]er the] r same would be true for bottom-up calculations, est I ma tes to be con scrva t I ve. but such calculations are typically undertaken for a single disease only, and potential in- ($240 million) is approximately double that ob- consistencies between known total expenditures tained by NCDD ($123 million) and, if correct, for all disease and the sum of disease-by-disease would imply that a physician visit for ulcer expenditures bottom-up calculations remain disease is twice as expensive as a typical physi- untested in typical bottom-up calculations. cian visit. Although this seems unlikely, it is im- NCDD and SRI both used a bottom-up ap- possible to judge the difference in the cost of proach to estimate hospital costs due to ulcer physician visits without a more comprehensive disease, but differed in the detailed assumptions analysis. We settled on a $182 million midpoint they employed. NCDD began with the number estimate of the cost of physicians’ services as a of hospital days for each ulcer diagnosis ob- reasonable compromise. tained by the Hospital Discharge Survey of Estimates for remaining direct costs are com- NCHS, and multiplied that number by the parable in the NCDD and SRI studies. We have average charge per hospital day, The average imputed the NCDD figure of $102 million from was obtained from Blue Cross/Blue Shield a more global estimate for selected digestive figures for Federal workers and from medicare diseases that included ulcer disease and was data for patients over 65 years of age. SRI also adopted by NCDD (113). Summing the above began with NCHS figures on numbers of dis- components for each report, we find that the charges, but it used a more complicated calcula- estimated direct costs presented in the two tion that involved an estimated proportion of reports differ by more than $400 million: surgical and nonsurgical cases from the Com- NCDD, $726 million; SRI, $1,157 million. Our mission on Professional and Hospital Activities final midpoint estimate is $942 million. (CPHA), an allocation to hospitals of different sizes based in part on American Hospital Asso- Indirect cost estimates for ulcer mortality loss ciation data, and estimated daily costs based on are straightforward. NCDD and SRI used iden- information from disparate sources combined in tical methods to estimate lost future earnings an unspecified manner. The end result of SRI’S from death due to ulcer. The small difference in calculation was an estimate of hospital costs the two studies’ figures for mortality loss ($803 million) that is approximately 60 percent (NCDD, $369 million; SRI, $357 million) is larger than NCDD’s estimate ($501 million). presumabl y due to the fact that SRI used Further exploration of the discrepancy between smaller, preliminary mortality figures (6,840 the two figures would require more details deaths) rather than the final NCHS figures about the calculation:; than was provided in (7,245 deaths) that NCDD used. We have either report. Interestingly, and usefully, SRI adopted NCDD’s $369 million estimate. also applied a top-down cross-check using esti- The very large difference in the NCDD and mated hospital expenditures for 1975 and the SRI studies’ estimated ulcer morbidity costs proportion of ulcer hospital days to total hos- pital days, and came up with an estimated cost (NCDD, $179 million; SRI, $1,116 million) stems from several sources. Most important, of $738 million, reasonably close to our $652 SRI attributed to ulcer disease morbidity as mill ion midpoint estimate for this cost compo- estimated in the Health Interview Survey cond- nent. ucted by NCHS in 1975. As discussed earlier, To estimate the cost of physician services, the Health Interview Survey estimates are based NCDD used a top-down approach, multiplying on the responses of people interviewed at home the cost of all physician services for fiscal year who say they have had an ulcer at some time 1975 by the proportion of total visits attribut- during the past year. These estimates are in- able to ulcer. SRI used a bottom-up approach, consistent with other evidence for the declining multiplying units of service (computed separate- prevalence of ulcer disease, and they almost ly for initial and followup visits) by unit costs, surely overestimate morbidity due to the dis- estimated on the basis of multiple sources. SRI’s ease. Furthermore, SRI assumed that the eco- estimate for physician visits for ulcer disease nomic effects of work loss are distributed by age in the same way the disease is distributed. Since would be very close to our midpoint estimate of older patients tend to lose more days of work $648 million. and earn less per day, the assumption of uni- The magnitude of indirect cost estimates is form effects inflates the actual productivity loss. very sensitive to the rate at which future costs This flaw is acknowledged in SRI’s report, but are discounted. Both NCDD and SRI discounted no correction or sensitivity analysis is offered. future earnings at 2.5 percent, although NCDD Ulcer patients who continue to work might have also presents some alternative calculations at a lower productivity, and this effect, also omitted 10-percent discount rate. Economists agree from SRI’s calculations, would increase the ac- more on the appropriateness of discounting tual loss of productivity due to ulcer disease and than on the appropriate rate to employ, but 2.5 tend to offset the effect of the assumption about percent is at the very low, end of the spectrum. age distribution. The smaller the discount rate, the higher the NCDD considered and expressly rejected present value of future earnings and the higher using data from the Health Interview Survey, the apparent indirect cost of illness. For exam- because “there were also serious questions ple, the “present” value of lifetime earnings for a raised by experts in digestive diseases about the 32-year-old man in 1975 was $148,195 at a 2.5- validity of the self-reported diagnosis-specific percent discount rate and $176,882 at a IO-per- morbidity information” (4). Instead, NCDD ac- cent discount rate (4). This is not a differential cepted a more global estimate of morbidity loss point between the NCDD and SRI analyses, due to 15 different digestive diseases, including since they both used the same low discount rate, liver disease, gallbladder disease, and hernia but the reader should be aware of the large dif- (113). The NCDD figure for morbidity loss due ference a change in the discount rate can make to ulcer disease shown in table 6 is approximate- and be wary of unadjusted comparisons be- ly 6 percent of that total, a percentage equal to tween these and other cost-of-illness studies that the ratio of the mortality cost for ulcer com- may use different discount rates. In addition, pared to that for all 15 diseases.7 The NCDD “present” values are usually expressed in terms report also refers to data collected for an earlier of dollars in the base year. Estimates discounted review of the medical and socioeconomic im- to different base years will differ in part because portance of digestive disease, published by of inflation and are directly comparable in re- Almy and his coworkers (3). That earlier source cost terms only if adjusted into constant publication included data on absenteeism due to dollars. digestive disease at a large northeastern U.S. In the SRI analysis, Von Haunalter and manufacturing company during the 13-year Chandler extrapolated their estimated costs to period from 1959 to 1972. In persons who 1977 (expressed in 1977 dollars) by assuming missed 3 or more days of work during that peri- variably inflated rates for different unit costs of od due to 1 of the 15 digestive diseases covered medical care and a 2-percent annual increase in by the NCDD morbidity estimate, more than 20 the number of persons with ulcer disease (see percent of days lost were attributed to ulcer. We table 7). The presumed 2-percent annual in- do not propose translating such figures, ob- crease, based on responses to the Health Inter- tained over a 13-year period from one large view Survey in 1968 and 1975, is contrary to all firm, to a national estimate of days of work lost other indicators of the changing epidemiology in a later year. However, if ulcer disease does of ulcer disease; it is also contradicted by sub- account for 20 percent of the total morbidity sequent preliminary data obtained in the 1978 costs assigned to the 15 digestive diseases in the Health Interview Survey (see table 5, p. 17). The NCDD report, the NCDD morbidity figure presumed growing population with ulcers is also treated by Von Haunalter and Chandler as having the identical age distribution and spec- trum of disease severity as assumed for the population in 1975. Their assumptions about 22 ● Background Paper #2 Case Studies of Medical Technologies
Table 7.—Costs of Ulcer Disease in 1975 and 1977 as Summary Estimated by SRI (millions of dollars)a — — We may summarize the salient clinical and 1975 1977 epidemiologic features of peptic ulcer disease as Direct costs follows, Hospital care...... $ 803 — $1,072 — Physicians ...... 240 — 283 – Ulcers probably have multiple causes, but Drugs ...... “loo — 113 — Nursing home care . . 11 — 15 — gastric acid and pepsin appear to be necessary Other professional . . 3— 3– ingredients. Epigastric pain is often a prominent Subtotal ...... $1,157 440/o $1,486 460/0 symptom of peptic ulcers, but the clinical pres- Indirect costsb entation is variable. Furthermore, typical ulcer Mortality...... 357 — 408 — symptoms may be caused by conditions other Morbidity ...... 1,116 — 1,330 — than ulcers. A definite diagnosis requires direct Subtotal ...... 1,473 56% 1,738 54% visualization by endoscopy or radiographic Total ...... $2,630 1000/0 $3,224 1000/0 imaging of the ulcer. Specific treatment of ulcer aFl~Ur~~ fOr 1975 and 1977 are expressed In terms of dollars In the re’ disease is directed at reducing the presence or ef- spectlve base years, not In constant dollars fects of gastric acid. SOURCE Adapted from G Von Haunalter and V V Chandler, Cos/ of U/cer D}sease In rhe Un//ed Stales, 1977(1 46) Ulcer disease is a chronic condition with spontaneous remissions and recurrences. Rates of complication and mortality from ulcers are these characteristics of the presumed growing relatively low. Excessive mortality appears to be ulcer population are questionable for reasons present only in the first year or so following discussed in the section of this case study above diagnosis. Little reliable information exists on epidemiologic patterns of peptic ulcer about the natural history of ulcer disease in the disease. Von Haunalter and Chandler’s projec- general population. tion of the population with ulcers to 1977 thus compounds the problem of overestimation of Peptic ulcer is a common condition that af- the costs of ulcer disease, particularly indirect fects millions of Americans at some time during costs. Some specific estimates that feed into their lives. The best available epidemiologic direct costs are also Inappropriately projected evidence suggests that about 250,000 Americans upward. For example, the percentage of hospi- develop new peptic ulcers each year. New duo- talized patients undergoing surgery for ulcer denal ulcers are more than four times as com- disease is presumed in the analysis to increase mon as new gastic ulcers. Some studies have between 1975 and 1977. According to data from found that the incidence of duodenal ulcer rises both NCHS and CPHA (42), however, the per- gradually with age, others have found that it re- centage actually decreased (see table 8). mains fairly constant after age 35. After age 40,
Table 8.—NCHS and CPHA Data on Number of Selected Surgical Procedures (partial Gastrectomy, Vagotomy) in the United States, 1966-78 .— — —.——— —— – — Partial gastrectomy Vagotomy Total Year NCHS CPHA NCHS — — CPHA —.—.—NCHS CPHA 1966 ...... 74,500 — 61,200 — 135,500 — 1970 ...... 55,800 59,000 62,800 30,000 118,600 89,000 1971 ...... — 57,000 — 28,000 — 85,000 1972 ...... 63,300 52,000 59,300 24,000 122,600 76,000 1973 ...... — 52,000 — 27,000 — 79,000 1975 ...... 53,300 45,000 52,800 23,000 106,100 68,000 1976 ...... 54,200 45,000 48,300 16,000 102,500 71,000 1977 ...... 51,100 37,000 45,500 19,000 96,600 56,000 1978 ...... 39,700 29,200 29,200 17,000 68,900 46,000 —. —————————— — — sOURCES fVCHS data: National Centfr for Health Statistics, National Hospital D!scharge Survey, Hyaltsvllle, Md CPHA data: Commlsslon 01 Professional and Hospital Acttvltles data compiled by J D Elashoff and M I Grossman, 1960 (42) the incidence of gastric ulcer appears to rise based on data from the Health Interview Sur- more dramatically than the incidence of duo- vey, which is an inflated indicator of disease- denal ulcer. Duodenal and gastric ulcers are epi- specific morbidity. In both the NCDD and SRI demiologically distinct. Several lines of clinical studies, estimates of indirect costs are based on and epidemiologic evidence suggest that over the relatively low discount rate of 2.5 percent, the past 20 years the occurrence of new ulcers although the NCDD report also supplied esti- has declined, or ulcer disease has become mates based on a lo-percent discount rate. SRI generally less severe than it was at one time, or also projected an estimate of peptic ulcer costs both. in 1977. Because of unwarranted assumptions of growth in the morbidity of ulcer disease and the The basis for some estimates of the costs of use of more expensive resources, the problem of ulcer disease and benefits of treatment is the overestimated costs is compounded for 1977. Health Interview Survey of NCHS. Results of the survey, based on self-reported conditions in We have briefly noted alternatives to cross- a household survey, however, appear to over- sectional expenditure assessments of the direct estimate the occurrence and consequences of costs of illness, including tracking patient co- ulcer disease. horts over time and measuring costs of treating episodes of illness. Results of a study of the lat- We estimate that the costs of ulcer disease in ter type in one setting found that an episode of 1975 were approximately $2 billion (see table 6, duodenal ulcer disease cost approximately the p. 19). Just under half of this total was due to same to treat in 1971 as in 1964, in constant health care expenditures (direct costs), and the dollar terms. remainder was due to productivity losses from The human capita] approach is the principal morbidity and mortality (indirect costs). our method used to assess indirect costs of illness. In estimate is based on a review of two independ- general, lost productivity is measured as the ent analyses of the costs of ulcer disease, one present value of discounted stream of future prepared by NCDD (4) and the other by SRI earnings. Use of a smaller discount rate in- (146). The NCDD and SRI studies estimates Of creases the present value of future earnings, the total costs of ulcer disease in 1975, $1.3 thereby increasing apparent costs of illness due billion and $2.6 billion, respectively, differ by to morbidity and premature death. approximately $1.3 billion. The approximately $400 million difference between the two studies’ The next four parts of this case study deal direct cost estimates (NCDD, $726 million; SRI, with the evaluation of cimetidine in peptic ulcer $1,157 million) arises in part from differences disease. We begin with background on the de- in the studies’ methodologies (top-down v. velopment and dissemination of cimetidine. bottom-up calculations) and in part from dif- Then we explore current understanding of the ferences in their more detailed assumptions and costs and benefits of this drug in the treatment procedures. The approximately $900 million of peptic ulcers, using the general benefit-and- difference in the two studies’ indirect cost esti- cost model as a framework. Finally, we critique mates (NCDD, $548 million; SRI, $1,473 mil- a major report on the costs and benefits of cime- lion) reflects differences in the two studies’ pro- tidine and offer a few suggestions for further jected morbidity losses. The higher estimate is research.
CIMETI DINE
Physiologic Rationale and but three chemical substances in the body are Development also known to stimulate acid secretion in the stomach: acetylcholine, gastrin, and histamine. The major physiologic stimulant to acid The first two are clearly involved in the physio- secretions in humans is the ingestion of food, logic release of acid; histamine appears to 24 Ž Background Paper #2: Case Studies of Medical Technologies
potentate the action of other acid stimulants cimetidine, Black and his colleagues developed, (136). Even before the physiologic role of hista- tested, and rejected more than 700 different mine was well understood, some researchers compounds (135). believed that a drug that would block histamine Cimetidine powerfully inhibits all phases of stimulation of gastric acid would be of great gastric acid production. The drug not only in- value in the treatment of ulcer disease. Conven- terferes with histamine-stimulated acid output, tional antihistamines have no effect on his- but also inhibits the effects of gastric and tamine receptors in the stomach. acetylcholine. Preliminary studies found that a By the mid-1960’s, J. W. Black and his col- 300 mg oral dose of cimetidine reduced noc- leagues at the British laboratory of Smith Kline turnal and basal acid secretion by 90 to 95 per- & French Laboratories (the pharmaceutical divi- cent (74,97). Cimetidine also lowers the acid sion of SmithKline Corp. ) had set up a research response to food by 70 percent, a reduction program to develop new kinds of histamine twice that ach eved by anticholinergic agents blockers. Their strategy in this effort was simi- (46,120). lar to that which had led to their successful development of beta-adrenergic blockers, name- Diffusion ly, systematic chemical manipulation to create nullifiers of the parent drug’s effects (136). They After prelim nary trials, cimetidine was re- reported their first successful effort in 1972 (12). leased for use in Great Britain in November This work demonstrated the existence of a 1976. FDA recognized the clinical promise of cimetidine and rated it 1A, FDA’s highest clas- new class of histamine receptors, designated H2- receptors, which were distinct from the classic sification, meaning the drug is a new molecular entity believed to represent a major therapeutic H1-receptors. The new histamine antagonist, called burimamide, was very effective in sup- advance over other drugs (47). FDA approved pressing stomach acid production, not only in cimetidine on August 16, 1977 (50), for up to 8 response to histamine, but from other stimuli weeks use in patients with duodenal ulcer dis- as well, Burimamide had to be injected to be ef- ease and in patients with hypersecretory condi- fective, and it was supplanted by an orally ac- tions such as Zollinger-Ellison syndrome, sys- tive Hz-receptor antagonist, metiamide. This tematic mastocytosis, and multiple endocrine drug was used in human trials in 1974, but was adenomas. Although cimetidine is not yet offi- abandoned when it was found to cause granu- cially approved in the United States for longer locytopenia and agranulocytosis (growth of term use, some physicians use it for more than 8 fewer white blood cells than normal) and at weeks in patients with duodenal ulcer (7). least one fatality (24,45). The chemical metia- The use of cimetidine spread rapidly in U.S. mide possessed a thiourea side chain that was clinical practice. By the beginning of 1978, believed to be the offending component, and it private practitioners prescribed cimetidine in was replaced by a cyanoguanidine chain. The approximately 40 percent of ambulatory visits result of this chemical manipulation was the made by patients with duodenal ulcers, By
third H1-receptor antagonist, cimetidine (SKF March 1978, the proportion of such visits result- Tagamet®). 8 Along the way to the discovery of .—— ————-. ing in a prescription for cimetidine reached ap- “The structural similarities of histamine and H, antagonists are proximately 60 percent, where it has remained evident from their chemical structures. — ——— since that time. A substantial fraction of total Structure ambulatory use of the drug, perhaps as much as Compound half, is for patients with acid reflux, gastritis, name Imidazole ring Side Chain (R) gastric ulcer, or problems other than duodenal Histamine A{ -C H CH NH 9 HN + N 2 2 2 ulcer. Hr{ Burimamide HN ~ N -CH2CH2CH2CH2CH2CH2CH2NHCNHCH, CH, 1{ s Meteamide HNx + N -CH2SCH2CH2NHCNCH , “Estimates based on figures published by the National Disease Lti, R !+ Therapeutic Index, which obtains reports of clinical practices from Cimetidine HN w@ N -CH 2SCH 2CH 2NHCNHCH , a sample of private practitioners. N-C = N Case Study #11 Benefit-arid-Cost Analysis of Medical Interventions. The Case of Cimetidine and Peptic Ulcer Disease ● 25
The amount of cimetidine used by hospital- cimetidine worldwide .10 A conservatively esti- ized patients is more difficult to estimate direct- mated 1.5 million to 2 million ambulatory U.S. ly, but such use is widespread. In addition to be- patients with ulcer disease and ulcer-like symp- ing used in patients with ulcer disease, the drug toms were treated with cimetidine in 1978.11 has been used to prevent and treat stress-related Cimetidine has thus become one of the most gastritis and bleeding (39,100). Many physicians widely used pharmaceuticals in the world in a are probably using cimetidine in seriously ill pa- remarkably short time. Part of the reason for tients who are susceptible to gastrointestinal this success rests in the widespread prevalence hemorrhage (48). A recent randomized trial of of ulcer disease and ulcer-like symptoms. Smith- patients hospitalized in an intensive care unit KIine pioneered and persevered in developing found that regular antacid therapy is more effec- and marketing a new class of pharmaceutical tive than cimetidine in preventing gastrointes- agents. Furthermore, as discussed in the next tinal bleeding (117). part of this case study, a substantial number of controlled trials attest to the effectiveness and From a commercial viewpoint, cimetidine is a relative safety of this drug in the treatment of spectacularly successful product. In 1977, cime- ulcer disease. tidine was marketed in 65 countries; in 1978, it 10This estimate follows from high and low estimates, as shown: was sold in 90 countries. In 1977, SmithKline High estimate Low estimate reported sales of gastrointestinal drugs of $90.5 Retail value of sales $500 million $300 million million; in 1978, sales of these drugs were $315 – Retail price per tablet $0.25 $030 = Number of tablets (A) 2 billion 1 billion million. In its 1978 annual report, SmithKline Weekly number of tablets 28 28 x Mean weeks of treatment 5 6 stated that Tagamet® was its most important = Number of tablets patient (B) 140 168 single product (135). Worldwide sales to hospi- Estimated number of patients (A/B) 14,300,000 6,000,000 11 tals and pharmacies in 1979 probably exceeded This estimate is based on a conservative projection of the num- bers of Americans living at home who report ulcer disease in 1968 $400 million. This translates into a rough esti- and 1975 and the proportion who visit their physicians for this mate of 10 million patients per year consuming problem at least once in the year (36).
THE BENEFIT-AND-COST MODEL APPLIED TO CIMETIDINE
Elements in the Analysis ulcer disease. Clearly, the model requires a very large amount of data. It is not possible in this The major components of the benefit-and- review to discuss potential sources of data for cost model presented earlier in this case study every estimate that follows each choice of strat- are shown in table 9. Listed under each compo- egy. Rather, we select for discussion the major nent are a number of measures pertinent to elements of information required by the model cimetidine. Ideally, benefit and cost estimates and the available evidence. would be made separately for each class of pa- tients that might be treated with cimetidine. The Our primary emphasis is on patients with basis for separating groups of patients could be duodenal ulcer, the most common form of ulcer demographic features (e.g., age, race, sex), clin- disease; we discuss patients with gastric ulcer in ical diagnosis (e. g., duodenal ulcer, gastric less detail. In addition to being used in these pa- ulcer, Zollinger-Ellison syndrome), or stage of tients, cimetidine is sometimes used in patients 12 disease (e.g., number of days since diagnosis, with gastrinoma. The traditional treatment for previous treatments, complications). patients with gastrinomas includes gastrectomy Figure 4 is a paradigm decision-tree that dis- I zThlS is a ~asl rin-secret ing tumor, usual ]y located In the Pan- plays the sequence of decisions and chance creas. It causes the Zoll inger-Ell ison syndrome of severe ulcers, in- tractable pain, and diarrhea. First described In 1955, the Zollinger- events that follow from the initial choice of in- Ellison syndrome has been recorded in more than 2,000 cases in the tervention in a particular group of patients with literature (101 }. 26 ● Background Paper #2: Case Studies of Medical Technologies
Table 9.—Components and Measures of (excision of the whole or part of the stomach) Components in a Benefit-and-Cost time of surgery for the primary tumor, but Analysis of Cimetidine cimetidine has been employed successfully as an
Clinical effects ● Number/time period alternative to gastrectomy in these patients Short-term Hospitalization (99,138). Because of the rarity of gastrinoma as ● Healing ● Number/time period a cause of ulcer disease, the costs and benefits of ● Relief of symptoms ● Duration ● Side effects and Surgery the use of cimetidine in patients with this disease adherence ● Number/time period are not significant from a societal viewpoint. ● Complications ● Type Since the clinical value of cimetidine for ● Recurrence Other Long-term ● Non-M. D. provider visits nonulcer disease such as dyspepsia (94) and up- . Recurrence ● Nursing care per gastrointestinal hemorrhage (41) is outside ● Side effects and Outcome the scope of this report, we do not address it adherence Health ● below. We limit our focus to elements of the Complications . Mortality Health system effects —Number of deaths cost effectiveness of cimetidine in peptic ulcer Medication —Age-adjusted mortality disease and do not attempt a global assessment ● Antacids —Years of life lost of the value of this drug. ● Anticholinergics ● Morbidity . Diet —Days and severity of . Other pain Clinical Effects Diagnostic tests — Days of disability Ž Laboratory Resource costs and savings No treatment for duodenal ulcer has been ● Monitoring chemistries ● Days of work lost . Imaging —Premature death subjected to as many randomized, controlled, —X-ray —Temporary and double-blind studies as cimetidine has (68). —Endoscopy permanent disability These studies of cimetidine vary in their metho- ● Physiologic function ● Cimetidine purchase dological stringency and completeness. In a re- ● Gastric acid ● Implications of health Physician visits system effects view of the quality of 10 published, random-
ized, controlled trials of H2 antagonists (includ-
Figure 4.—Paradigm Decision Tree: Cimetidine and Alternative Intervention Strategies
Patient population: Initial treatment Patient adherence Clinical effect: Clinical effect: Disease/stage/ decision to treatment Healing (in a given Pain relief in a I I demographic features I regimen (spectrum) time period) I given time period I I I spectrum I (spectrum)
❑ : Decision node (matters of choice) O: Chance node (probabilistic events) Figure 4.— Paradigm Decision Tree: Cimetidine and Alternative Intervention Strategies (Continued) Health system effect: Clinical effect: Health system effect: Health system effect: Clinical effect: Number of physician Tests used (yes/no Treatment side Disease course and Change in use of other effects (spectrum) complications medication (by type visits/time period choice for each test I in each time period) (short and long I. (short and long I of medication related I term) . term) 1 to change in clinical 1 I
Outcome: Resource Health system effect: I Health system effect: I Outcome. Health I Surgery (by type, (for each strategy) costs (net, for each Hospitalization (in each strategy) time period) I i n each time period) I I
I I I ❑ Decision node (matters of choice) O Chance node (probabilistic events) 28 ● Background Paper #2: Case Studies of Medical Technologies ing several on metiamide), Chalmers, et al. (25) observed in the proportions healed (67 and 56 rated only one “poor” —a record that compared percent, respectively). [t is evident that the quite favorably with Chalmers, et al. ’s assess- statistical conclusions from this study are dif- ment of clinical trials of other treatments for ferent from the others not because of worse per- ulcer disease. formance of cimetidine, but because of a sub- stantially higher rate of healing within the pla- There is one important methodological differ- cebo group. ence between the controlled studies of ulcer dis- ease done in the 1970’s and those done earlier. In It is possible that the patients in the U.S. trial the more recent studies, fiberoptic endoscopy differed from those in the European studies replaced gastrointestinal X-rays as the means either because of differences in the natural used to verify the presence and healing of ulcers. history of the disease in different countries or This direct visual confirmation of ulcer status because the U.S. subjects tended to be at a dif- can reduce diagnostic errors and consequent ferent stage of illness. For example, some of the variability in experimental results. As a result, earlier European studies were restricted to pa- endoscopy-controlled studies may be more like- tients who were considered candidates for sur- ly to find statistically significant differences in gery. The importance of criteria for patient the clinical effectiveness of various treatments, selection and evaluation, as well as possible variation in the course of disease in different In addition to controlled studies, several sym- countries, was stressed in a Swiss study that posia have been devoted to cimetidine (22,52, found a very high proportion of patients with 150), and a number of review articles have ap- peptic ulcer healing under placebo treatment peared in major medical journals (e.g., 48,126). (125). This work has provided reliable information that can contribute to estimates of clinical bene- It is possible that the discrepant results are fits and risks in a CEA, but a number of impor- partly related to differences in antacid consump- tant areas of uncertainty remain. tion. With one exception (108), all the con- trolled studies permitted ad libitum antacids for Short-Term Clinical Effects all patients. Patients in the European studies were usually provided tablet antacids, which HEALING are less potent than the type of liquid antacid At least 10 double-blind, placebo-controlled used in the U.S. study (81,106). Overall, the studies examining the short-term clinical effects U.S. patients consumed more antacid than their of cimetidine in patients with duodenal ulcers European counterparts. More to the point, have been published in the English language. among the subjects in the U.S. study, placebo- Together these 10 studies (see table 10) provide treated patients whose ulcers healed consumed compelling evidence that cimetidine promotes more antacid than those whose ulcers did not healing of duodenal ulcers. Overall, the rate of heal. (Mean antacid consumption was 12 per- healing in 4 to 6 weeks among cimetidine- cent higher among inpatients whose ulcer healed treated patients was approximately 70 percent, and 112 percent higher among outpatients than almost twice the level achieved by placebo- in those whose ulcers failed to heal; differences treated patients (36 percent). Similar results in median antacid consumption were 68 and 21 were obtained in a half-dozen additional studies percent, respectively. ) conducted in France, West Germany, Italy, and This raises the possibility that a partial Spain (7). therapeutic effect was realized in the placebo One notable exception to the almost uniform- group in the U.S. study. Underlying this pos- ly significant findings of cimetidine’s superiority sibility is the assumption that antacids promote over placebo is the large, multicenter U.S. study ulcer healing. Antacids have been shown in at by Binder, et al. (11). Among outpatients assess- least two endoscopy-controlled studies to have a ed at the end of 4 and 6 weeks (57 on cimetidine; greater effect than placebo on healing of duo- 54 on placebo), no significant differences were denal ulcer (93,116). One, a study by Lam, et al. Case Study #11 Benefit-and-Cost Analysis of Medical Interventions. The Casc of Cimetidine and Peptic Ulcer Disease ● 29
Table 10.—Short-Term, Double-Blind, Placebo-Controlled Studies of Cimetidine: Effect on Duodenal Ulcer Healing
Cimetidine v. placebo; Cimetidine Placebo Cimetidine significant Investigator a daily dose Duration Number of Number/o/. Number of Number/o/o difference b healed patients b healed (ps0.05) Study year/country — .— ——..—(grams) . (weeks) patients D1 Bank, et al. (6) 1.2 8 (8) 7 (86%) Yes (p< 0.01) 6 19 (19) 8 (420/o) 1976/South 1.6 11 (11) 9 (82°/0) Africa D2 Bardhan, et al. (8) 1 70 (78) 43 (61 %) Yes (p< 0.001) 4 46 (50) 13 (28°/0) 1979/United 2 64 (72) 45 (70%) Kingdom D3 Binder. et-al. (11) ‘- 12 2 (inpatient) 49 (53) 18 (37%) 43 (45) 24 (56%) Yes (p< 0.05) 1978/United States 2 (outpatient) 27 7 (260/. ) 26 12 (46%) Yes (p< 0.05) 4 (outpatient) 27 (103) 13 (48°/0) 28 (107) 16 (570/’) No 6 (outpatient) 27 17 (63%) 29 } 22(76%) No —— D4 B-lack wood, et al. (13) 1.6 - 6 12 (NA)d 3 (25%) 11 (NA)d 9(82%) Yes (p< 0.025) 1976/United KingdomC . — D5 ‘ Bodemar and Walan(15) 0.8 15 (15) 12 (80°/0) Yes (p< 0.001) 6 14 (15) 2(1 4°/0) 19761 Sweden 1.2 15 (15) 14 (93°/0) D6 Gray, et al. West Germany 1 4 20 (20) 5 (20°/0) 20 (20) 17 (850/o) Yes (p< 0.0005)
D7 Hetzel, et al, (76) 1.2 ‘- 6 42 (44) 16 (380/o) 43 (44) 36 (840A) Yes (p< 0,001) 1978/Australia
D8 Moshal, et al. (108)-
1977/South g 14 (74°/0) 0.8 19 (21) ‘ (40) Yes (p< 0.05) Africa 6 8 (42°/0) 1.2 17 I 11 (65%) — D9 Northfield and 6 21 4 (19°/0) 21 13 (620/o) 1.6 Yes (p< 0.05) Blackwood (1 10) (NA)d (NA)d 1977/United e 12 15 ) 4 (27%) 17 15 (88°/0) Kingdom
D10 Semb, et al. (129) 1977/Norway 1.2 4 20 (20) 12 (60°/0) 20 (22) 17 (850/o) No
aNumber~ [n parentheses refer to references listed at the end of this case study ‘NA Not available bN “mbers , “ p’rerl~heses are numbers enterln9 study elncludes Patients from study D4 cpatlents Included In sfudy D9 SOURCE Modlf!ed after K D Bardhan C(metldlne (n Duodenal Ulceration “ 1978 (7), and D H. Wlnshlp, “Clmetldlne In the Treatment of Duodenal Ulcer,’” 1978 (154)
(93) found that 20 (77 percent) of 26 Chinese pa- cidental patients (93). The second study, by tients experienced ulcer healing after 4 weeks’ Peterson, et al. (116) in the United States, used treatment with aluminum-magnesium antacid higher doses of liquid aluminum-magnesium an- tablets (25 mEq per dose; seven doses per day). tacid (150 mEq per dose; seven doses per day). Only 8 of 24 patients treated with placebo ex- In this double-blind trial, 28 (78 percent) of 36 perienced healing at the end of 4 weeks, a sig- patients on high-dose antacids experienced heal- nificantly lower fraction (p < 0.005). Relatively ing ulcers at 28 days, compared to 17 (45 per- low doses of antacids were effective in the Lam cent) of 38 patients on placebo (p < 0.005). A study; Chinese patients have similar parietal cell recent British review, prompted by the lesser masses and lower acid production than Oc- reliance on antacids by British clinicians com- 30 ● Background Paper #2. Case Studies of Medical Technologies pared to Americans, concluded that antacids level of confidence. However, also of concern is were effective in promoting healing of duodenal the complementary error, namely the failure to ulcer (106). reject the null hypothesis when in fact a differ- ence in treatment outcomes in present (the B or Notice that the rates of healing with antacids type 11 error) (49). This error, which may be in the Lam (93) and Peterson (116) studies (77 clinically important, has been overlooked and 78 percent, respectively) are much higher frequently in trials of the treatment of duo- than the healing rate (56 percent) in the placebo denal ulcer (27), as well as in other medical re- group using ad libitum antacids in the multi- search (54). center U.S. trial of cimetidine (11). In fact, the healing rates with antacids in the Lam and Pe- We have estimated that if cimetidine truly terson studies were even higher than the rate of healed 10 percent more ulcers than did antacids healing with cimetidine (67 percent) in the U.S. (62 V. 52 percent, the findings of the Ippoliti multicenter trial (11) study), then, given the number of patients in the trial, there was less than one chance in three that This observation leads to an important ques- the investigators would have found a statistical- tion: Is cimetidine more effective than a con- 14 ly significant difference. This would argue for certed antacid program in promoting ulcer heal- a more tentative clinical conclusion. It argues as ing? The question is important because a CEA well for more extensive research on the ques- should seek to compare the incremental effects tions of the relative clinical effectiveness of of competitive alternatives with one another, as 15 cimetidine and antacids. well as with a do-nothing strategy. Several double-blind randomized trials have It is statistically unsound and maybe mislead- compared cimetidine to placebo in patients with ing to compare selected groups from different gastric ulcer. These are summarized in table 11. studies. Fortunately, at least one randomized, (A number of additional reports of interim re- double-blind study has compared cimetidine sults (150) and studies without endoscopic as- with intensive antacid therapy in patients with sessment of healing (95) are excluded. ) Two of duodenal ulcers (80). This multicenter trial the European trials—one by Bader, et al. (5), the found that in 15 (52 percent) of 29 patients tak- other by Frost, et al. (56)-—found a statistically ing antacids seven times daily, and in 40 (62 per- significant improvement in healing with cimeti- cent) of 65 patients taking cimetidine, ulcers dine at 4 and 6 weeks, respectively. However, healed after 4 weeks .13 The rate of healing in pa- this finding was not borne out in the trials by tients taking cimetidine was not significantly Ciclitira, et al. (28) and Dyck, et al. (40). The better than the rate in patients taking antacid (p > 0.1), and the authors concluded that “800 and latter trials did tend to favor cimetidine (14 perc- ent more patients healed at 4 weeks in the Cicli- 1,200 mg of cimetidine daily produced duodenal tira study (28) and 19 percent more at 6 weeks in ulcer healing and pain relief equivalent to 210 the Dyck study (40)), but these differences were ml of Al-Mg antacid daily” (80). not statistically significant. The point made This conclusion should be qualified. Conven- above concerning the chance of B-error applies tional tests of significance, as employed by these to the interpretation of these studies as well. investigators, are concerned with the risk of Also pertinent is the earlier discussion of the falsely rejecting the null hypothesis of “no dif- tendency of U.S. patients to consume greater ference” between treatments (the a or type I ItMore Preclse]y, given the stated assumptions, the power of the error). In the Ippoliti study, the observed dif- experiment (1 -~) is estimated to be 0.68. ference did not justify a conclusion to reject the ‘51ppoliti has conducted a second, unpublished randomized trial hypothesis of “no difference” at a 95-percent of patients with duodenal ulcers, treating 65 patients with cimetidine and 62 patients with an intense antacid regimen. In this study, the proportion showing healed ulcers at 4 and 6 weeks was IJThe Cimetidine patients were divided into two groups with dif- virtually identical in the two groups. At 4 weeks, the proportions ferent dosage regimens: 33 patients received 1,200 mg daily and 21 with healed ulcers were 62 percent for patients taking cimetidine (64 percent) experienced healing; 32 patients received 800 mg daily and 66 percent for patients taking antacids; at 6 weeks, the propor- and 19 (59 percent) experience healing. tions were 85 percent and 84 percent, respectively (67). Case Study #11. Benefit-and-Cost Analysis of Medical lnterventions: The Case of Cimetidine and Peptic Ulcer Disease ● 31
Table 11 .—Short-Term, Double-Blind, Placebo-Controlled Studies of Cimetidine: Effect on Gastric Ulcer Healing
Cimetidine v. placebo; Cimetidine Placebo Cimetidine significant Investigatora daily dose Duration Number of Number/O/O Number of Numberl% difference Study year/country (grams) (weeks) patients b healed patients b healed (p<0.05) G1 Bader, et al. (5) 19771 France 1 4 27 10 (37°/0) 26 18 (690/o) Yes (p <0.02) G2 Ciclitira, et al. (28) 1977 United Kingdom 1 4 25 13 (52%) 35 23 (66°/0) NO G3 Dyck, et al. (40) 19781 United States 1.2 2 28 4 (14%) 29 7 (24%) NO G4 Frost, et al. (56) 1977/ United Kingdom 1 6 22 6 (270/o) 23 18(78°/0) Yes (p< 0.002)
aNumber~ in parentheses refer to references hsted at the end of this case study SOURCE Based on J W Freston, “Clmetldlne In the Treatment of Gastric Ulcer R@vlew and Commentav “ 1978 (55), and H R Wulff and S J Rune, “A Comparison of Studies on the Treatment of Gastric Ulceration With C!met!dlne, 1978 (156) amounts of antacid, which hinders comparison than placebo in patients with gastric ulcer .17 In among studies done in the United States and general, European studies have found more fa- Europe. vorable results with cimetidine than have U.S. trials. In patients with gastric ulcers, cimetidine The effectiveness of antacids alone in the has not been shown convincingly to be more ef- healing of gastric ulcer is debatable, with con- fective than an intense course of antacids. trolled studies reaching conflicting conclusions Whether cimetidine is more effective than an in- (55). One multicenter, randomized study of pa- tense antacid program in healing duodenal tients with gastric ulcer in the United States ulcers is still open to question. Of course, pro- compared three treatment regimens: cimetidine motion of healing is only one aspect of short- alone, antacid alone, and cimetidine plus ant- term clinical performance (see table 9, p. 26). acid (43). This study found no significant differ- ences in healing among these three groups at 12 16 PAIN RELIEF days or 6 weeks. N. control group taking pla- cebo only was included, apparently because of Seven of the 10 randomized, controlled stud- ethical concerns about withholding a potentially ies of duodenal ulcer listed in table 10 also com- effective treatment (i. e., antacids) from all pa- pared cimetidine to placebo in terms of pain tients (55). This omission, subsequently la- relief. Those findings are summarized in table mented by at least some of the investigators 12. Comparison across studies is complicated by (53), leaves open the question of whether treat- the variety and subjectivity of measures em- ment with either cimetidine or antacids is supe- ployed. These measures include frequency of rior to placebo in patients with gastric ulcer. painful days and nights, number of pain-free weeks, severity of pain, proportion of asympto- In summary, cimetidine has been shown con- matic patients, and days of treatment required clusively to promote healing of duodenal ulcer, to achieve symptom relief. An additional com- and some evidence suggests it is more effective plication arises because the time frame for meas-
‘OAfter 12 days, 16 percent of 67 patients taking antacids, 20 per- “In addition to cimetidine and antacids, three other drugs have cent of 71 patients taking clmetldine, and 25 percent ot 65 patients been shown in controlled clinical trials to promote healing of taking both experienced ulcer healing: after 6 weeks, the results ulcers better than a placebo: colloidal bismuth, carbenoxolone, were, respect ivei y, 61 percent (JI 62 pat]ents, 59 percent (If 68 pa- and trimipramine (139). None is now used for this purpose in the tients, and 70 percent (lt 60 patient+. United States. 32 ● Background Paper #2 Case .Studies of Medical Technolologies
Table 12.—Short-Term, Double-Blind, At the end of 4 weeks’ treatment, 63 percent of Placebo-Controlled Studies of Cimetidine: patients taking antacids and 80 percent of those Effect on Duodenal Ulcer Pain Relief taking cimetidine were asymptomatic, a differ-
a Study Summary of results ence that was not statistically significant (p > D1 Cimetidine group asymptomatic for mean of 4 out 0.1). of 6 weeks; placebo group free of symptoms for a mean of 2.4 out of 6 weeks; in other words, Placebo-controlled studies of patients with the cimetidine group had a 44% reduction in gastric ulcer varied in the extent to which the mean number of weeks with some pain. cimetidine-treated groups (Statistical significance not reported.) experienced more D2 Cimetidine group experienced a 34% reduction in rapid or complete pain relief than those treated days with pain and a 36% reduction in nights with antacids (see table 13). The Englert study with pain compared to the placebo group. Dif- ferences in the frequency of pain were sig- (43) comparing antacids and cimetidine found nificant in each of the 4 weeks of the study (p similar symptom response in all groups. < 0.005). D3 Inpatients: significantly more patients taking Investigators differ in their conclusions about cimetidine than taking placebo had day and the correspondence between ulcer healing and night pain relief at the end of 3 days (61 v. 30%; p < 0.01); difference not significant at the end pain relief. Several investigators report a poor of 1 week (69 v. 55%). correlation between healing and symptom relief Outpatients: significantly more patients taking (e.g., 6,62,108), and others say the correlation is cimetidine had day and night pain relief at the good (e.g., 8,61,80). Part of the reason for dif- end of 1 week (45 v. 31 O/.; p < 0.05); difference not significant after the first week. fering assessments may be a difference in what D4 Not reported. various investigators consider a good or a poor D5 Cimetidine group had “significantly lower pain score” (p range < 0.02 to < 0.1) both day and correlation. For example, Bardhan (8) found the
night during the first 3 weeks (method of meas- association between healing and symptom relief urement and computation not fully explained). to be significantly different from what would After 3 weeks, cimetidine group had “signifi- cantly” (p < 0.1) less day pain in weeks 5 have been expected to occur by chance. On the and 6. other hand, the same data show that the ability D6 Cimetidine group had significantly more pain-free of pain relief to predict ulcer healing is not very days each week of the study (p < 0.01). 18 07 Not reported. strong. Da At the end of 6 weeks, cimetidine group had sig- As in our discussion of B-error above, this nificantly more asymptomatic patients (780/’) than did the placebo group (47°/0) (p < 0.025). points out the important distinction between the D9 Not reported. interpretation of results based on statistical D10 Cimetidine group required significantly fewer days to achieve symptom relief (8.1 ± 9.9 [S. D.]) than criteria and that based on clinical criteria: did the placebo group (20.6 ± 9.1 [S.D.]) (p‹ Results that fail a test of statistical significance 0.01). may still be clinically meaningful; conversely,
asee table 10 for lnvestlgator, year, and country statisticall y significant differences may not be
particularl y meaningful clinically. The degree of association between healing and pain relief is pertinent to a cost-effectiveness assessment, urement varies from study to study. Nonethe- because a patient’s decision to return to normal activity depends at least as much on symptoms less, these studies fairly consistently report greater pain relief with cimetidine than with pla- as on the physical repair of the ulcer. If esti- cebo. Again, the multicenter U.S. trial (11) mates of a drug’s comparative effectiveness in returnin patients to work are based primaril shows less striking differences than the other g y on healing, the may be misleadin insofar as trials. y g The Ippoliti study (80) comparing cimetidine ‘“The probability (If ulcer healin g given symptc)m improvement to antacid found prompt symptom relief with IS 50 60 = 0.77, and the pr(~babi] I t y of nonhea] ing given no both treatments (55 percent of cimetidine- improvement In symptc~ms is 42/72 = 0..58, These are n[)t ~lar. ticularly large predictive values. In the Ippoliti study (80), the cor- treated patients and 58 percent of antacid- resp~~nding values are a bit lt]wer in the first case (42 ’60 = O 70) treated patients became asymptomatic by day). and somewhat h]gher in the second (18 20 = 0,90), Table 13.—Short-Term, Double-Blind, part, not systemically absorbed. The most com- Placebo.Controlled Studies of Cimetidine: mon adverse side effect of these antacids is diar- Effect on Gastric Ulcer Pain Relief rhea, which is related to the dose of magnesium Study a Summary of results salts. In studies with intense antacid regimens, G1 Patients taking cimetidine tended to have more 27 percent (80) and 36 percent (43) of patients rapid and greater relief of pain, but differences taking antacids developed diarrhea. In the were not statistically significant. Peterson study (116) comparing antacids with a G2 Cimetidine-based group had significantly fewer attacks of pain during each week of the study. placebo, 66 percent of the antacid group and 21 G3 No systematic or significant differences in the percent of the placebo group were switched for severity or frequency of pain at 2 weeks or at 6 at least 7 days to an alternative medication weeks between the cimetidine-treated and placebo-treated groups. because of diarrhea. Mild diarrhea may not be G4 Group taking cimetidine had fewer days of pain, very important medically, but this effect, along but differences were not statistically with the need for frequent administration, does significant. discourage patient adherence to high-dose an- aSee table 11 for Investigator year and country tacid regimens. Aluminum salts bind phosphate ions, and this may produce hypophosphatemia in patients who have intestinal malabsorption pain relief and healing do not correspond to one problems. This rare consequence may be another, Almy (2) suggests a further possibility countered by selecting a different type of an- if a patient returns to work after symptoms have tacid or giving phosphate supplements. 19 remitted but before healing has occurred: Work- Cimetidine in short-term use has been associ- days gained might be lost later on owing to late ated with a wide range of side effects. The consequences of unhealed ulcer. manufacturer instituted a formal, postmarked surveillance system that covered 9,907 ambula- In summary, evidence from most controlled, tory patients and found a total of 577 adverse double-blind studies suggests that cimetidine events in 442 patients (4.4 percent of all pa- promotes faster and more complete pain relief tients) (59). Only a fraction of the adverse than does a placebo in duodenal ulcer, but not events were believed to be attributable to cimeti- necessarily in gastric ulcer. An intense antacid dine; for example, 30 of 254 adverse gastrointes- program appears to be about as effective as tinal events occurred in circumstances that cimetidine, but more evidence on this question strongly suggested an association with cimeti- is needed. The correspondence between healing dine. No deaths were attributed to use of the and symptom relief is imperfect: The associa- drug. An extensive review by Kruss and Littman tion is not random, but relief of symptoms is not in 1978 (92) of publications, manufacturers’ a reliable clinical predictor of healing. files, and submissions to FDA concluded that cimetidine was safe enough to be used in pa- SAFETY AND ADHERENCE tients with duodenal ulcer disease for up to 8 No pharmacologic agent is perfectly safe. A weeks, and indeed, this is the use currently ap- drug’s side effects depend on its toxicity, the proved by FDA. A high proportion of patients dosage and duration of administration, and the develops clinically insignificant elevations in individual susceptibility of the patient. The im- serum creatinine which resolves promptly with portance of side effects of any one treatment cessation of therapy (92). Gynecomastia (ex- should be judged in relation to the severity of cessive development of breast tissue in males) the disease being treated and the risks of alter- has been reported in under 1 percent of patients native interventions. on short-term treatment; the incidence increases
Before turning to cimetidine, let us briefly consider the alternative of antacid therapy as a ‘“A ditterent arr~y (Jt metabolic problems may Itlllow use of calclurn cdrbt~ndte antacid (which 1s abs~~rbed systemical [y ), but baseline. Unlike cimetidine, the Al-Mg antacid +1 nce this is nc~t usual]}’ presc rlbed hy physician+ in the United suspensions usually prescribed are, for the most State<. we will not c~~nslder It I urt ht’r 34 Ž Background Paper #2: Case Studies of Medical Technologies with longer term use (72). Mental confusion study included no control group of ill patients (102), reversible hepatitis (145), and several not taking cimetidine. Sperm counts remained cases of severe allergic reaction (33) have also within the wide fertile range, but the antiandro- been reported. Agranulocytosis, the principal genic side effects of cimetidine should be eval- problem with cimetidine’s predecessor, meti- uated further. 21 amide, has been reported to occur transiently Thus, cimetidine used for up to 2 months ap- with cimetidine (32,90). In addition, at least one pears to be a relatively safe drug, but reported fatality due to aplastic anemia has been reported increases and shifts in gastric flora and en- in association with cimetidine (26). docrinologic effects are disturbing. Cimetidine Recent bacteriological studies of the gastric is more risky than antacids, but less trouble- juice of patients before and after 4 weeks’ treat- some to the patient. The more extensively a ment with cimetidine found major increases in drug is used, the more difficult it is to impute a total bacterial counts, including large numbers causal relation to sporadically reported side ef- of fecal-type organisms, following treatment fects or case fatalities. On the other hand, truly (122), This effect, noted after short-term use, associated but rare side effects can affect sub- would be of greater concern with long-term use stantial numbers of patients if a drug is very of cimetidine, as explained below. The principal widely prescribed, as is cimetidine. One’s at- determinant of gastric flora in humans is the titude toward the safety of cimetidine depends acidity of the stomach, and increases in fecal in part on the weight placed on the possibility of types of bacteria are found in the stomachs of unanticipated and remotely occurring side ef- achlorhydric patients such as those with per- fects such as those that have occurred with other nicious anemia (38). Patients with pernicious medications like diethylstilbestrol (75). anemia have long been recognized to have a sig- nificantly increased risk of developing gastric COMPLICATIONS cancer (107). Possibly, the increased incidence The major complications of ulcer disease are of cancer is related to the metabolic activity of bleeding from the base of the ulcer, obstruction fecal-type bacteria that reduce nitrates and may due to swelling or fibrosis, perforation through lead to the development of carcinogenic N-ni- the intestinal wall into the peritoneal cavity, troso compounds in the stomach (123). At pres- and penetration into the pancreatic bed. As ent, however, this long-term risk of cimetidine noted previously, these complications are rela- (or any agent that chronically reduces gastric tively uncommon and rarely occur as the initial acidity) is speculative. manifestation of ulcer disease. In the past year, new evidence has accumu- The principal question of interest here is lated concerning the effects of cimetidine on the whether short-term use of cimetidine alters the reproductive function in males. Earlier animal likelihood of near-term complications. Several studies had clearly shown an antiandrogenic ef- British investigators have reported patients who fect of large doses of cimetidine administered for developed perforation of peptic ulcers shortly 6 to 12 months (92). During the past year, at after the cessation of cimetidine therapy least one case of reversible impotence has been (60,148). An increased risk of perforation fol- attributed to cimetidine (155). In addition, a lowing cimetidine therapy is not substantiated study of seven patients with ulcer disease, duo- by controlled studies comparing longer term use denitis, gastritis, or esophagitis found a 30- per- of cimetidine and placebo following an initial cent reduction in mean sperm count after 9 course of cimetidine. These studies, discussed in weeks of cimetidine treatment; the luteinizing the section on long-term clinical effects below, hormone response to luteinizing hormone- releasing factor was also reduced (144).20 This statement is apparently based on dividing the difference in mean “’The mean iperrn c~mnts were 134.3 mllli(>n per ml bet(>re sperm count (40. 3 million per ml3) by the final, rather than the in- cvmet tdine and 94.0 mlllif)n per ml at ter treat men t. The in ves- itial, count, t ig~t{lrs state that the reduct Ion wa~ 43 percent, but this ~]ver- ‘ ‘Additional studies are underw~y, accc~rding to FDA (5 I I. assess whether maintenance doses of cimetidine The choice between antacids and cimetidine is can reduce the likelihood of ulcer recurrence, clearly closely balanced. Rather than adopt ei- ther approach exclusively, a conscientious clini- ULCER RECURRENCE FOLLOWING SURGERY cian might better weigh the choice for each pa- Cimetidine has been used to treat ulcers that tient individually, taking account of present recur following surgery for ulcer disease. We are uncertainties as well as each patient’s personali- aware of two randomized, controlled trials of ty and preferences. For example, patients vary cimetidine’s effectiveness in preventing ulcera- in their willingness to persevere with antacids in tion after surgery (71,88). These studies reached the face of mild to moderately uncomfortable different conclusions. In Britain, Kennedy and side effects. In addition, patients, as well as doc- Spencer (88) compared cimetidine with placebo tors, vary in their attitudes toward known and in patients who had undergone one of a variety unknown risks. Thus, a young man trying to of surgical procedures (including gastrectomy start a family would surely view possible anti- and vagotomy with and without a drainage pro- androgenic effects differently than would a cedure) and who, after surgery, had developed woman or elderly man. ulcers at various locations (stomach, duo- As times goes on, new evidence may reduce denum, or jejunum). The 12 patients treated present uncertainties about the comparative with 1 g of cimetidine daily did not show signifi- benefits and risks of cimetidine. Individual pa- cantly more healing at 6 weeks than the 12 pa- tient characteristics and values might still make tients treated with placebo. the preferred treatment different for different A more recent study in West Germany (71) patients who are all classified in the same gen- was restricted to patients who had undergone eral diagnostic category. partial gastrectomy and developed ulcers at or near the site of the surgery. After 4 weeks of Long-Term Clinical Effects treatment, ulcers had healed in six of seven pa- The use of cimetidine beyond the short-term tients treated with 1 g of cimetidine daily, but treatment of ulcer may take two forms: 1 ) inter- none of the eight treated with placebo had heal- mittent administration if symptoms or ulcera- ed (difference significant, p < 0.01). After 8 tions recur, and 2) maintenance treatment with weeks, all seven cimetidine-treated patients, but the aim of preventing ulcer recurrence. only one of eight placebo-treated patients had healed (difference significant, p < 0.01). The in- Cimetidine is probably very commonly used cidence of relapse after cessation of cimetidine for intermittent treatment of ulcers (7), but we and effects of maintenance on preventing recur- are aware of no controlled studies comparing rence after surgery have not yet been reported in cimetidine to alternative approaches. One study controlled trials. (64) suggests that with cimetidine, healing of a second ulcer is slower than healing of an initial RECOMMENDATIONS FOR TREATING NEWLY ulcer. In 25 patients with recurrent ulcers, 52 DIAGNOSED, UNCOMPLICATED ULCER percent healed after 4 weeks of treatment with Gastroenterologists differ in their recom- cimetidine compared to 76 percent who had mended treatment for patients with newly diag- healed within 4 weeks after diagnosis of their nosed, uncomplicated duodenal ulcers. Some, first ulcer. Interpretation of the results of this stressing comparable rates of healing, long ex- study, however, is clouded by differences in the perience with antacids, and uncertainties atten- initial treatment history of these patients and ding any recently introduced drug, recommend ambiguity in the report. For example, the 25 pa- an initial trial of intense antacid therapy (140). tients with recurrent ulcers included a majority Others, impressed with cimetidine’s per- whose first ulcers had been treated with cimeti - formance and concerned about lack of patient dine and others whose first ulcers had healed adherence to an antacid regimen, prefer to use spontaneously. In addition, most of the 25 pa- cimetidine (98). tients had been maintained on placebo, but an 36 Ž Background Paper #2: Case Studies of Medical Technologies unspecified number (between 1 and 7) had been of cimetidine daily. Investigators consistently maintained on low-dose cimetidine. report a statistically significant reduction in symptoms and recurrent ulceration during the We are aware of no studies comparing main- period of treatment in the cimetidine-treated tenance cimetidine to maintenance antacids. group compared to those given placebo. The Perhaps it has been assumed that few patients consistency of results is particularly striking would adhere to long-term treatment with effec- given the range of criteria used to select tive doses of antacids. Grossman (67) suggests patients —with some studies including patients in light of the re- that this might be reconsidered with recently treated new ulcers (e. g., 70), cent study by Lam, et al. (93), who found that others limited to chronically ill patients (e.g., relatively small doses of antacids given in the 16), and others restricted to patients considered form of tablets were effective in promoting the candidates for surgery (e. g., 64). healing of duodenal ulcers. Most research on long-term use has compared The conclusions from these studies are rein- maintenance doses of cimetidine to placebo forced by a recent review by Burland, et al. (23). (with antacids ad libitum). These studies form These authors compiled results from 15 double- the basis for the following discussion. blind maintenance trials, either completed or in progress, involving 695 patients. Overall, the ULCER RECURRENCE number developing recurrent ulcers while tak- Table 14 summarizes the results of six double- ing placebo appears to be twice that observed blind controlled studies, published in English, with maintenance cimetidine. Approximately 10 comparing maintenance cimetidine to placebo percent of patients treated with placebo and 50 for periods ranging from 80 days to 1 year. Pa- percent of cimetidine-treated patients remained tients in these studies were given 400 or 800 mg in remission during 12 months of treatment.
Table 14.—Controlled Trials of Maintenance Cimetidine in Peptic Ulcer
Ulcer recurrence Symptomatic relapse (by endoscopy) Initial Duration Difference Investigator (premaint.) of maint. Maint. Number Number/% Number Number/% significant Study year/country treatment (months) treatment analyzed relapse analyzed recur (p <0.05) M1 Bardhan, et al. (9) 53 cimetid. 6 P bid 31 18 (58%) 27 20 (74%) Yes 1979/United 7 other C 400 mg 29 4 (14%) (p< 0.005) Kingdom bid recurrence M2 Blackwood, et al. (13) Not 6 P hs 24 12 (50%) 24 21 (88%) Yes 1976/United specified C 800 mg hs 21 8 (380/. ) 21 5 (250/.) (p< 0.0005) Kingdom recurrence M3 Bodemar & Walan (16)/ 65 cimetid. 12 P bid 36 30 (83%) 36 38 (83%) Yes 1978/United 3 other C 400 mg 32 12 (38%) 32 6 (38%) (P< 0.0005) Kingdom bid M4 Gray, et al.(64) 1978/United 52 cimetid. 6 P hs 30 24 (80%) 29 24 [83%) Yes Kingdom 8 other C 400 mghs 26 11(42%) 22 7 (32%) M5 Gudmand-Hbyer, Not 12 P bid 25 20(80%) — — Yes et al. (70) specified C 400 mg 26 3(12%) – — (p< 0,1301) 19781 Denmark bid M6 Hetzel, et al. (78) Not 2 2/3 P bid 31 10 (32%)c — — Yes- . Australia specified 14 (4570) — — C 400 mg 36 0 bid aNumber~ in parentheses refer to references listed at the end of this case study bp = pla~eboi c = clrnetldlne; bld = twice daily; hs = at bed!lrne. CThe repo~ states in the same paragraph both that 10 patients on placebo suffered relapse and that 45 perCer)t of those on placebo had relapsed Results were identical with 400 and 800 mg of Empirical evidence consistent with such an cimetidine daily. adverse selection of patients whose ulcers heal initially with cimetidine may be found in the The performance of different maintenance results collected by Burland, et al. (23). Among regimens may depend on the initial treatment patients treated with maintenance placebo, 245 received by patients. Those whose ulcers have (50 percent) of 290 patients initially treated with healed initially with placebo, antacids, or cime- cimetidine developed symptomatic re-ulcera- tidine may differ in their susceptibility to recur- tion, compared to 9 (30 percent) of 30 patients rence. Consider the possibility that patients initially treated with placebo (difference signifi- with newly developed ulcers fall into two clini- cant, p c 0.05). On the other hand, there may cally indistinguishable subpopulations, one not be an adverse selection of patients who heal (type A) being more resistant to treatment and following cimetidine treatment as compared to prone to relapse than the other (type B). Now those who heal after antacid treatment. Ippoliti consider the hypothetical experimental situation followed patients with duodenal ulcer who had illustrated in table 15. Seventy patients in each been assigned randomly to treatment for up to 6 of two groups are assigned randomly to initial weeks with a concerted antacid program or with treatment with cimetidine or with antacids. In cimetidine. 22 Among those whose ulcers healed, each group of 70, 40 are type A and 30 are type the rate of recurrence at 6 months (as deter- B. Both treatments produce healing in 75 per- mined by endoscopic examination at 3 and 6 cent of type A patients, but cimetidine is twice months) was 54 percent among the 41 patients as effective as antacids (67 v. 33 percent) in pro- who had been treated with cimetidine and 60 ducing healing in type B patients. percent among the 35 patients who had been After initial treatment, only those patients treated with antacids. who have healed are followed for possible re- Following cessation of treatment, patients lapse. (In the case of maintenance studies, only who had been taking cimetidine begin to relapse patients initially healed are tested with mainte- at the same rate as the initial rate of relapse nance therapy. ) Assuming that a given propor- among patients who were treated with mainte- tion (one-third) of all type A patients and that a nance placebo. This important finding is dem- larger proportion (one-half) of all type B pa- onstrated in the study by Gudmand-Høyer, et tients both relapse within 6 months, then cimeti- al. (70). Once it is discontinued, maintenance dine-treated patients will appear to be more cimetidine appears neither to accelerate recur- prone to relapse (40 v. 38 percent). This can be rence nor to effect any more permanent cure. true even when, as shown in the last column of table 15, cimetidine results in a greater fraction of the initial population of patients remaining asymptomatic. “Unpublished study (79).
Table 15.—Results of Treatment With Two Hypothetical Subpopulations of Ulcer Patients: Type A More Resistant to Treatment and Prone to Relapse Than Type B
Relapse in 6 months Response to initial after treatment treatment: Number discontinued: Number Number remaining 0 Starting population healed (o/o of those relapsed (o/o of initially asymptomatic ( /0 of Initial treatment of patients entered) healed) starting population) Cimetidine - Total = 70 Total = 50 (71 O/. ) Total = 20 (400/. ) 30 (43°/0) Type A = 40 Type A = 30 (75°/0) Type A = 10 (33°/0) 20 (50°/0) Type B = 30 Type B = 20 (67%) Type B = 10 (500/. ) 10 (33°/0) Antacids Total = 70 Total = 40 (570/. ) Total = 15 (380/. ) 25 (36°/0) Type A = 40 Type A = 30 (750/. ) Type A = 10 (330/. ) 20 (50°/0) Type B = 30 Type B = 10 (33%) Type B = 5 (500/. ) 5(1 70/o) 1 L------_–--- –..–-.––_ -.._. _....__ 38 ● Background Paper #2 Case Studies of Medical Technologies
The implications drawn from these studies are clinicians express concern that rare, but severe, less consistent than are the findings. To some in- side effects may not be evident in relatively vestigators, the high relapse rate after cessation small controlled trials and that risk of toxicity is of treatment “suggests that prolonged cimeti- greatly magnified if treatment continues for pro- dine therapy is necessary to retain most patients longed periods of time (70). in remission” (76). Others, cognizant of the potential unknown risks in treatment for longer COMPLICATIONS than 12 months, wonder whether “those pa- Available controlled trials tell us very little tients would have been better off if surgery had about possible effects of cimetidine on long- been advised at a much earlier stage. A year has term complications of ulcer disease (hemor- been wasted in which they have been taking tab- rhage, obstruction, perforation, and penetra- lets daily when the end-result was surgery after tion). The reasons rest mainly in the nature of all” (Wulff, quoted in 150). But not all patients the disease, absence of reliable estimates of who relapse become candidates for surgery, and baseline rates (no randomly selected population a key question is the likelihood of their healing of ulcer patients has been followed over many without surgery. Even if maintenance cimeti- years), and the comparative rarity of severe dine accomplished nothing more than a l-year complications, believed to be not more than a delay in surgery, it might be worthwhile for few percent per year following initial diagnosis some patients to defer the small, but definite, (140). mortality risk from surgery in favor of the risks of cimetidine for 12 months. Indeed, as a pa- As stressed by Grossman (70), the size of a tient’s surgical risk increases, cimetidine’s un- study needed to detect clinically relevant known consequences become more acceptable changes in complication rates would be enor- (29). mous. If, as he posits, 5 per 1,000 recurrences result in perforation, and we wanted to detect at In summary, compared to placebo, mainte- a 0.05 significance level a treatment that would nance treatment with cimetidine significantly halve the rate of recurrence, we would need reduces the chance of ulcer recurrence. Once more than 15,000 patients in each of two ex- cimetidine is discontinued, patients begin to perimental groups to have a 90-percent chance relapse at the same rate as they would have of finding that difference (49). without maintenance treatment. We found no controlled studies of maintenance cimetidine It may be that insofar as a treatment such as comparing alternative treatments other than cimetidine therapy can reduce or delay recur- placebo and no published reports studying peri- rence, it will reduce or delay complications. ods longer than 1 year of maintenance therapy. However, insofar as patients at higher risk of complications are also more resistant to treat- SAFETY ment that delays recurrence, reductions in com- Long-term studies with cimetidine turn up no plication rates will be less than reductions in important new side effects other than those recurrence. The reasons are analogous to the ad- mentioned in relation to short-term treatment. verse-selection bias hypothesized above. There The incidence of gynecornastia may be as high is little convincing evidence that cessation of as 4 percent in patients treated for 2 months to 1 cimetidine treatment can promote complica- year (131). Presumably, changes in the bacterial tions (see earlier discussion), and likewise, there flora of the stomach found after 4 weeks of are no convincing data from clinical trials that cimetidine treatment would persist with long- cimetidine reduces complications. Given the size term therapy (122). As discussed earlier, this of studies that would be required, it seems un- raises the possibility that patients taking likely that compelling evidence on this question maintenance cimetidine might have an increased will be forthcoming from controlled clinical risk of developing gastric cancer. Experienced trials. PENDING APPROVAL BY FDA tion among patients in the experimental and At the present time, FDA is considering ap- control groups. Five (D2, D5, D6, G2, M3) of proval of cimetidine for use longer than 8 weeks the eight studies were conducted in Europe and in patients with duodenal ulcer disease. Its ad- one (D1) in South Africa. In these six studies, visory committee reportedly recommended in cimetidine-treated patients consumed between October 1979 the approval of maintenance 47 and 84 percent less antacid. In the remaining cimetidine for patients who are at “high risk” for two studies (D3 and G3), both done in the surgery (50). This probably includes both pa- United States, differences were less marked, and tients who are more likely to require surgery there were no consistent trends toward de- and patients who are less likely to survive sur- creased antacid consumption among cimetidine- gery. We understand that final decisions on this treated patients. question, as well as revised limits on the ap- Possible effects of cimetidine use on the con- proved duration of treatment, are not yet for- sumption of other drugs have not been reported. mulated. The principal drawback to longer term use is the risk of unknown side effects. Avail- Diagnostic Tests able evidence supports the effectiveness of cime- tidine in delaying recurrence. Physicians and Insofar as persistent or recurrent ulcer symp- patient attitudes toward the unknown risks of toms lead physicians to perform diagnostic cimetidine will vary, but for those with relative- tests, and insofar as cimetidine reduces or delays ly large and tangible risks from surgery, symptoms, the drug could result in fewer diag- cimetidine is likely to be judged as a less danger- nostic tests if used without the constraints of ous course. controlled triail protocols. It is important to bear in mind that cimetidine’s effectiveness in long- FDA has not yet approved cimetidine for use term use has been tested against placebo, but in patients with gastric ulcer. This is apparently not, to our knowledge, against an antacid pro- related to the conflicting evidence about the ef- gram or other regimen. To the extent that cime- ficacy of cimetidine for gastric ulcer (see table tidine produces biochemical or other abnormal- 11, p. 31) and to a more general policy concern ities that physicians choose to evaluate further, about the possible role of nitrosoaminated com- it could increase the number of laboratory tests pounds in the development of cancer. performed. Health System Effects In addition, if physicians felt obliged to screen for unlikely but potentially serious side effects, Empirical data on the health system effects of such as granulocytopenia, the number of diag- cimetidine are more sparse than available in- nostic tests in patients treated with cimetidine formation about clinical effects. Some pertinent could increase. The presence and extent of these information is available, and several studies are different effects are currently matters for spec- in progress that may shed more light on these ef- ulation. fects, but at the present time, available evidence is suggestive rather than conclusive. As dis- Physician Visits cussed in the next part of this case study, the The range of potential effects posited for diag- lack of empirical evidence to inform estimates of nostic tests applies as well to physician visits. cimetidine’s health system effects seriously Secondary induced effects are also possible: If handicaps available benefit-and-cost analyses. physicians are visited less often for a principal problem of ulcer disease, then less medication Medication and fewer procedures may be used for a less Eight of the 20 placebo-controlled studies of troublesome problem, such as mild to moderate cimetidine shown in table 16 (D1, D2, D3, D5, joint pain, that in itself might not prompt a per- D6, G2, G3, M3) compared antacid consump- son to seek medical care. 40 ● Background Paper #2: Case Studies of Medical Technologies
Hospitalization and Surgery Two principal sources of nationwide hospital data are the Hospital Discharge Survey of Costs of hospitalization and surgery are the NCHS and the Hospital Record Study of largest single component of medical expendi- CPHA. Data from both sources are used in this tures for ulcer disease (see table 6, p. 19). Hence, analysis. Unless otherwise stated, Hospital the effects of an intervention such as cimetidine Record Study data are taken from a review by on the rates of hospitalization and surgery are Elashoff and Grossman (42). Hospital Discharge particularly important to a CEA. Survey data were obtained directly from NCHS Because, as discussed earlier, cimetidine was and then compiled for this case study. disseminated widely in a short period of time, it Information from NCHS and CPHA is not in seems possible that its effects might be reflected perfect agreement. Estimates in both the in global trends of hospitalization and surgery. Hospital Record Study of CPHA and the Hos- Data we have compiled and analyzed from pital Discharge Survey of NCHS are based on NCHS do indicate an unexpectedly sharp de- samples of non-Federal, short-term hospital cline in surgery in the first calendar year (1978) discharges, stratified by hospital size and loca- following the introduction of cimetidine in the tion. The fraction of records sampled is inverse- United States. According to data from CPHA ly proportional to hospital size, so that the compiled by Elashoff and Grossman (42), how- overall probability of selecting a particular ever, the decline was less precipitous. Hospital- discharge is approximately the same for each related effects that are linked more directly to class of hospital size. Both sources estimate the use of cimetidine may emerge in the next few discharges, not patients, so multiple admissions years from several studies currently in progress, for an individual patient are indistinguishable which we will describe briefly. from one-time-only admissions. One major distinction between the two Table 16.—Short-Term, Double-Blind, sources is the difference in parent populations of Placebo-Controlled Studies of Cimetidine: Effect on Antacid Consumption hospitals. For the Hospital Discharge Survey, NCHS selects a representative sample from all Antacid consumption of U.S. hospitals. CPHA draws its sample for the cimetidine group compared to Hospital Record Study from the more than 750 Study a Time period that of placebo group hospitals in its parent file. These hospitals com- D1 6 weeks 83% reduction D2 4 weeks “Significantly” fewer tabletsb prise approximately 13 percent of all U.S. hos- 03 First weekc Inpatients: no differences pitals, but they account for nearly 40 percent of Outpatients: 40% reduction all hospital discharges. Thus, large hospitals are D4 — Not reported D5 6 weeks 84% reduction overrepresented in the CPHA parent file. The D6 4 weeks 47% reduction subset selected for the Hospital Record Study — D7 Not reported data is chosen to represent the size distribution D8 — No antacids permitted D9 — Not reported for all U.S. hospitals, but the extent to which D10 — Not reported any bias is introduced by the inclusion or exclu- — G1 Not reported sion of U.S. hospitals in the CPHA parent set is G2 4 weeks 61% reduction G3 2 weeks No significant differences not well defined .23 6 weeks G4 — Not reported Table 4 (p. 16) showed NCHS Hospital Dis- Ml — Not reported charge Survey data for peptic ulcer disease for — M2 Not reported the years 1966 and 1970 through 1978. The first- M3 12 months 700/. reduction (approximately) M4 — Not reported z lone ind ica kc)r t~f tfle represen ta t iveness of Hospital Rec~)rd- M5 — Not reported Study based figures is a comparison of Hospital Record Study es- M6 — Not reported timated deaths from peptic ulcer and total counts (not pr(~jrcti(~ns) tabulated by the NCHS Division c)f Vital Statistics. Between 1970 asee tables 10, I 1, and 14 for Investigator, year, and cOuntrY bscatter PIOIS of antacid consumption presented, no numbers provided or sta. and 1978, Hospital Rec~~rd Study estimates of annual deaths from tlstlcal tests reported. peptic u]cer were 92 to 114 percent of U, S. \’itd] Statistics counts cN t reported for later weeks of study o (42). Case Study #11 Benefit-and-Cost Analysis of Medical Interventions: The Case of Cimetidine and Peptic Ulcer Disease ● 41 listed diagnoses count those discharges for missions for uncomplicated ulcer disease and which one of the ulcer diseases was listed as the those for ulcer disease associated with hemor- primary diagnosis. These data, plotted in figure rhage or perforation (42). Between 1970 and 3 (p. 17), show a distinct downward trend over 1978, uncomplicated duodenal ulcer admissions the past decade for hospitalization of patients declined by 46 percent; admissions for hemor- whose first-listed diagnosis was ulcer disease. rhage declined by 37 percent; and admissions The CPHA Hospital Record Survey data show a for perforation declined 24 percent, though fail- similar and significant downward trend, with an ing to reach statistical significance because of even greater difference in the total decline from the small number of admissions for perforation. 1970 to 1978 (42).24 According to both sets of Uncomplicated gastric ulcer admissions showed data, the number of hospitalizations for ulcer a small, but significant, decline (18 percent). No disease in 1978 is approximately what would be clear trend emerged for complicated gastric expected by extrapolating the trend established ulcer admissions. through 1977. The number of surgical procedures for ulcer Furthermore, both sets of data confirm that disease has shown a decline during the 1970’s hospitalizations during the 1970’s have declined that roughly parallels that for hospitalizations. for duodenal ulcer and remained constant for Both NCHS and CPHA collect data on surgical gastric ulcer. Between 1970 and 1978, the ratio procedures, but neither routinely relates oper- of hospitalizations for duodenal ulcer to those ations to discharge diagnoses. The principle sur- for gastric ulcer declined by 37 percent ac- gical procedures used for ulcer disease are par- cording to the Hospital Record Study and by 49 tial gastrectomy (excision of part of the stom- percent according to the Hospital Discharge ach) and vagotomy (cutting of the vagus nerve), Survey. This is further evidence for the epidemi- with pyloroplasty (enlargement of the pyloric ologic distinction between duodenal and gastric canal) or other drainage procedure (134). The ulcer. The figures are incomplete because a rela- numbers of these procedures performed during tively small number of diagnoses categorized as selected years from 1966 through 1978 are “peptic ulcer—site unspecified” is omitted, but shown in table 17 (NCHS data). During this their inclusion would not alter the trends period, pyloroplasty and drainage procedures indicated. were almost invariably performed in association with vagotomy. Virtually all vagotomies were Data from CPHA’s Hospital Record Study probably undertaken for the treatment of ulcer can also be used to estimate the number of ad- disease. Presumably, the great majority of par- tial gastrectomies were also done for ulcer “Elashott and Grossman def]ne a trend as significant if: 1 ) the disease, but there are also several less common Spearman rank (}rder correlation is significant (p< O.OS), and 2) the difference between the 1970 and 1978 values exceeds the size of indications for partial gastrectomy (e.g., gastric the Q5-percent c(~ntidence interval tor the med]an value (42). carcinoma and trauma).
Table 17.—Number of Selected Surgical Procedures (Partial Gastrectomy, Vagotomy, Pyloroplasty and Drainage”) in the United States, 1966-78
Pyloroplasty Year Partial gastrectomy Vagotomy and drainage 1966 ...... 74,500 61,000 56,800 1970 ...... 55,800 62,800 45,500 1972 ...... , . . . 63,300 59,300 42,000 1975. , ... , ...... 53,300 52,800 38,500 1976 ...... 54,200 48,300 31,200 1977 .., ...... 51,100 45,500 26,300 1978 ...... 39,700 29,200 20,600
aulcer dl~ea~e ,~ by far the most common Indlcatlon for these surgical procedures Over the time period shown PY1oroPlastY and drainage were almost Invanably associated with vagotomy SOURCE National Center for Health Statmtlcs, National Hospital Discharge Survey, Hyattsville, Md Thus, the sum of partial gastrectomies and Figure 5.— NCHS Data on Number of Selected vagotomies can serve as a reasonable prox for Surgical Procedures (Partial Gastrectomy and y Vagotomy) in the United States, 1966.78 the number of surgical operations done for pep- tic ulcer disease. Summing these two procedures may double count some patients who undergo surgery, because a patient who receives both 140 partial gastrectomy and vagotomy is recorded under both procedures. Despite the possibility of some double counting, the trend over time in the total of these two procedures would remain a useful index. Estimates for the number of partial gastrec- tomies and vagotomies from NCHS tend to be higher than estimates from CPHA, but data from both sources show a distinct downward trend over time in the number of operations (see table 8, p. 22). An acceleration (or deceleration) 60, of this downward trend in surgery following the 1965 1970 1975 1980 advent of cimetidine might be ascribable to the introduction of this new, widely used medica- ● Best fit computed by least-squares method. Confidence intervals tion. shown for curve fit to years 1966-77, We tested whether the number of surgical SOURCE Based on data from the Nat fonal Center for Health Stat[s ICS Hyatts V1/1~ Md procedures performed in 1978 was different from that which would be predicted by the previous trend in the following way. First, we fitted a least-squares, linear regression line to Figure 6.—CPHA Data on Number of Selected the surgical data available through 1977. The Surgical Procedures (Partial Gastrectomy and predicted number of procedures in 1978 is based Vagotomy) in the United States, 1966-78 on a direct extension of the regression line. This is shown in figures 5 and 6, respectively, for the NCHS and CPHA surgery data. The NCHS es-
timates of surgery are consistently higher than the CPHA estimates, but the rates of decline (slopes of the regression lines) are quite similar, within one standard error of each other .25 The plots also show the 95- percent confidence inter- val about this regression line for individual estimates in each year for which data are available. According to the NCHS data (figure 5), the rate of surgery in 1978 is significantly (p< 0.01) below the rate that would have been predicted I 1 1 1 I on the basis of the trend through 1977. The drop 40,000, -- J E I I I I I J in 1978 is less striking in the CPHA data (figure 1970 1975 1980 6), but even here there is only about a 10- percent chance that the estimated amount of ● Best fit computed by least-squares method. Confidence Intervals shown for curve fit to years 1966-77.
“Thr ~l(~pc (){ the regre~~lon line tor the’ NCHS data ts 0.33cII; SOURCE Based on data from the Comnllsslon on Professional and +ospltal that for the CPHA data is 0.3Q4s. Actlvttles compiled by J D Ela Shoff and M I Grossman 1981)(42) surgery in 1978 is in line with the preceding If an unexpected decline in ulcer surgery did, trend. The number of surgical procedures in in fact, occur in 1978, the question is, why? Did 1978 was approximately 11,000 fewer than the cimetidine play any role in the apparent drop? predicted number based on CPHA data, and Are there other plausible explanations? What 26,000 fewer than the predicted number based sorts of data might be obtained that could on NCHS data. answer these questions? Further evidence for the apparent excessive Table 19 shows numbers and rates of surgical drop in surgery in 1978 compared to earlier procedures for all abdominal surgery and for years comes from a comparison of the number selected abdominal surgical procedures for of surgical procedures as a proportion of hos- selected years from 1970 through 1978. There pitalizations for ulcer disease for various years was no general decline in abdominal surgery (see table 18). Each year from 1966 to 1977, the over these years. Only surgery for peptic ulcer number of operations was between 25 and 29 disease shows a marked decline in 1978 com- percent of hospital admissions; in 1978, the pared with the rates in earlier years. Some number of operations for ulcer disease was 19 surgery for peptic ulcer is elective, and one percent of hospitalizations. Roughly speaking, might imagine that part of the decline could be for the decade before 1978, more than one in related to a newly emerging, more cautious at- four patients hospitalized for peptic ulcer re- titude toward elective operations. This might ceived surgery; in 1978, the proportion dropped occur, for example, as a result of more patients below one in five. seeking second opinions or of greater cost-con-
Table 18.— Proportion of Patients With First-Listed Diagnosis of Ulcer Disease Having Surgery, 1966-78
B A Number of patients Number of surgical discharged with b Year procedures——. diagnosis of ulcer A/B 1966: : 135,500 526,000 0.258 1970. ...., . . . . 118,600 438,000 0.271 1972, 122,600 429,300 0.286 1975 ...... 106,100 411,700 0.258 1976 . . . . 102,500 385,400 0.267 1977 .., ...... 96,600 385,400 0.251 1978 68,900 360,400 0.191
al ~~1 udes part Ial gast rectom~ and va90t0mY blncludes gastric duodenal, gastrole)unal and peptic ulcer (site unspeclfled) SOURCE Nat(onal Center for Health Statlstlcs, National Hosp/tal Dwcharge Survey, Hyattsvtlle, Md
Table 19.— Number and Rate of All and Selected Abdominal Surgical Procedures in the United States, 1970-78
Partial gastrectomy a b All abdominal surgery—. and vagotomy Appendectomy Cholecystectomy Herniorrhaphy C C C C C Year Number—— —.. Rate Number Rate Number Rate Number Rate Number Rate 1970 2,440,000 122 119,000 6 325,000 16 367,000 18 496,000 25 1975 . . . . 2,894,000 138 106,000 5 319,000 15 442,000 21 549,000 26 1976 ...., ., 2,809,000 133 102,000 5 306,000 14 442,000 21 507,000 24 1977 2,937,000 139 97,000 4 342,000 16 446,000 21 533,000 25 1978 2,830,000 132 69,000 3 299,000 14 432,000 20 510,000 24 a~urglca~ remo~~l o~~he gal I blad(er bsurglcal repa[r of a hernia c Rates shown are per 10000 poputatlon
SOURCE Based on dala from the National Center for Health Stat[stlcs, National Hospital Discharge Survey, Hyatt svllle, Md sciousness on the part of physicians. However, tients who were scheduled for an elective opera- we find no parallel decline between 1977 and tion may have decided with their physicians to 1978 in other abdominal surgery, such as her- delay surgery in order to try the new drug. Since niorrhaphy (surgical repair of a hernia), which patients appear to relapse at the same rate is probably more frequently elective than is following cessation of cimetidine, the decline in surgery for ulcer disease. surgery might be followed by a compensatory rebound, especially if more reports (e. g., 121) A dramatic change in the criteria used to suggest increased risks or adverse side effects decide on surgery or use of a different type of with long-term use of cimetidine. surgery for patients with ulcer disease might ac- count for some decline. To our knowledge, To date, only circumstantial evidence and however, neither the recognized indications for argument by exclusion can make the case for the surgery nor the types of operations have role of cimetidine in decreased rates of surgery. changed dramatically in the past few years. However, more direct evidence may be forth- Also we know of no changes in the standard coming from several sources. Murray Wylie of coding for operative procedures in 1978 that the University of Michigan is engaged in a might account for the observed decline. Diag- detailed analysis of CPHA data on patients hos- nostic advances, such as fiberoptic endoscopy, pitalized with ulcer disease .27 Wylie has data on may provide greater- assurance of benignity of a all patients discharged with a diagnosis of ulcer slowly healing gastric ulcer and thus avert some disease from a cohort of 790 hospitals that par- surgery that would have been performed ticipated continuously in the CPHA data system previously. Even if present, however, such ef- from January 1974 through October 1978. Al- fects seem very unlikely to reach the propor- though the data do not specifically identify pa- tions of the evident decline in 1978. tients who did and did not receive cimetidine, he is able to examine surgical rates on a month-to- Results from at least one of the maintenance month basis. Thus, he can test the corre- trials comparing cimetidine with placebo sup- spondence between any accelerated decline in port the possibility that the decline in surgery in surgery and the introduction of cimetidine in the 1978 is related to the availability of cimetidine. United States in August 1977. In a year of maintenance treatment, Bodemar and Walan (16) found that 1 patient in 32 who Wylie’s preliminary impression is that the fre- received cimetidine and 15 in 36 who received quency of surgery began to drop even a few placebo underwent surgery because they had months before the release of cimetidine. He two recurrences or because of severe symptoms speculates that this might be attributable to a at the first recurrence (difference significant, delay in elective surgery in anticipation of the p < 0.0005). 26 Thus, one possible explanation new medication. It would be very informative for the decline in surgery for ulcer disease in to compare changes in rates of surgery separate- 1978 is that the dramatic growth in the use of ly for uncomplicated cases (presumably ad- cimetidine enabled more patients to be treated mitted because of pain) and for those with hem- successfully medically. If cimetidine were orrhage or perforation. If cimetidine is reducing responsible, the effect could be temporary. Pa- surgery by effecting a medical remission after patients are hospitalized, the largest drop in ‘@In a second maintena ace study that rept~rted sur~lcal ex- surgery as a proportion of admissions should be perience, p[wsible effects t~t cimetldine <~n ~urgery are obscured by for patients hospitalized because of pain. the practice of treating “placebo tal I ures ” with a L (~urse (~t L i met i- dine rather than surgery; th \ ettectwi a remissi{~n in m,]st ‘placebo Wylie will also be able to analyze his data failures” durtng the 6 months [~t the study (M ~ In thi~ ~tudy, 30 patients wew treated in]t ially with Imaintenance p]acebt~, 24 re- separately for surgical and medical admissions, lapsed, al! t~t wht~m were then trc>a ted with c I met i dine, and ~ including length of stay. This is of particular in- underwent surgery wit h In t Ilt, ~-m on t h period L)} t hc \t udv. Ot the terest to a cost-effectiveness assessment of the 26 patients in it ial]y t rea tetl wtth rn~ in tenanct’ t inlet Idlnt>, 7 r~,- ]apsed; 1 received surgery then ~nd ~ rm elved a w>c(~nci ct~urw of (higher dcwe) c imetidine: 2 { t t h(wc ~ undt’rwwnt >urgc,rv wlthln the ‘‘\$’e are gr<]tt’t ul t{) l’r(~tt’sw)r \4 }IIIL 1(, J \lIJ r lrl~ t }1 I> (l~,w rl p! It,n 6-m(~nth perl(xi t~t the ~tudy {~t h t~ W( lrl, i n pr{~~r(’~~. Case Study #11: Benefit-and-Cost Analysis of Medical Interventions: The Case of Cimetidine and Peptic Ulcer Disease ● 45 number of days of hospital care that might be claims do not include the patient’s diagnosis; saved by cimetidine. Presumably, some fraction medicaid patients over 65 years old are also of the reduction in surgery that might be at- covered by medicare, about which the investi- tributable to cimetidine is due to patients not gators have no information; and the data do not being hospitalized, and another fraction is due include information concerning patient status at to hospitalized patients being treated medically discharge or work history. The major difficulty only. (The large drop in surgery in 1978 com- Weisbrod and Geweke face, however, is con- pared with the drop in hospitalizations suggests trolling for selectivity bias in those patients who that the latter fraction may be the larger. ) On do receive cimetidine. Their approach is to the average, surgical lengths of stay would be stratify patients according to demographic fac- expected to be longer than medical, and a shift tors and clinical history. Although it will be im- from surgical to medical care in a hospital possible to overcome the aforementioned bar- should typically produce a reduction in hospital riers completely, Weisbrod and Geweke’s study days. If a very large number of patients who are promises to be the first large-scale, patient- considered potential candidates for surgery are based study providing data on the direct and in- first treated medically, however, any failures on duced health system effects of cimetidine. The the medical regimen would then undergo sur- data base can also be used to describe the diffu- gery after a delay, and this could add to the sion of the drug in a given patient population average length of stay for patients. In addition, and the pattern of present use by medical practi- successful medical treatment with cimetidine tioners in one State. might or might not take longer than a medical regimen without the drug. A few points of data We are aware of a few additional studies of would be preferable to a lot of speculation. the health system effects of cimetidine that are in more preliminary stages of development. At Another approach to assessing cimetidine’s least one of these involves a health maintenance effects on the health system has been undertaken organization (HMO); if the HMO’s population by Professors Burton Weisbrod and John is sufficiently stable, it may be a particularly Geweke at the University of Wisconsin .28 They valuable setting for study. Ideally, one would are analyzing patient records developed for ac- seek results from a long-term, randomized, con- counting purposes by the Texas medicaid pro- trolled study of patients with ulcer disease who gram. Weisbrod and Geweke aim first to recon- are or are not treated with cimetidine, but for struct medicaid expense records on a patient-by- ethical and practical reasons, such a study is patient basis for all patients with a diagnosis of unlikely to materialize. ulcer disease. They have identified 1,206 pa- tients with ulcers in a sample that begins in In summary, hospitalization and surgery for January 1976 and will extend to August 1979. peptic ulcer disease have both declined signifi- These investigators have conducted a pilot cantly during the past decade. The decline in study with 81 patients randomly selected from hospital admissions for 1978 is consistent with this population, 36 with and 45 without a his- earlier trends. However, the fall in surgical pro- tory of cimetidine use. Their intent is to com- cedures for ulcer disease in 1978 is unexpectedly pare the health and expenditure history (includ- large, amounting to 11,000 to 26,000 fewer pro- ing nearly 50 categories of various expenses for cedures in 1978 than would be expected from the hospitalization, physicians, drugs, nursing trend leading up to that year. The introduction homes, etc. ) for patients treated with and with- and widespread use of cimetidine is one plausi- out cimetidine. ble explanation for this unexpected decline. More specific information from studies in prog- Weisbrod and Geweke recognize some in- ress, including a month-by-month tracing of herent limitations in the available data. For ex- surgical rates and a comparison of health ample, approximately one-fifth of the medicaid resources used by patients who did and did not
‘F\\’c’ are gratet UI to [’r(lfes~t~r Cewcke t(lr \harlng intt~rmatl(ln receive cimetidine, would help strengthen or abc~u t t hcl r \t udy t or t h 1+ reptlrt refute this inference. 46 ● Background Paper #2: Case Studies of Medical Technologies
Outcome Table 3 (p. 16) shows that mortality from ulcer disease has been declining steadily over the The outcome effects of cimetidine are conse- past 15 years. Figure 7 shows NCHS ulcer mor- quences of its clinical and health system effects. tality statistics on a quarterly basis from 1976 to We have already discussed how clinical and mid-1979. It shows both a continuing down- health system effects interest and lead to the two ward trend and a seasonal variation in mor- components of outcome: health status and re- tality, No unexpected mortality reduction fol- source costs. In this section, we present addi- lowing the introduction of cimetidine in August tional empirical evidence about cimetidine’s 1977 is evident. If cimetidine has saved lives of possible effect on outcome. ulcer patients, the lives saved are too few to The available empirical evidence plus meth- have a substantial effect on overall mortality to odologic and other considerations raised in a date. Of course, these figures are mute on the later section entitled “Guidelines for Review of question of whether even more widespread and Health Care Benefit-and-Cost Analyses” serve consistent use of cimetidine might demonstrably as a basis for our review of published analyses delay or prevent deaths from ulcer disease in the of cimetidine’s benefits and costs in the next part future. of this case study. In summary, there are some reasons to be- lieve cimetidine might have beneficial effects on Health Status ulcer mortality and other reasons to doubt it. If As we have already discussed, it is convenient cimetidine did have a small beneficial effect on and usual to think of health status in terms of mortality, it would be very difficult to detect in mortality and morbidity. controlled cohort studies or from national mor- tality trends. MORTALITY We are aware of no empirical studies of the Figure 7.— Number of Deaths in the United States effects of cimetidine on mortality from peptic From Ulcer Disease (Gastric, Duodenal, and Peptic— ulcer disease. This is not surprising, because Site Unspecified), 1976-79 mortality from this disease is relatively low. A controlled cohort study would require enor- mous numbers of patients, for reasons presented earlier in the discussion of possible effects of ci- metidine on complication rates. One might argue that insofar as cimetidine delays or sup- plants surgical intervention and attendant sur- gical mortality and delays the development of complications, it will forestall some deaths. However, it is conceivable that patients who would naturally develop the more virulent com- plications of peptic ulcer might benefit less from cimetidine or that complications following cessation of the drug would be more severe than they might have been had cimetidine not been administered. Any of these circumstances January- April- July- October- would counter potential improvements in sur- March June September December vival related to cimetidine. In addition, any severe and unanticipated side effects from long- NOTE: 1978 and 1979 figures extrapolated from a 10-percent sample. term use would further compromise cimetidine’s SOURCE Based on data from the Natlooal Center for Health Statistics, Dlvlslon beneficial effects on mortality. of Vital Stat jstics, Iiyattsvllle, Md MORBIDITY Thus, the cimetidine-treated patients reported to From the perspective of BCA, in which there work an average of approximately 36 more days is an effort to translate morbidity into social per patient during the year of the study (dif- resource costs, an important consideration is the ference significant, p < 0.001). effect of cimetidine on disability and days lost The effectiveness of cimetidine compared to from work. Cimetidine produces more prompt other treatments, such as antacids, in enabling and consistent relief from ulcer pain than does patients to return to work is not addressed in placebo. In the short-term treatment of peptic any of the controlled trials we have reviewed. ulcers, it is reasonable to expect that faster heal- ing and pain relief can mean earlier return to Resource Costs work. This potential benefit may be reduced in- sofar as doctors prescribe and patients follow The economic implications of an intervention “rest at home” for a set number of days or weeks such as cimetidine include the costs of the in- following diagnosis of a new ulcer, irrespective tervention itself, the resource costs and savings of the promptness of symptom remission. That related to induced effects on the health care policy would be reasonable, for example, if system, and indirect effects on productivity re- clinicians believed that patients returning to the lated to change in mortality and morbidity. In stress of work with unhealed ulcers would be this section, we offer a few observations on the more likely to develop bleeding or other com- direct costs of cimetidine compared to alter- plications of ulcer disease. natives. We defer consideration of the resource value attached to the induced and indirect ef- A number of the randomized clinical trials of fects of cimetidine until the next part of this cimetidine in the United States included a spe- study, in which we review some of the benefit- cial protocol to assess time lost from work and-cost analyses that have been carried out. (118). A preliminary report presented results in 64 outpatients, 37 treated with cimetidine and The daily cost of cimetidine is less than the 27 with placebo. (Many of the 217 potential daily cost of antacid in doses that have been subjects were disqualified because of uncertain shown to be as effective in promoting the heal- employment status, a problem that is being rec- ing of newly discovered duodenal ulcers (80). tified with a revised protocol. ) Among the pa- The retail cost of cimetidine is approximately tients analyzed, there was a striking tendency to $0.25 to $0.30 per 300-mg tablet.29 Assuming be absent full time or to work full time. Com- consumption of four tablets daily, the daily cost pared to the number of days lost from work of cimetidine is $1.00 to $1.20. during the week prior to treatment, the group Antacids vary in their compositions, neu- receiving cimetidine averaged significantly more tralizing capacities, and costs (115). Two of the days of work in weeks one, two, and four more popular blends of aluminum hydroxide (p< 0.001) and in week six (P< 0.05) following and magnesium hydroxide are Maalox® and the initiation of treatment. This report is Mylanta II®. 30 The latter was the antacid used in notable not only for its results, but because it the studies by Peterson, et al. (116) and Ippoliti, represents an admirable effort to collect data et al. (80). Mylanta II® has approximately 50- pertinent to the economic consequences of a percent more neutralizing capacity than the medical practice in the context of a controlled same quantity of Maalox® and costs approx- clinical trial. imately $3.80 per 12-ounce bottle compared to One of the trials comparing maintenance ci- $1.80 for Maalox®.31 metidine with placebo also reported on the work experience of patients (15). During the year of -“’Ba+wi (In inlc~rmati(ln pr{>vicjecj b} tour Bostf}n-area drug the study, 1 of 32 patients taking cimetidine did st(~res a nci ct~n~i~ten t w’i t h est im a tw (}} the man utacturer. not report to work for 79 days, and 23 of 26 pa- ‘OMylanta 11 c(~ntains, in addltit~n to antacid, the det(~arning si I ictlne a ncl a n t Itla t ulen t ~imeth ic(~nc. tients taking placebo did not report to work for ‘lC~~st e~timatcs bawd on average charge> at tour B(wt(>n-area a total of 1,405 days because of symptoms. drug St (}res. If we assume administration of the same maintenance cimetidine do not alter this assess- amount of antacid as used in the studies cited ment. As with any new drug, uncertainty exists above (seven daily doses, each with approx- as to possible long-term consequences of the imately 120 mEq of buffering capacity), the drug’s use. daily cost would be approximately $1.58 for Maalox® (seven 45-ml doses) and $2.22 for Compared to an intense course of antacids, Mylanta® (seven 30-ml doses). If patients who cimetidine is comparably effective, more risky, are prescribed cimetidine consume three or four and less troublesome to the patient with duo- additional doses of antacid daily, their medica- denal ulcer. Cimetidine plus a moderate amount tion costs would still be comparable to those of of antacids costs no more than a therapeutically patients who follow an intense antacid regimen. equivalent course of intense antacid therapy, Thus, a typical patient can expect to pay no Experts now differ in their recommendations for more, and possibly somewhat less, for ci- initial therapy of duodenal ulcer, some favoring metidine than for a therapeutically equivalent cimetidine and others antacids. A reasonable course of popular, brand-name antacids .32 approach is to select therapy based on each pa- tient’s preferences and personality. Summary Compared to placebo, maintenance treatment Organized according to the benefit-and-cost with cimetidine as long as 1 year significantly model for medical interventions presented earli- reduces the chance of ulcer recurrence. Once er, this part of our case study has described cimetidine is discontinued, patients appear to available information about the effects of cime- relapse at the same rate as they would have tidine—its clinical effects, its health system ef- without maintenance treatment. We are aware fects, and its potential impact on outcome. of no controlled trials comparing maintenance Numerous controlled studies of patients with cimetidine to treatments other than placebo. duodenal ulcer confirm that cimetidine pro- There is little empirical evidence either that motes healing and provides faster and more cimetidine prevents future complications of complete pain relief than placebo. Less con- ulcer disease or that cessation of cimetidine pro- clusive evidence suggests the drug may be more motes complications. At present, FDA is con- effective than placebo for patients with gastric sidering approval of cimetidine for use longer ulcer. An intense antacid program appears to be than 8 weeks in patients with duodenal ulcers about as effective as cimetidine for patients with who are at high risk for surgery. duodenal ulcer, but more evidence on this mat- In European trials, but not in U.S. studies, ter is needed. Clinical studies have also shown cimetidine-treated patients tend to consume less that relief of symptoms is not a reliable in- antacid than placebo-treated patients. Very dicator of healing. In general, European studies limited empirical data are currently available on have found more favorable results with the possible effects of cimetidine on use of other cimetidine than have’ U.S. trials. medication, on diagnostic tests, or on physician Cimetidine used for up to 2 months appears visits. Several studies are underway that may to be a relatively safe drug. Most known side ef- shed light on these matters. fects are minor or reversible, but recently re- ported changes in gastric flora and endocrino- Data we have compiled from NCHS show an logic effects are disturbing. Available studies of unexpectedly sharp decline in the rates of sur- gery for ulcer disease in 1978, the first full calen- “It may be pos~ible to tind less expensive, generic brands (Jt an- dar year after the introduction of cimetidine. tacids with equivalent neutralizing capacity, but the costs (It Maalox ” and Mylanta ” are no more than thcwe CJ[ m~wt other This drop occurred against a background of fall- brands (~f aluminum-magnesium antacids (63), Antacids are ~va]]- ing rates of surgery and hospitalization for ulcer ablc wit h(~ut a presc rip t itm, and their use d(w>s nc~t nccessart 1 y en- disease over the previous decade. Other expla- tail the ctwt tlt a phys]clan visit, but in this dlscussl(~n we have assumed that a high -cl(w .lnt~cid regimen (Ir clmet i dine would bc~ nations are possible, but the widespread use of consumed on I y tol Ic)wi ng a ph ys]cia n \ ad~r ict’. cimetidine may have contributed to the mag- nitude of the 1978 decline in surgery for ulcer lost significantly fewer days of work than pa- disease. tients taking placebo, but no controlled study compares work loss among patients on differ- There is little evidence of any effect on ent, effective treatments. cimetidine on mortality from ulcer disease. In several studies, patients treated with cimetidine
— REVIEW OF BENEFIT-AND-COST ANALYSES OF CIMETIDINE
Available Analyses saved in medical care costs. The estimated $271 million savings is the net result of a $34 million We are aware of two analyses of the social re- increase in drug costs, offset ninefold by $305 source implications of cimetidine (109, 121). million in savings in other expense categories; Both were sponsored by Smith Kline & French the bulk of the $305 million medical care savings Laboratories, through their office of cost-benefit is from estimated reductions in hospital care studies. One study, published by the Nether- ($258 million) and surgeons’ fees ($30 million). lands Economic Institute in February 1977 (109), In addition to the $271 million net savings in analyzed the possible effect of cimetidine on the medical expenditures, the study estimated that Dutch economy. That analysis estimated that if $373 million would have been gained from in- cimetidine had been used by half of all ulcer pa- creased productivity—$329 million (88 percent) tients in the Netherlands, the potential savings from decreased morbidity, and the remainder would have been $23 million, or 21 percent of from decreased mortality. the estimated $111 million total costs of ulcer disease in 1975, We will not comment on this The Robinson Associates analysis was based study, because most of the issues it raises are on two types of estimates. First, physician ex- also raised in the second study, and the latter is perts were asked in late 1977 to estimate the a more recent analysis which focuses on the likely clinical and health system effects of United States. cimetidine compared to traditional therapy for duodenal ulcer patients. Then, applying cost The lmpact of The second study, entitled figures derived principally from SRI’s assess- Cimetidine on the National Cost of Duodenal ment of the costs of ulcer disease in the United Ulcers (121), 33 was conducted by Robinson Asso- States (146), Robinson Associates estimated ciates, Inc., a marketing research and manage- the potential savings in 1977 due to the average ment consulting organization located in Penn- predicted changes in health status and medical summary of the methods and con- sylvania. A care. Summing the results for each cost cat- elusions of the Robinson Associates study, egory, the analysis yielded the conclusions sum- along with our critique of the study, are marized in the preceding paragraph. presented in the section below. A detailed reconstruction of the Robinson The Study by Robinson Associates, Inc. Associates analysis is beyond the scope of this review. Below we provide a description of cer- Summary of Methods and Conclusions tain methodologic features of the analysis as a The Robinson Associates study (121) esti- basis for our comments in the critique that mated that if cimetidine had been used in 80 per- follows. First, we consider the expert estimates cent of duodenal ulcer patients in the United of the clinical and health system effects of cime- States, 1977 national health care costs for duo- tidine; then, we consider the conversion of these denal ulcer disease would have been reduced by estimates into projected annual savings. $645 million (29 percent of that study’s esti- mated total expenditures for duodenal ulcer). An estimated $271 million would have been 50 ● Background Paper #2. Case Studies of Medical Technologies
Twenty-three physicians who were familiar costs for each type of patient were calculated as with cimetidine served as expert consultants for the sum of costs for the proportion of those pa- the Robinson Associates analysis. Each was tients given surgery plus costs for those not asked in an interview about five specified ulcer- given surgery, as follows: patient types—ranging from a patient with typical symptoms and newly diagnosed ulcer to proportion of patients of this type who are hospitalized x [(proportion of patients hospitalized without surgery a patient hospitalized with the complication of x number of nonsurgical hospitalizations per year bleeding but not requiring immediate surgery— x average length of stay for nonsurgical patients which were intended to represent a spectrum of x cost per day) severity of illness in patients with duodenal + (proportion of patients hospitalized with surgery x cost per surgical admission)] ulcer. The 23 physicians first estimated the pro- = total annual hospital cost per patient of this type portion of all ulcer patients represented by each type. Then they described what they believed to Similar calculations yielded an estimate of the be the usual treatment for each patient type and annual costs in each cost category for each type any changes in that treatment that would be of patient with and without cimetidine. made in a program that would include cimeti- Next, the percentage difference in costs in dine. Finally, they estimated clinical and health each cost category due to cimetidine was calcu- system effects (including such elements as re- lated for each type of patient. The percentage currence, physician visits, hospitalizations, change for each type of patient was then surgery, diagnostic tests, missed work, com- weighted by the proportion of all ulcer patients plications, and mortality) for each type of pa- estimated by the physicians to be represented by tient treated without cimetidine and with up to 8 that type. This yielded the percentage change in weeks of cimetidine. The physicians were not a given cost category for an “average” patient asked to estimate dollar costs for any postulated treated with cimetidine rather than traditional effects. therapy. The methods that were used in the Robinson The percentage change in cost per “average” Associates study to convert estimated clinical patient was further adjusted to reflect: the and health system effects into dollar savings posited extent of use of cimetidine. The physi- were as follows. As a baseline for estimating the cian consultants predicted that an average of 80 costs of duodenal ulcers, Robinson Associates percent of the five patient types would be used estimates of the costs of peptic ulcer disease treated with cimetidine 2 to 3 years after the in 1977 developed by SRI (146). Within each time of the interviews. This figure, used as the direct and indirect cost category, the analysts basis for dollar projections in Robinson estimated from secondary sources the fraction Associates study’s conclusion, is a composite of of peptic ulcer costs attributable to duodenal the estimated extent of use (ranging from 73 to ulcer disease (with the remainder attributable to 93 percent) for each of the five types of patients. gastric ulcer). Next, the percentage change in cost for each To estimate the proportion of costs that cost category, as adjusted for the proportion of would be saved by cimetidine, the analysts then patients using cimetidine, was multiplied by proceeded as follows. First, they assigned prices the costs of duodenal ulcer disease assigned to to each component of each cost category. For that category. This provided a dollar estimate of example, in the category of hospital costs, they savings in each category. Summing the dollar established the cost per hospital day for patients estimates over all cost categories yielded the who do not have surgery and the cost per hos- total projected savings attributable to the use of pitalization for patients who do undergo cimetidine by a given proportion of patients. surgery. Next, the analysts combined these cost components with physician estimates of the In short, the Robinson Associates analysis management and course of patients with and used prices of the components of medical care without cimetidine. For example, the hospital only as a basis for estimating the percentage change in cost due to cimetidine. Once derived, from cimetidine. The accuracy of the estimated these percentages were applied to independent savings attributable to cimetidine in the Robin- assessments of the cost burden of all duodenal son Associates study depends on at least five ulcer disease to estimate dollar savings. features: 1) the accuracy of the clinical and health system effects projected by their physi- Critique cian experts; 2) the relation between a percent- The cost-and-benefit analysis that Robinson age reduction in health services devoted to ulcer Associates prepared for Smith Kline & French disease and savings in health resources; 3) the has many positive attributes. First, the study accuracy of the estimated total costs of all represents the kind of serious analysis of the duodenal ulcer disease used as a baseline for economic effects of a new drug that is important percentage savings; 4) the applicability of pro- and valuable. If society is to attend to both the jected percentage effects to the total population economic and clinical implications of medical of patients with duodenal ulcer disease; and 5) interventions, careful analyses of costs and the validity of the methods used to compute benefits are essential. Second, we believe the average percentage effects due to cimetidine. We analysts selected appropriate categories of question some of the assumptions and methods resource costs to assess. Their direct cost com- used in each of these five areas. ponents correspond roughly to the health system effects outlined in the benefit-and-cost Let us consider first the physician experts’ model we presented earlier in this case study. opinions of the clinical courses of patients with Their translation of mortality and morbidity and without cimetidine. The mean of these components into indirect costs is appropriate estimates is intended to represent an unbiased for a resource cost analysis. Third, their ap- estimate of the course of duodenal ulcer disease proach of comparing estimated net resource ef- using conventional treatment, and an unbiased fects of cimetidine to resource use without estimate of the effects of cimetidine. An unbias- cimetidine is a reasonable one. Fourth, their ed estimate of the former is best achieved by method of obtaining physician estimates of physicians of varied specialty backgrounds who clinical and health system effects was an im- together treat the full range of patients with aginative one, and it required no guesses about ulcer disease, An unbiased estimate of the latter costs from clinicians. Finally, the report pro- requires both knowledge of cimetidine’s clinical vides sufficient detail about its methods and effects and a neutral attitude toward the drug. assumptions to allow the reader to reach in- dependent conclusions. The 23 physicians whose opinions form the basis of the Robinson Associates study were all We believe this report deserves scrutiny, be- gastroenterologist-researchers who had partici- cause, to our knowledge, it is the most com- pated in early clinical trials of cimetidine and prehensive analysis of the resource implications whose participation in this study was solicited of cimetidine in the United States. As a by Smith Kline & French (121). This selection, thorough economic assessment of a recently in- the authors state, ensured informed opinion troduced drug, the study may serve as a model about the potential effects of cimetidine—but it for future evaluations of other emerging medical does not ensure individual objectivity or a practices. In the discussion of the study that balanced range of views. Of 32 physicians con- follows, we have attempted to examine the tacted by Smith Kline & French to participate in analysis carefully in light of the benefit-and-cost the study, 4 refused either because they were too model and data presented earlier and the guide - 34 busy or for unknown reasons. It is possible lines for review of benefit-and-cost analyses that are presented in the next section of this case study. “Four others were disqualified or unavailable because of exten- We believe the Robinson Associates study sive travel. One of the 24 physicians who agreed to participate was substantially overestimates expected savings not interviewed because of illness (121). that researchers who were less enthusiastic Cost savings in the Robinson Associates about the drug were less eager to express their study are estimated as a proportion of the total views when contacted by the manufacturer. costs of duodenal ulcer disease. Two aspects of the Robinson Associates calculations deserve To enhance the credibility of subjective physi- comment, and we expand on these points be- cian estimates, Robinson Associates cite a low. First, a given percentage reduction in Danish study (66) that compared observed ex- health services requirements for a particular perience in 154 patients over 13 years with phy- disease probably does not convert directly to an sician estimates of some of the long-term con- equivalent proportion of health resource sequences of ulcer disease (proportion treated savings. Second, we believe that the baseline surgically and proportion of medically treated costs of duodenal ulcer disease employed by patients with varying degrees of symptoms). Robinson Associates are too large, primarily The Danish study found that the mean estimates because of an inflated indirect cost estimate. of 143 physicians corresponded fairly closely to patient experience. The Danish investigators An implicit assumption in applying a percent- interviewed a wide range of general practi- age cost reduction to the health system expend- tioners, medical specialists, and surgeons to ob- itures for ulcer disease is that savings will be tain their mean estimates. These investigators realized in direct proportion to the decreased also noted that there were some systematic use of medical services. For example, if hospital biases that tended to balance one another. For days decline by 10 percent, then 10 percent of example, the 65 general practitioners in the resources devoted to hospital care are assumed Danish study estimated that 15 percent of pa- to be saved. This calculation uses average costs tients would undergo operations for ulcers, and per hospital day rather than marginal costs of the 50 surgeons predicted 27 percent; the the last 10 percent of hospital days. To the ex- observed proportion was 22 percent. Thus, this tent that fixed and semivariable costs contribute study suggests the importance of using a broad- to the cost of a hospital day, the marginal sav- ly based sample to achieve unbiased mean ings from reducing a given fraction of hospital estimates. Just as surgeons’ estimates alone days will be less than the average cost of those might not accurately represent surgery experi- days.35 The remaining fixed cost components ence, a group of research gastroenterologists will simply be redistributed over the remaining seems unlikely to represent a fair cross-section hospitalized patients, Thus, the direct conver- of physician experience with and expectations sion of percentage reduction in hospital days to for patients who have ulcer disease. percentage savings in resource costs of hospital care may be questioned.36 Short-term resource The effects estimated by the physician con- savings might even be less than the averted sultants in the Robinson Associates study varied marginal costs, insofar as available supply of widely. The projected cost consequences of 37 hospital resources induces other demand. If using cimetidine in 100 percent of duodenal hospital beds previously occupied by patients ulcer patients ranged from a savings of 67 per- with ulcer disease are filled by other patients cent based on one physician’s estimates to an in- (without ulcer disease) who previously would creased expenditure of 40 percent based on not have been hospitalized, then potential sav- another’s estimates. Seven of the physicians ings would be eroded further. projected effects that yielded net losses or small savings (of less than 10 percent), while eight “Fixed c[~sts are independent ot the volume t~f services. Semi- physicians projected effects that led to savings variab]e costs are a t unct i~)n (>f both time and volume of services. “A related problem is the trequent use of charges as pr[~xies for of 40 percent or more. If the selection was resource costs t~t care. Charges rel]ect average rather than mar- biased in favor of physicians at the “optimistic” ginal costs, and tor a variety of reasons, charges for particul~lr ser- end of the spectrum of clinical and health sys- vices may differ trom their average rew~urce c[~sts. “The notion ot hospital bed supply creating demand for mc~re tem effects of cimetidine, the mean cost savings hospital services, called Rt)emer’s Law, was t)riginally proposed 20 estimate will be similarly biased. yedrs ago ( 130). The total costs of duodenal ulcer disease used ample, consider the area of hospital costs alone. by Robinson Associates are based on the esti- Assuming traditional therapy, Robinson As- mated costs of peptic ulcer developed by SRI sociates estimate total hospital costs to be $732 (146). SRI’s estimate is substantially higher than million. At 80-percent cimetidine use, they es- another recent, independent estimate of the cost timate savings in hospital costs to be $258 mil- of ulcer disease by NCDD (4), and, as we dis- lion, a 35-percent reduction from hospital costs cussed earlier, we believe a more correct figure with traditional therapy. According to the SRI lies between the two. If Robinson Associates figures that served as a baseline for the Robin- had based their projected savings from cimeti- son Associates estimates, nearly 72 percent of dine use on the costs of ulcer disease as hospital costs for ulcer patients in 1977 were due estimated by NCDD, making no other changes to the estimated 20 percent of hospitalized pa- in their analysis, the resulting estimated savings tients who underwent surgery (146). Assuming would have been over 50 percent less. Use of the excluded patients, who are most severely ill, NCDD’s cost figures, without altering any other were responsible only for a proportionate share assumption or calculation used in the Robinson of costs for surgical cases, the proportion of Associates study, would have produced an es- total hospital costs for duodenal ulcer disease timated savings of only $307 million, in contrast devoted to these patients would be approx- to the $645 million savings projected on the imately 32 percent, and the dollar amount de- basis of SRI’s figures. Use of our midpoint cal- voted to their care would be $237 million .38 culation developed in the section of this case Although the expert consultants were not study on the cost of peptic ulcer disease yields asked about this group of most severely ill pa- estimated savings of only $476 million. tients, we think that cimetidine would not have Another important source of misestimation in been expected to alter the acute management of the Robinson Associates study is the assumption more than a small fraction of them. Assuming that the five patient types represent the full that 80-percent cimetidine use would have been range of patients with duodenal ulcer disease. estimated to save as much as 15 percent (ap- The most severely ill type of patient included in proximately $36 million) of the hospital costs the Robinson Associates study is one who is for these patients, and then applying the propor- hospitalized and bleeding but not in need of im- tion of savings estimated for “all” duodenal mediate surgery. Thus, the study omits patients ulcer patients in the Robinson Associates study who have very severe bleeding or other life- to the hospital costs attributable only to the in- threatening complications of ulcer disease such cluded patients, we compute the savings in hos- as perforation. According to CPHA data (42), pital care to be $209 million rather than $258 nearly 6 percent of patients hospitalized for million. 39 duodenal ulcer disease in 1977 had perforation, and 28 percent had bleeding. The number of ex- ‘pProp(~rtlc~n of hospital costs due to surgical care (~t excluded cluded patients who require prompt surgery patients = proportion of surgical cases excluded x prc)pc>rt](>n of total costs due to surgical cases: 0.324 = (0.09 0.20) x 0,72. may be estimated conservatively to include 90 Dollar amf~unt devoted to hospital care of excluded patients = percent of patients with perforation (or 5 per- proporticln of hospital costs due to excluded patients x t[>tal hos- cent of hospitalized patients) and between 10 pita] costs: $237 mi]]ion = 0.324 X $732 mi]]i{}n, “Let : and 20 percent of patients admitted for bleeding Cs estimated hospital costs due to all pat]ents with (or an additional 4 percent of hospitalized pa- traditional therapy tients). Thus, approximately 9 percent of CE ~ estimated hospital costs due tcl excluded patients with traditi<>nal therapy hospitalized patients, all of whom receive cl ~ estimated h(}spital costs due t o included patients with surgery, are excluded from the range of patients traditional therapy in this study. SE estimated hosplta] savings from all patients with 80-percent cimetldine use The omission of these patients from the PSE ~ estimated pr[lp(~rt ion [~t costs saved by 80-percent cimet idlne use a t tribu table to excluded patients Robinson Associates study has substantial con- PSI ~ estimated prtlporti(~n ot costs saved by 80-percent sequences for the study’s cost estimates. For ex- clmetid]ne use a t tribu table t o Included patients 54 ● Background Paper #2: Case Studies of Medical Technologies
Thus, the incomplete spectrum of patients in- The method used by Robinson Associates to cluded in the study produces an overestimate in compute the expected reduction in costs caused savings of nearly $50 million in the area of by cimetidine use has another subtle, but po- hospital costs alone. The exclusion of the most tent, effect on their estimate. Assume for the severely ill patients also incurs additional, if moment that the interviewed physicians did smaller, overestimates of savings in other cost constitute a representative sample of informed areas. If cimetidine reduces the fraction of pa- opinion about the effects of cimetidine. It would tients who reach the most severely ill category, be desirable, then, for the overall estimated per-
however, then this source of overestimation centage reduction in costs to be a statistically would be reduced proportionately. The authors unbiased measure of individually perceived per- of the Robinson Associates report repeatedly centage reductions. Take a simplified case. If point out that their projected percentage savings physician A provides estimates of cimetidine’s are unaffected by changes in estimated baseline effects that produce a 70-percent decrease in costs for ulcer disease. As we have just seen resource consumption, and physician B pro- above, however, the percentage savings cal- vides estimates that produce a 50-percent culated in the study are quite sensitive to the in- decrease, we would like the overall estimated clusion or exclusion of different types of pa- reduction to be midway between the two, or 60 tients with duodenal ulcer. percent. Since we presumably trust each physi- cian’s judgment equally, each perceived percent- Two other sets of assumptions in the Robin- age reduction should contribute equally to the son Associates study also affect the calculated overall estimate of percentage reduction. How- savings. The first of these is the relative dollar ever, the method used by Robinson Associates values assigned to the components of each cost to compute percentage reduction in costs has the category (e.g., how much less expensive is a effect of placing greater weight on the percent- hospital stay for nonsurgical than for surgical age reduction estimates of physicians who patients?). The second set of assumptions is the perceive ulcer disease as more severe and requir- estimated proportion of all included patients in ing higher levels of resources. each of the five patient types. The data underly- ing these assumptions can be expected to vary Mathematically speaking, this distortion oc- over some range. To accommodate such varia- curs because the ratio of estimated means is not tion, one could, for example, estimate a con- the same as the mean of estimated ratios. To see fidence interval about physician estimates of the how this distortion can arise, again consider proportion of patients of each type.40 The two simplified examples. First, physician A and Robinson Associates study would have been .physician- B are asked about the consequences of strengthened by explicit sensitivity analysis, ulcer disease with and without cimetidine for a testing the effect on the conclusions of given type of patient. The effects are translated systematic alteration of key assumptions. into various categories of resource cost, such as hospital care. Physician A estimates effects that (continued from p. 53) lead to a total annual cost of $1,000 without Given: c- $732 million (from Robinson Associates study) cimetidine and $500 with cimetidine use. Physi- CE - $237 million (from preceding footnote) cian B estimates effects that lead to a cost of CI - C – CE = $(732 – 237 million) = $495 million (by $50 definition, C = CI + CE) $100 without cimetidine and with the drug. P SE - 0.15 (assumption; see text) In each case, the estimated percentage reduction P SI - 0.35 (from Robinson Associates study) is 50 percent. Proceeding as Robinson Then: p P S- CE x sE + CI x SI Associates did, we can compute an average cost - ($237 million) (0.15) + ($495 million) (0.35) without cimetidine and an average cost with = $209 million. cimetidine. d’JT~iS is separate from the question of bias in the mean estimate, $1,000 + $100 average cost without = $550 i.e., whether a group of gastroenterologist-researchers would = cimetidine 2 perceive the world of ulcer patients to be made up of as high a pro- $500 + $50 portion of “initial diagnosis patients” (type 1) as would a group of average cost with = = $275 general practitioners or less specialized internists. cimetidine 2 Then the “average” percentage reduction at- The estimation method used by Robinson tributed to cimetidine, as computed by Robin- Associates confounds the estimate of perceived son Associates, would be the difference between effects of cimetidine, on the one hand, with these average costs divided by the cost without variability in the perceived severity and overall cimetidine, or: management of ulcer disease, on the other. If the Robinson Associates study had taken the mean $550 – $275 0.50 = of physician estimates with traditional therapy $550 as the baseline from which percentage reduc- In this case, both physicians projected the same tions were calculated, there might be a stronger percentage reduction, and the calculated percen- case for an approach like that used. However, tage reduction agrees with both of them. So far, the calculated percentage reductions were ap- this approach appears sound. plied to an independently determined baseline cost. This reinforces the argument for seeking Now consider the following variation. Physi- an unbiased measure of expected percentage cian A estimates effects that cost $1,000 without reduction, namely the mean of the physicians’ cimetidine and $400 with cimetidine, a 60-per- percentage estimates. cent reduction in costs. Physician B estimates ef- fects that lead to a cost of $100 without cimeti- The practical consequences of this distortion dine and $60 with the drug, a 40-percent re- are substantial. A series of bar graphs provided duction. The average estimated reduction is: in the Robinson Associates report (their tables 0.60 + 0.40 34 through 43, pp. 54-63) shows percentage = 0.50 changes in cost based on the estimates of each of 2 the 23 physician informants. A separate figure or 50 percent. Calculated by the method of in the report depicts the distribution of physi- Robinson Associates, the percentage reduction cian percentage estimates for each of nine cost IS: categories and overall costs. On the basis of the bar graph for the distribution of physician (51,000 + $100) – ($400 + $60) estimates of overall cost savings, we calculate $1,000 + $100 that the mean of the estimated percentage reduc- $1,100 – $460 = tions by the 23 physicians was approximately 24 $1,100 percent (see table 20). By contrast, the “mean” $640 shown in the Robinson Associates bar graph = — =0.58 $1,100 and used in the analysis was a percentage cost reduction of 34 percent (at 100-percent cimeti- Thus, the calculated reduction of 58 percent is dine use). much closer to the perceived reduction of physi- This suggests that the “average” percentage cian A, who viewed ulcer disease in this type of reduction used in the Robinson Associates patient as more severe and costly than did physician B.41 Robinson Associates estimates “mean” percentage cost savings as an “average of total costs”: ~ i sY ~b{)] iC~ ] Iv the ~1 I [~~(,nce beth,een the rncttl {~cj in effect used by Rc&lnwln A’s~tlcidtes to calculdk’ a ‘ mean” percentage cost i=1 x 100 (1) reduction and the mean of the percentage reducti(>ns estimated by the phy’>lcl.ln+ c a n be expres>ed a~ lt~ll[~w~ — number t~t physician expert% 1=1 ;Cl ; c(wt ca]cu Iated }rom physlclan t est tmates ok effects The mean of percentage savings estimated by physicians is: WI th tradl tlt~ndl tred tment ~ wlth(w t clmet]dlne) cc, —= C(M t cd ]CU [a ted [ r(~m phv~lclan I est I ma tes of et[ec ts W. I t h d ] ] pat len t~ reccl v ln~ c i met i d I ne treatment Then: (2) TC1 _ ~~1 = c{)~t ~al,lng+ ~d]~ul~ted tr~,rn ~hy,~lclan I estlma te~ n TCI – CCI = percentage c(wt reduc t](~n calculated trorn physician In general, eqn. 1 # eqn. 2, although the two may give the same TCI i e~t t ma te~ result in exceptional circumstances. Table 20.—Percentage Cost Savings Estimated percentage reduction in costs we believe the From Robinson Associates Study estimated $645 million savings are probably two Physician number Percentage savingsa to three times too large. Potential bias intro- 1 ...... 68% duced by the selection of physician informants 2 ...... 62 would increase the magnitude of that over- 3 ...... 62 estimate. 4 ...... 55 5 ...... 50 6 48 Despite our criticisms of the Robinson Associ- 7: : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : 47 ates study, we believe its basic thrust is prob- 8 ...... 42 ably correct. Cimetidine does appear to save 9 36 10: : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : 35 more medical resources than it costs. The $305 11...... 28 million savings in medical costs that Robinson 12...... 27 Associates estimates from the use of cimetidine 13...... 19 are approximatel nine times the estimated $34 14...... 13 y 15...... 12 million direct costs of the drug. Thus, even if the 16...... 11 drug costs were tripled and the estimated sav- 17...... 8.5 18...... 8.5 ings reduced by two-thirds, use of cimetidine 19...... 3 would still appear to be an economically sound 20...... o investment. Also, the estimated savings in 21...... –9b b health resources omit potential gains in produc- 22...... –24 23...... –40b tivity from use of the drug. Total ...... 562% The emerging empirical evidence cited in the Mean percentage cost savings = 562/23=24.4% section of this case study on health system ef- aGauged from the height of the bar graph for each physlclan In Robinson Assoclatestable43 fects supports the belief that use of cimetidine bEstlmated st s co increa e probably saves medical resources. In the coming SOURCE Robinson Associates, Inc, The /mpacfof C/met/d/neon the Naf/ona/ years, more evidence will probably accumulate CosfofDuoderra/U/cers, 1978(121) about the costs, risks, and benefits of cimetidine compared to alternatives. We may learn, for ex- analysis was approximately 42 percent larger ample, about newly recognized adverse effects than the mean of the estimated percentage of the drug or about rebound in the number of reductions provided by the physician experts.42 ulcer patients undergoing surgery or about the (Similar discrepancies of varying degree are development of safer, equally effective and ac- found with each category of cost shown in the ceptable treatments. The comparative cost effec- Robinson Associates bar graphs.) Basing overall tiveness of cimetidine for patients with ulcer percentage cost savings on the mean of percent- disease in the long run is a matter of continuing age reductions estimated by the 23 physicians empirical study, would reduce the projected savings at 80-per- Our discussion of the Robinson Associates cent cimetidine use by approximatel $190 y study illustrates some of the difficulties of de- million, from $645 million to approximately signing and conducting economic analyses of $455 million. newly introduced medical practices. The work In summary, we believe the Robinson Associ- of the Robinson Associates analysts must be viewed in the context of the information avail- ates analysis substantially overestimates ex- pected savings from cimetidine. Considering the able at the time it was done. The Robinson exaggerated baseline costs of ulcer disease Associates study was undertaken before there assumed in the analysis, the incomplete spec- was widespread clinical experience with cimeti- trum of patients included, and the distortion in- dine, and the analysts faced a dearth of em- troduced by the method of calculating mean pirical findings relating directly to resource costs. Given the information available at that 42 0.34 –0.24 = 0.416 time, the analysts might have considered the fol- 0.24 lowing procedure. First, define prototypical pa- -
tients that represent the full range of patients Specification of the Problem with ulcer disease, including the most severely 1. Is the population of interest appropriately ill. Second, obtain from a broad, representative defined (e.g., a population with a particular group of physicians baseline estimates of the diagnosis, or having a particular clinical course of disease using traditional therapy. symptom, or undergoing a particular test or Third, check how closely these estimates corre- treatment)? Is the population consistently spond to other estimates of the total cost of defined throughout the analysis? examine critically duodenal ulcer disease, 2. Does the analysis specify the interventions assumptions that underlie the estimates of the of interest and address them consistently health system effects in each major cost cate- throughout the analysis? gory, and reach consensus estimates. Fourth, 3. Are the conditions of use (e.g., ideal v. present to physicians familiar with cimetidine average) specified and consistently treated in the consensus-estimated clinical courses for each the analysis? patient type with traditional therapy; ask them to assume the consensus represents actual pa- Methods of Analysis tient experience; and then ask them to estimate what changes, if any, would follow from the in- 1. Are the analytic methods selected appropri- troduction of cimetidine. Finally, calculate the ate to the objectives of analysis? (e. g., CEA mean of the estimated percentage cost reduc- v. BCA, use of decision-analytic framework, tions and apply it to appropriately estimated etc. ) costs of illness. 2. Is the time frame of analysis appropriate to the objectives (e. g., is patient lifetime a more Guidelines for Review of Health Care suitable focus than a cross-section of pa- tients for a limited time?) Cost Analyses 3. Are clinical effects and other benefits appro- Presented below are guidelines in the form of priately specified? Are the methods of as- a series of questions that may aid in the design sessment explained? Are incremental bene- and review of cost-benefit and cost-effectiveness fits the basis for analysis? studies. These guidelines cover matters of 4. Are cost estimates complete and appro- definition and purpose, analytic methods, and priately categorized? Has double counting conclusions. They are presented here in concise been avoided? Are induced costs and savings form and presume familiarity with the rationale considered? Are marginal resources costs the and basic components of benefit-and-cost basis for analysis? Are methods fully ex- analyses in health care (see, e.g., 89). plained? 5. Are benefits and costs aggregated properly across the population and intervention of in- Objectives of the Analysis terest? Is the analysis restricted to a few uses 1. What is the purpose of the analysis? Is it of multipurpose intervention? a) to assess the optimal management of in- 6. Are benefits and costs appropriately aggre- dividual patients with a particular clinical gated over time? Is discounting employed? Is condition; b) to measure the clinical and the discount rate appropriate? economic importance of particular clinical 7. Are projected effects justified? Are the problems; c) to compare alternative strate- estimates based on empirical data or opin- gies for addressing a particular health prob- ion? Are uncertainties recognized? Are the lem in a particular population; d) to com- sources of all estimates clearly explained? pare alternative investments in health pro- Are estimates unbiased? Are assumptions grams; or e) to compare health and other acknowledged, fully exposed, and justified? social resource investments? Are estimates based on evidence from the 2. Are the interests and potential biases of the same population and intervention that are analyst and client acknowledged? Are meas- the subjects of analysis? Are extrapolations ures taken to guard against potential bias? and interpolations reasonable? 8. Are underlying trends in disease distribution Conclusions and severity taken into account? Are other 1. Are the conclusions consistent with the anal- pertinent population trends assessed? ysis and appropriately qualified? 9. Are technological changes and evolution of 2. Are conclusions robust? Have assumptions practices taken into account? and key uncertainties been subjected to a 10. Are the distributions of benefits and costs sensitivity analysis? important and are they considered?
SUGGESTIONS FOR FURTHER RESEARCH
Our suggestions for further research are baseline the epidemiologic trends in the disease cognizant of broadened clinical experience with discussed in this case study. As mentioned cimetidine in recent years and newly emerging previously, the rate of surgery for ulcer disease empirical evidence of health system effects of shows a steeper decline in 1978 than would be the drug. Any analysis must take account of the predicted from the previous trend. Confirma- shifting epidemiologic pattern of ulcer disease. tion of this drop and additional evidence linking We believe that sound CEAs comparing effects it to cimetidine would provide a sounder basis of different strategies over an ulcer patient’s for projecting direct cost savings in one area, lifetime would provide valuable guidance to and for attributing such savings to the use of medical decisions for patients with ulcer disease. cimetidine. Additional evidence of health sys- tem effects of cimetidine may emerge from the As discussed earlier in this case study, a ongoing research that we have described. number of well-controlled clinical trials have assessed the clinical effects of cimetidine in the In further analyses of cimetidine, one fun- past few years. These trials have not dealt with damental concern must be the time frame of the every important clinical comparison (e.g., analysis. Calculations based on a single year, maintenance antacids v. cimetidine), but they for example, will overlook the important dis- have provided a much sounder empirical base tinction between avoidance of surgery and delay for projecting some of the clinical consequences in surgery. From the evidence we have cited in of the drug. Since clinical use of cimetidine is so this case study, there is a good reason to believe widespread, a broad group of clinicians could that a year of maintenance cimetidine imparts a be consulted for subjective estimates of likely delay in inevitable surgery rather than a long- consequences in areas where clinical trials are lasting cure of ulcer disease, lacking. It would be possible to begin by send- More generally, with diseases such as peptic ing participating physicians a summary of em- ulcer, which are chronic, and with interventions pirical clinical findings with cimetidine. A such as cimetidine, whose long-term effects may systematic method, such as a Delphi process, be very important, a benefit-and-cost analysis could then be used to reach group consensus on might best focus on a cohort of patients, project- key probabilities .4: ing effects over their lifetimes. Rather than at- There is still little empirical information on tempt to enumerate all resource implications for health system effects of cimetidine to serve as a a cross-section of the population in a single basis for estimating resource costs and savings. year, it might be more helpful to estimate the Any analysis of the health system effects of an present-value lifetime resource costs and health intervention in ulcer disease must take as a effects for a given population of ulcer patients, Then, on the basis of available research evi- 43 The Delphi method is an iterative process for reaching group dence and subjective clinical judgments, one consensus that attempts to separate the reasons for an opinion from the authority of the opinionholder. It has been employed in could estimate the consequences for a given type the analysis of health care decisions to obtain estimates of prob- of patient of pursuing different management abilities from a group of medical experts (127). strategies. This approach would allow compari- son of marginal costs with incremental benefits If the object of analysis is to help inform clini- for each shift in strategy. Focusing on each pa- cians and health policy decisionmakers about tient’s lifetime rather than on a given calendar the efficient use of resources in the care of pa- year would highlight, among other things, un- tients with ulcer disease, then the most helpful certainties in the long-term side effects of use of approach would be to do a CEA, oriented to a relatively new agent such as cimetidine. particular groups of patients, comparing incre- mental clinical benefits, in terms of morbidity The prototype decision tree shown in figure 4 and mortality, to marginal resource costs. An (PP. 26-27) could serve as a starting point for assessment of the cost effectiveness of different such an analysis. At least one group of research- management strategies in all patients with ulcer ers, in Switzerland, has begun to take a de- disease would be an enormous undertaking, but cision-analytic approach to the lifetime conse- analyses do not have to be global to be valid quences of duodenal ulcer treatments (137). and useful. As long as their limitations are Their published analysis is restricted to a understood and taken into account, such studies specific 50-year-old male patient, and one might can aid both health policy formulation and fault their figures for not discounting future medical decisionmaking. costs and benefits, but these researchers do ap- proach the problem in an appropriate way.
REFERENCES
1. Acton, J. P., Evaluating Public Programs To Lance (eds. ) (New York: Churchill Livingstone, Save Lives–The Case of Heart Attacks, Rand 1978). report R-950-RC (Santa Monica, Calif.: Rand 8. Bardhan, K. D., et al., “Comparison of Two Corp., 1973). Doses of Cimetidine and Placebo in the Treat- 2. Almy, T. P., Dartmouth Medical School, Han- ment of Duodenal Ulcer: A Multicentre Trial, ” over, N. H., personal communication, 1980. Gut 20:68, 1979. 3. Almy, T. P., et al., “Panel I: Prevalence and 9. “Double-Blind Comparison of Cimeti- Significance of Digestive Disease, ” Gastroenty. dine a;d Placebo in the Maintenance of Heal- 68:1351, 1975. ing of Chronic Duodenal Ulceration, ” Gut 4. “Report of the Workgroup on the So- 20:158, 1979. cioeconomic Impact of Digestive Diseases of 10. Belber, J. P. “Gastroscopy and Duodenosco- the Subcommittee on Epidemiology and Im- py, ” in Gastrointestinal Disease, vol. 1, 2d cd., pact, ” in Report to the Congress of the United M. H. Sleisenger and J. S. Fordtran (eds. ) (Phil- States of the National Commission on Diges- adelphia: W. B. Saunders Co., 1978). tive Diseases, VOI. 4, pt. 4, DHEW publication 11. Binder, H. J,, et al., “Cimetidine in the Treat- No. (NIH) 79-1885 (Bethesda, Md.: National ment of Duodenal Ulcer: A Multicenter Dou- Institutes of Health, 1979). ble-Blind Study, ” Gastroenty. 74:380, 1978. 5. Bader, J. P., et al., “Treatment of Gastric Ulcer 12. Black, J. W., et al., “Definition and Antag- by Cimetidine: A Multicentre Trial, ” in Cime- onism of Histamine Hz-Receptors, ” Nature, tidine —Proceedings of the Second Interna- 236:385, 1972. tional Symposium on Histamine Hz-Receptor 13. Blackwood, W. S., et al., “Cimetidine in Duo- Antagonists, W. L. Burland and M. A. Sim- denal Ulcer: Controlled Trial, ” Lancet 2:174, kins (eds. ) (Amsterdam-Oxford: Excerpta Med- 1976. ica, 1977). 14. Blumenthal, I. S., Research and the Ulcer Prob- 6. Bank, S., et al., “Histamine H,-Receptor An- lem, Rand report R-336-RC (Santa Monica, tagonists in the Treatment of Duodenal Calif,: Rand Corp., June 1959). Ulcers, ” S. Afr. Med. }. 50:1781, 1976. 15. Bodemar, G., and Walan, A., “Cimetidine in 7. Bardhan, K. D., “Cimetidine in Duodenal Ul- the Treatment of Active Duodenal and Prepy - aeration, ” in Cimetidine: The Westminster loric Ulcers,” Lancet 2:161, 1976. Hospital Symposium, 1978, C. Wastell and P. 16. , “Maintenance Treatment of Recurrent Peptic Ulcer by Cimetidine,” Lancet 1:403, Risks, and Benefits of Surgery, J. P. Bunker, et 1978. al. (eds. ) (New York: Oxford University Press, 17. Bonnevie, O. E., “The Incidence in Copenha- 1977). gen County of Gastric and Duodenal Ulcersin 31. ~ooper, B. S., and Rice, D. P., “The Economic the Same Patient,” Sc, IGastr. 10:529, 1975. Cost of Illness Revisited, ” Soc. Sec. Buil. 39:21, 18. , “The Incidence of Duodenal Ulcer in 1976, Copenhagen County,” SC. 1. Gastr. 10:385, 32. DeGalocsy, C., and Van Ypersele de Strihou, 1975. c., “Pancytopenia With Cimetidine” (letter), 19. , “The Incidence of Gastric Ulcer in Ann. lnt, Med. 90:274, 1979. Copenhagen County,” SC. J. Gastr-. 10:231, 33. Delaunois, L., “Hypersensitivity to Cimeti- 1975. dine” (letter), N. Erzg. }. Med. 300:1216, 1979. 20. “Survivali nPepticUlcer,” Gastroerzty. 34. Department of Health, Education, and Wel- 75:1055,1978 fare; Public Health Service, The .Vatiorza/ 21. Brown, R.C., etal., “HospitalA dmissionsfor Ambulatory Medical Care Survey: 1975 Sum- Peptic Ulcer Xring 1958-1972;’ Br. Med. 1. mary, United States, January-December 1975, 1:35,1976. Vital and Health Statistics Series 13, No. 33, 22. Burland, W. L., and Simkins, M. A. (eds.L DHEW publication No. (PHS) 78-1784 (Hyatts- Cimetidine: P~oceedings of the Secorzdlnterna- ville, Md.: National Center for Health Statis- tional Symposium on Histurnine Hz-Receptor tics, January 1978). A~I tago)lists (Amsterdam-Oxford: Excerpta 35. , Health Services and Mental Health Ad- Medica, 1977). ministration, Acute Conditions: Incidence and 23. Burland, W. L., et al., “The Longer Term Associated Disability, United States, ]Llly 1970- Treatment of Duodenal Ulcer With Cimeti- )une 2972, Vital and Health Statistics Series 10, dine, ” in Cin~etidi)~e: The Westminster Hos- No. 82, DHEW publication No. (HSM) 73-1508 pital Symposium, 1978, C. Wastell and P. (Hyattsville, Md,: National Center for Health Lance (eds. ) (New York: Churchill Livingston, Statistics, April 1973). 1978) . 36. , Office of Health Research, Statistics, 24. “Reversal of Metiamide-Induced and Technology, Prevalence of Selected Agran;locytosis During Treatment With Cime- Chronic Digestive Conditions, United States, tidine, ” L.uncet 2:1085, 1975. 1%’s, Vital and Health Statistics Series 10, No. 25. Chalmers, T. C., et al., “Randomized Con- 123, DHEW publication No. (PHS) 79-1558 trolled Trials in Gastroenterology With Par- (Hyattsville, Md.: National Center for Health ticular Attention to Duodenal Ulcer, ” Report to Statistics, July 1979). t}le Congress of t}ze U~zited States of the Nation- 37. Doll, R., “Introductory Remarks, ” in A Syrn- al Commission on Di.gestit~e Diseases, vol. 4, posiurn on Carbenoxolone Sodium, M. Robson pt. 2B, DHEW publication No. (NIH) 79-1885 and F. M. Sullivan (eds. ) (London: Butter- (Bethesda, Md.: National Institutes of Health, worths, 1968). 1979). 38. Drasar, B. S., et al., “Studies on the Intestinal 26. Chang, H. K., and Morrison, S. L., “Bone- Flora, I: The Bacterial Flora of the Gastrointes- Marrow Suppression Associated With Cimeti- tinal Tract in Healthy and Achlorhydric Per- dine” (letter), Ann, lnt. Med. 91:580, 1979. sons, ” Gastroenty. 56:71, 1969. 27, Christensen, E;., et al., “Treatment of Duodenal Ulcer: Randomized Clinical Trials of a Decade 39. Dunn, D. H., et al., “The Treatment of Hemor- (1964 to 1974),” Gastroenty. 73:1170, 1977. rhagic Gastritis With the Hz-Blocking Antihis- 28, Ciclitira, P. J., et al., “A Controlled Trial of tamine, Cimetidine, ” Gastroenty. 72:1053, Cimetidine in the Treatment of Gastric Ulcer, ” 1977. in Cirtletidine. Proceedirlgs of the Secorld lrlter- 40. Dyck, W. P., et al., “Cimetidine and Placebo in nutiorlal Syrnvosium on Histamine H2-Recep- the Treatment of Benign Gastric Ulcer A Mul- tor Antagonists, edited by W. L. Burland and ticenter Double-Blind Study, ” Gastroenty. M. A. Simkins (Amsterdam-Oxford: Excerpta 74:410, 1978. Medica, 1977). 41. Dykes, P. W., et al., “Treatment of Upper Gas- 29. “Cimetidine for Ever (and Ever and Ever. ..)?” trointestinal Hemorrhage With Cimetidine, ” in (editorial), Br Med. ]. 1:1435, 1978. Cimetidine: Proceedings of the Second Interna-
30< Cochran, W. G., et al., “Experiments in Surgi- tional Symposium on Histamine H2-,?eceptor cal Treatmen ! of Duodenal Ulcer, ” in Costs, Antagonists, W. L. Burland and M. A. Sim- kins(eds.) (Amsterdam-Oxford: Excerpta Meal- 57. Fry, I., “Peptic Ulcer: A Profile, ” Br. Med. ). ica, 1977). 2:809, 1964. 42. Elashoff, J. D., and Grossman, M. I., “Trends 58. Geweke, J. F., Department of Economics, Uni- in Hospital Admissions and Death Rates for versity of Wisconsin, Madison, Wis., personal Peptic Ulcer in the United States From 1970 to communication, 1979. 1978, ” Gastroe~zty. 78:280, 1980. 59. Gifford, L. M., et al., Medical Affairs Depart- 43. Englert, E., Jr., et al., “Cimetidine, Antacid, ment, Smith Kline & French Laboratories, and Hospitalization in the Treatment of Benign Philadelphia, “ ‘Tagamet’ Post-Market Outpa- Gastric Ulcer: A Multicenter Double-Blind tient Surveillance Program: Interim Report on Study, ” Gastroe/zty. 74:416, 1978. Phase I,” unpublished report. 44. Farris, J. M., and Greenburg, A. G., “Truncal 60. Gill, M. J., and Saunders, J. B., “Perforation of Vagotomy With Drainage for the Elective Chronic Peptic Ulcers After Cimetidine” (let- Treatment of Duodenal Ulcer Disease, ” in Co) Z- ter), Br. Med. ]. 2:1149, 1977. trol~ersy ill Surgery, R. L. Varco and J. P. 61. Gillespie, G., et al., “Short-Term and Mainte- Delaney (eds. ) (Philadelphia: W. B. Saunders nance Cimetidine Treatment in Severe Duoden- Co., 1976). al Ulceration, ” in Cimetidine: Proceedings of 45. Feldman, E. J., and Isenberg, J. I., “Effects of tl~e Seco~zd lnternatio~zal Symposium on Hista- Metiamide on Gastric Acid Hypersecretion, tni?ze Hz-Receptor Antagonists, W. L. Burland Steatorrhea, and Bone-Marrow Function in a and M. A. Simkins (eds. ) (Amsterdam-Oxford: Patient With Systemic Mastocytosis, ” N. E/lg. Excerpta Medica, 1977). ]. Med. 295:1178, 1976. 62. Gillies, R. R., et al., “Controlled Comparison 46. Feldman, M., et al., “Effect of Low-Dose Pro- of Two Dosage Regimens of Cimetidine in pantheline on Food-Stimulated Gastric Acid Duodenal Ulcer: A Multicenter Study, ” Gas- Secretion: Comparison With an ‘Optimal Effec- troe~lty. 74;396, 1978. tive Dose’ and Interaction With Cimetidine, ” 63. Gray, G. M., “Peptic Ulcer Disease, ” in Medi- N. E?I~. ]. Med. 297:1427, 1977. cine, E. Rubenstein and D. D. Federman (eds. ) 47. Finkel, M. J., “The FDA’s Classification System (New York: Scientific American, October for New Drugs: An Evaluation of Therapeutic 1979). Gain, ” N. E)lg. ]. Med. 302:181, 1980. 64. Gray, G. R., et al., “Long-Term Cimetidine in 48. Finkelstein, W., and Isselbacher, K. J., “Cime- the Management of Severe Duodenal Ulcer tidine, ” N. ErI~. ]. Med. 299:992, 1978. Dyspepsia, ” Gastroenty. 74:397, 1978. 49. Fleiss, J. L., Statistical Methods for Rates and 65. , “Oral Cimetidine in Severe Duodenal Proportio}ls (New York: John Wiley & Sons, Ulceration, ” L.ancet 1:4, 1977. 1973). 66. Griebe, J., “Long-Term Prognosis of Duodenal 50. Food and Drug Administration, Rockville, Ulcer: Follow-Up Study and Survey of Doctors’ Md., personal communication, 1979. Estimates, ” Br. Med. ). 2:1572, 1977. 51. Rockville, Md., personal communica- 67. Grossman, M. I., Center for Ulcer Research tion, 1980. and Education, Veterans Administration Cen- 52. Fordtran, J. S., and Grossman, M. I., “Third ter, Los Angeles, personal communication, Symposium on Histamine H,-Receptor An- 1980. tagonists: Clinical Results With Cimetidine, ” 68. “Closing Remarks (Cimetidine Sym- Gastroerlty. 74:431, 1978. podium’), ” Gastroenty. 74:487, 1978. 53. Fordtran, J. S., et al., “Round Table Discussion 69. “Resume and Comment. Chapter 10, on Gastric Ulcer, ” Gastroenty. 74:431, 1978. Veterans Administration Co-Operative Study 54. Freiman, J. A., et al., “The Importance of Beta, on Gastric Ulcer, ” Gastroenty. 61:635, 1971. Type II Error, and Sample Size in the Interpre- 70. Gudmand-H@yer, E., et al., “Prophylactic Ef- tation of the Randomized Control Trial, ” N. fect of Cimetidine in Duodenal Ulcer Disease, ” EIIg. /. Med. 299:690, 1978. Br. Med. ]. 1:1095, 1978. 55. Freston, J. W., “Cimetidine in the Treatment of 71. Gugler, R., et al., “Cimetidine for Anastomotic Gastric Ulcer: Review and Commentary, ” Gas- Ulcers After Partial Gastrectomy: A Random- troetlty. 74:426, 1978. ized Clinical Trial, ” N. Eng. J. Med. 301:1077, 56. Frost, F., et al., “Cimetidine in Patients With 1979. Gastric Ulcer: A Multicentre Controlled Trial, ” 72. Hall, W. H., “Breast Changes in Males on Br. Med. ]. 2:795, 1977. Cimetidine, ” N. Eng. ). Med. 295:841, 1976. 73. Hallenbeck, G. A., “Proximal Gastric Vagot- 90. Klotz, S. A., and Kay, B. F., “Cimetidine and omy Without Drainage for Duodenal Ulcer, ” in Agranulocytosis” (letter), Ann. Znt. Med. Controversy in Surgery, R. L. Varco and J. P. 88:579, 1978. Delmey (eds. ) (Philadelphia: W. B. Saunders 91. Krause, U., “Long-Term Results of Medical Co., 1976). and Surgical Treatments of Peptic Ulcer, ” Acta 74. Henn, R. M., et al., “Inhibition of Gastric Acid Clzir. Sc. suppl. 310, 1963. Secretion by Cirnetidine in Patients With Duo- 92. Kruss, D. M., and Littman, A., “Safety of denal Ulcer,” N. f%g. ]. Med. 293:371, 1975. Cimetidine,” Gastroenty. 74:478, 1978 75. Herbst, A. L., et al., “Adenocarcinoma of the 93. Lam, S. K., et al., “Treatment of Duodenal Vagina: Association of Maternal Stilbestrol Ulcer With Antacid and Sulpiride: A Double- Therapy With Tumor Appearance in Young Blind Controlled Study, ” Gastroenty. 76:315, Women, ” N. Eng. ]. Med. 284:878, 1971. 1979. 76. Hetzel, D. J., et al., “Cimetidine Treatment of 94. Lance, P., et al., “Non-Ulcer Dyspepsia, Duo- Duodenal Ulceration: Short-Term Clinical Tri- denitis, and Cimetidine, ” in Cirnetidine: The al and Maintenance Study, ” Gastroenty. Westminster Hospital Symposium, 1978, C. 74:389, 1978. Wastell and P. Lance (eds. ) (New York: Chur- 77. Hirschowitz, B. I., et al., “Demonstration of a chill Livingstone, 1978). New Gastroscope, the ‘Fiberscope’, ” Gastr-o- 95. Landecker, K. D., et al., “Cimetidine and the enty. 35:50, 1958. Gastric Ulcer: A Double-Blind Controlled Tri- 78. Hollender, L. F., and Marrie, A., Highly Selec- al, ” Med. ]. Aust. 2:43, 1979. tive Vagotorn;j (New York: Masson Publishing 96. Laufer, I., “Assessment of the Accuracy of U. S. A., Inc., 1979). Double-Contrast Gastroduodenal Racliology, ” 79. Ippoliti, A. F., UCLA Center for Ulcer Re- Gastroenty. 74:874, 1976. search, Los Angeles, Calif., personal communi- 97. Longstreth, G. F., et al., “Cimetidine Suppres- cation, 1980. sion of Nocturnal Gastric Secretion i n Active 80. Ippoliti, A. F., et al., “Cimetidine Versus Inten- Duodenal Ulcer, ” N. Eng. ]. Med. 294:801, sive Antacid Therapy for Duodenal Ulcer: A 1976. 74:393, 1978. Multicenter Trial, ” Gastroenty. 98. McCarthy, D. M., “Peptic Ulcer: Antacids or 81. Isenberg, J. I., “Therapy of Peptic Ulcer, ” Cimetidine?” Hospital Practice 14:52, 1979. ), A.M.A. 233:540, 1975. 99. “Report on the United States Experi- “Pathogenesis of Peptic Ulcer, ” in Gas- 82. ence W’ith Cimetidine in Zollinger-Elli:;on Syn- tr-ointe;tinal Diseases, vol. I, 2d cd., M. H. drome and Other Hypersecretory States, ” Sleisinger and J. S. Fordtran (eds. ) (Philadel- Gastroenty. 74:453, 1978. phia: W. B, Saunders Co., 1978). 100. McDougall, B. R. D., et al., “Histamine H,- 83. , “Round Table Discussion on Duodenal Receptor Antagonists in the Prophylaxis and Ulcer,” Gastrc~enty. 74:407, 1978. Control of Acute Gastrointestinal l-laemor- Ivy, A. C., “The Problem of Peptic Ulcer, ” 84. Cimetidine: Pro- ]. A.M.A. rhage in Liver Disease, ” in 1321053,1946. ceedings of the Second international Symposiu- 85. Peptic Ulcer (Philadelphia: Blakiston m o)? Histamine Hz-Receptor Antagonists, W. co., 1950). L. Burland and M. A. Simkins (eds. ) (Amster- 86. Jones, F. A., et al., Peptic Ulcer Healing: Re- dam-Oxford: Excerpta Medica, 1977). cent Studies on Car-benoxo/one (Baltimore, Md.: University Park Press, 1978). 101. McGuigan, J. E., “The Zollinger-Ellison Syn- Gastrointestinal Disease, 87. Keeney, R. L., and Raiffa, H., Decision With drome, ” in vol. 1, 2d Multiple Objectives: Preferences and Value cd., M. H. Sleisenger and J. S. Fordtran (eds. ) Tradeoffs (New York: John Wiley and Sons, (Philadelphia: W. B. Saunders Co., 1978). 1976). 102. McMillen, M. A., et al., “Cimetidine and Men- 88. Kennedy, T., and Spencer, A., “Cimetidine for tal Confusion, ” N. Eng. ]. Med. 293:284, 1978. Recurrent Ulcer After Vagotomy or Gastrec- 103. Meade, T. W., et al., “Recent History of Is- tomy: A Rardomised Controlled Trial, ” Br. chaemic Heart Disease and Duodenal Ulcer in Med. ]. 1:1242, 1978. Doctors, ” Br Med. ]. 3:701, 1968. 89. Klarman, H. E,, “Application of Cost-Benefit 104. Mendeloff, A. I., “What Has Been Happening Analysis to the Health Services and the Special to Duodenal Ulcer?” Gastroenty, 67:1020, Case of Technologic Innovation, ” lnt, ]. Hlth. 1974. Serv. 4:325, 1974. 105. Monson, R. R., and MacMahon, B., “Peptic Ulcer in Massachusetts Physicians, ” N. Eng. ]. dine on Days of Work Lost in a Short-Term Med. 281:11, 1969. TriaI in Duodenal Ulcer, ” J. Clin, Gastroenty. 106. Morris, T., and Rhodes, J., “Progress Report: 2:37, 1980. Antacids and Peptic Ulcer, A Reappraisal, ” 119. Richardson, C. T., “Gastric Ulcer, ” in Gastro- Gut 20:538, 1979. intestinal Disease, vol. 1 , 2d ed., M. H. 107. Mosbech, J., and Videbaek, A., “Mortality Sleisenger and J. S. Fordtran (eds. ) (Philadel- From and Risk of Gastric Carcinoma Among phia: W. B. Saunders Co., 1978). Patients With Pernicious Anaemia, ” Br. Med. 120. Richardson, C. T., et al., “The Effect of Cimeti- ]. 2:390, 1950. dine, a New Histamine H,-Receptor Antago- 108. Moshal, M. G., et al., “Treatment of Duodenal nist, on Meal-Stimulated Acid Secretion, Ulcers With Cimetidine, ” S. Afr. ). Med. Serum Gastrin, and Gastric Emptying in Pa- 52:760, 1977. tients With Duodenal Ulcer, ” Gastroenty. 109. Netherlands Economic Institute, Present Cost 71:19, 1976. of Peptic Ulceration to the Dutch Economy and 121. Robinson Associates, Inc., The impact of Possible Zmpact of Cimetidine on This Cost Cimetidine on the National Cost of Duodenal (Rotterdam: Netherlands Economic Institute, Ulcers (Bryn Mawr, Pa.: Robinson Associates, 1977). Inc., 1978). 110. Northfield, T. C., and Blackwood, W. S., 122. Ruddell, W. S. J., et al., “Effect of Cimetidine “Controlled Clinical Trial of Cimetidine for on the Gastric Bacterial Flora, ” Lancet 1:672, Duodenal Ulcer, ” in Cimetidine: Proceedings 1980. of the Second International Symposium on His- 123. “Pathogenesis of Gastric Cancer in tamine Hz-Receptor Antagonists, W. L. Bur- Pernici~us Anaemia, ” L.ancet 2:521, 1978. land and M. A. Simkins (eds. ) (Amsterdam- 124. Sawyers, J. L., “Truncal Vagotomy and An- Oxford: Excerpta Medica, 1977). trectomy as the Preferred Operation for Treat- 111. Ochsner, A., “Treatment of Peptic Ulcer Dise- ment of Duodenal Ulcer, ” in Controversy in ase, ” in Controversy in Surgery, R. L. Varco Surgery, R. L. Varco and J. P. Delaney (eds. ) and J. P. Delaney (eds. ) (Philadelphia: W. B. (Philadelphia: W. B. Saunders Co., 1976). Saunders Co., 1976). 125. Scheurer, U., et al., “Gastric and Duodenal 112. Office of Technology Assessment, U.S. Con- Ulcer Healing Under Placebo Treatment, ” Gas- gress, Assessing the Efficacy and Safety of troenty. 72:838, 1977. Medical Technologies (Washington, D. C.: 126. Schlippert, W., “Cimetidine: Hz-Receptor U.S. Government Printing Office, 1978). Blockage in Gastrointestinal Disease, ” Arch. 113. Paringer, L., and Berk, A., Cost of illness and Int. Med. 138:1257, 1978. Disease, Fiscal Year 1975 (Washington, D. C.: 127. Schoenbaum, S. C., et al., “The Swine Influen- Georgetown University, Public Services Lab- za Decision,” N. Eng. J. Med. 295:759, 1976.
oratory, 1977). 128. Scitovsky f A. A. and McCall, N., “Changes in 114. Paringer, L., et al., Economic Cost of Illness, the Costs of Treatment of Selected Illnesses, Fiscal Year 197’5, Report BIA (Washington, 1951 -1964-1971,” Palo Alto Medical Research D. C.: Georgetown University, Public Services Foundation, DHEW publication No. (HRA) Laboratory, 1977). 77-3161 (Rockville, Md.: National Center for 115. Peterson, W. L., and Fordtran, J. S., “Reduc- Health Services Research, 1976). tion in Gastric Acidity, ” in Gastrointestinal 129. Semb, L. S., et al., “A Double-Blind Multi- Disease, vol. I, 2d cd., M. H. Sleisenger and J. center Comparative Study of Cimetidine and S. Fordtran (eds. ) (Philadelphia: W. B. Saun- Placebo in Short-Term Treatment of Active ders Co., 1978). Duodenal Ulceration, “ in Cimetidine: Proceed- 116. Peterson, W. L., et al., “Healing of Duodenal ings of the Second international Symposium on Ulcer With an Antacid Regimen, ” N. Eng. ). Histamine Hz-Receptor Antagonists, W. L. Med. 297:341, 1977. Burland and M. A. Simkins (eds. ) (Amster- 117. Priebe, H. J., et al., “Antacid Versus Cimeti- dam-Oxford: Excerpta Medica, 1977). dine in Preventing Acute Gastrointestinal 130. Shain, M., and Roemer, M. I., “Hospital Costs Bleeding: A Randomized Trial in 75 Critically Relate to the Supply of Beds, ” Mod. Hosp. Ill Patients, ” N. Eng. ]. Med. 302:426, 1980. 92:71, 1959. 118. Ricardo-Campbell, R., et al., “Preliminary 131. Sharpe, P. C. and Hawkins, B. W., “Efficacy Methodology for Controlled Cost-Benefit and Safety of Cimetidine: Long-Term Treat- Studies of Drug Impact: The Effect of Cimeti- ment With Cimetidine, ” in Cimetidine: Pro- ceedings of the Second International Symposi- 146. Von Haunalter, G., and Chandler, V. V., Cost um on Histamine Hz-Receptor Antagonists, of Ulcer Disease in the United States [Menlo W. L. Burland and M. A. Simkins (eds. ) (Am- Park, Calif.: Stanford Research Institute, sterdam-Oxford: Excerpta Medica, 1977). 1977). 132. SK&F Lab Co., The History and Development 147, Walker, C. O., “Chronic Duodenal Ulcer,” in of Hi-Receptor Antagonists (Carolina, Puerto Gastrointestinal Disease, M. H. Sleiseng;er and Rico: 1979). J. S. Fordtran (eds. ) (Philadelphia: W. B Saun- 133. Sleisenger, M. H., and Fordtran, J. S. (eds. ), ders Co., 1973). Gastrointestinal Disease (Philadelphia: W. B. 148. Wallace, W. A., et al. “Perforation of C’hronic Saunders Co., 1978). Peptic Ulcers After Cimetidine, ” Br. A4ed. ]. 134. Smith, M. P., ‘ Decline in Duodenal Ulcer Sur- 2:865, 1977. gery, ” ]. A.M.A. 237:987, 1977. 149. Warner, K., et al., “Cost-Benefit and Cost- 135. SmithKline Corp., 1O-K Reports filed with the Effectiveness Analysis in Health Care: Metho- U.S. Securities and Exchange Commission, dology and Literature Review, ” draft report Washington, DC., 1977 and 1978. submitted to the Office of Technology Assess- 136. Soil, A. H., and Walsh, J. H., “Regulation of ment, U.S. Congress, Washington, D. C., Oc- Gastric Acid Secretion, ” An??. Rev. Physiol. tober 1979. 41:35, 1979. 150. Wastell, C., and Lance, P. (eds. ), Cimctidine: 137. Sonnenberg, A. and Hefti, M., “The Costs of The West) ninster Hospital Symposium, 1978 Postsurgical Syndromes (Based on the Example (New York: Churchill Livingstone, 1978). of Duodenal Ulcer Treatment ),” Clinics in Gas- 151. Weinstein, M. C., “Economic Evaluation of troenty. 8:235, 1979. Medical Procedures and Technologies: Prog- 138. Stadil, F., and Stage, J. G., “Cimetidine and the ress, Problems, and Prospects, ” in hledical Zollinger-Ellisoa (Z-E) Syndrome, ” in Cimeti- Technology, NCHSR Research Proceedings , dine: The Westminster Hospital Syrnposiunl, Series, DHEW Publication No. (PHS) 79-3254 \ 1978, C. Wastell and P. Lance (eds. ) (New (Hyattsville, Md.: National Center for Health York: Churchill Livingstone, 1978). Statistics, 1979). 139. Sturdevant, R. A. L., “How Should Results of 152. Weinstein, M. C., and Stason, W. B., Hyper- Controlled Trials Affect Clinical Practice?” tensio)~: A Policy Perspective (Cambridge,
(editorial), Gas/roenty. 73:1179, 1977. Mass.: Harvard University Pressr 1976).
140. Sturdevantr R. A. L., and Walsh, J. H., “Duo- 153. Welsh, J. D., “Diet Therapy of Peptic Ulcer denal Ulcer, ” in Gastrointestinal Disease, vol. Disease,” Gastroenty. 72:740, 1977. 1, 2d cd., M. H. Sleisenger and J. S. Fordtran 154. Winship, D. H., “Cimetidine in the Treatment (eds, ) (Philadelphia: W. B. Saunders Co., of Duodenal Ulcer, ” Gastroenty. 74:402, 1978. 1978). 155. Wolfe, M. M., “Impotence on Cim[?tidine 141. Susser, M., “C,~uses of Peptic Ulcer: A Selec- Treatment” (letter), N, E)lg. ]. Med 303:94, tive Epidemiologic Review, /. Chro)z. Dis. 1979. 20:435, 1967. 156. Wulff, H. R., and Rune, S. J., “A Comparison 142. Susser, M., and Stein, Z., “Civilization and of Studies on the Treatment of Gastric LJlcera- Peptic Ulcer, ” Lancet, 1 :115, 1962. tion With Cimetidine, ” in Cimetidi/ze: The 143. Thompson, P. L., et al., “Late Radiation Ne- Westminster Hospital Symposium, 1978, C. phritis After Gastric X-Irradiation for Peptic Wastell and P. Lance (eds. ) (New York: Chur- Ulcer,” Q. ]. Mcd, 40:145, 1971. chill Livingstone, 1978). 144. Van Thiel, D. H., et al., “Hypothalamic-Pitui- 157. Zeckhauser, R., and Shepard, D., “Where Now tary-Gonadal Dysfunction in Men Using Cime- for Saving Lives?” Law & Conternp. Prob. tidine, ” N. Eng. ), Med. 300:1012, 1979. 40:5, 1976. 145. Villeneuve, J. P., and Warner, H. A., “Cimeti- dine Hepatitis, ” Gastroetzty. 77:143, 1979.
* U, S (X)V ERNMENT PRINTING OFFICE 1981 341 -844/ 1018