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-ized patients is more difficult to estimate direct-ly, but such use is widespread. In addition to be-ing used in patients with ulcer disease, the drughas been used to prevent and treat stress-relatedgastritis and bleeding (39,100). Many physiciansare probably using cimetidine in seriously ill pa-tients who are susceptible to gastrointestinalhemorrhage (48). A recent randomized trial ofpatients hospitalized in an intensive care unitfound that regular antacid therapy is more effec-tive than cimetidine in preventing gastrointes-tinal bleeding (117).

From a commercial viewpoint, cimetidine is aspectacularly successful product. In 1977, cime-tidine was marketed in 65 countries; in 1978, itwas sold in 90 countries. In 1977, SmithKlinereported sales of gastrointestinal drugs of $90.5million; in 1978, sales of these drugs were $315million. In its 1978 annual report, SmithKlinestated that Tagamet® was its most importantsingle product (135). Worldwide sales to hospi-tals and pharmacies in 1979 probably exceeded$400 million. This translates into a rough esti-mate of 10 million patients per year consuming

cimetidine worldwide .10 A conservatively esti-mated 1.5 million to 2 million ambulatory U.S.patients with ulcer disease and ulcer-like symp-toms were treated with cimetidine in 1978.11

Cimetidine has thus become one of the mostwidely used pharmaceuticals in the world in aremarkably short time. Part of the reason forthis success rests in the widespread prevalenceof ulcer disease and ulcer-like symptoms. Smith-KIine pioneered and persevered in developingand marketing a new class of pharmaceuticalagents. Furthermore, as discussed in the nextpart of this case study, a substantial number ofcontrolled trials attest to the effectiveness andrelative safety of this drug in the treatment ofulcer disease.

10This estimate follows from high and low estimates, as shown:High estimate Low estimate

Retail value of sales $500 million $300 million– Retail price per tablet $0.25 $030= Number of tablets (A) 2 billion 1 billionWeekly number of tablets 28 28

x Mean weeks of treatment 5 6= Number of tablets patient (B) 140 168Estimated number of patients (A/B) 14,300,000 6,000,000

11This estimate is based on a conservative projection of the num-bers of Americans living at home who report ulcer disease in 1968and 1975 and the proportion who visit their physicians for thisproblem at least once in the year (36).

THE BENEFIT-AND-COST MODEL APPLIED TO CIMETIDINE

Elements in the Analysis

The major components of the benefit-and-cost model presented earlier in this case studyare shown in table 9. Listed under each compo-nent are a number of measures pertinent tocimetidine. Ideally, benefit and cost estimateswould be made separately for each class of pa-tients that might be treated with cimetidine. Thebasis for separating groups of patients could bedemographic features (e.g., age, race, sex), clin-ical diagnosis (e. g., duodenal ulcer, gastriculcer, Zollinger-Ellison syndrome), or stage ofdisease (e.g., number of days since diagnosis,previous treatments, complications).

Figure 4 is a paradigm decision-tree that dis-plays the sequence of decisions and chanceevents that follow from the initial choice of in-tervention in a particular group of patients with

ulcer disease. Clearly, the model requires a verylarge amount of data. It is not possible in thisreview to discuss potential sources of data forevery estimate that follows each choice of strat-egy. Rather, we select for discussion the majorelements of information required by the modeland the available evidence.

Our primary emphasis is on patients withduodenal ulcer, the most common form of ulcerdisease; we discuss patients with gastric ulcer inless detail. In addition to being used in these pa-tients, cimetidine is sometimes used in patientswith gastrinoma.

12 The traditional treatment forpatients with gastrinomas includes gastrectomy

I zThlS is a ~asl rin-secret ing tumor, usual ]y located In the Pan-

creas. It causes the Zoll inger-Ell ison syndrome of severe ulcers, in-tractable pain, and diarrhea. First described In 1955, the Zollinger-Ellison syndrome has been recorded in more than 2,000 cases in theliterature (101 }.

26 ● Background Paper #2: Case Studies of Medical Technologies

Table 9.—Components and Measures ofComponents in a Benefit-and-Cost

Analysis of Cimetidine

Clinical effectsShort-term● Heal ing● Relief of symptoms● Side effects and

adherence● Complications● RecurrenceLong-term. Recurrence● Side effects and

adherence● Complications

Health system effectsMedication● Antacids● Anticholinergics. Diet. OtherDiagnostic testsŽ Laboratory● Monitoring chemistries. Imaging

—X-ray—Endoscopy

● Physiologic function● Gastric acidPhysician visits

● Number/time periodHospitalization● Number/time period● DurationSurgery● Number/time period● T y p eOther● Non-M. D. provider visits● Nursing care

OutcomeHealth. Mortality

—Number of deaths—Age-adjusted mortality—Years of life lost

● Morbidity—Days and severity of

pain— Days of disability

Resource costs and savings● Days of work lost

—Premature death—Temporary and

permanent disability● Cimetidine purchase● Implications of health

system effects

(excision of the whole or part of the stomach)time of surgery for the primary tumor, butcimetidine has been employed successfully as analternative to gastrectomy in these patients(99,138). Because of the rarity of gastrinoma asa cause of ulcer disease, the costs and benefits ofthe use of cimetidine in patients with this diseaseare not significant from a societal viewpoint.Since the clinical value of cimetidine fornonulcer disease such as dyspepsia (94) and up-per gastrointestinal hemorrhage (41) is outsidethe scope of this report, we do not address itbelow. We limit our focus to elements of thecost effectiveness of cimetidine in peptic ulcerdisease and do not attempt a global assessmentof the value of this drug.

Clinical Effects

No treatment for duodenal ulcer has beensubjected to as many randomized, controlled,double-blind studies as cimetidine has (68).These studies of cimetidine vary in their metho-dological stringency and completeness. In a re-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/ I decision

Ito treatment I Healing (in a given I Pain relief in a

demographic featuresI

regimen (spectrum)I

time period)I spectrum

given time periodI (spectrum)

❑ : Decision node (matters of choice)O: Chance node (probabilistic events)

Figure 4.— Paradigm Decision Tree: Cimetidine and Alternative Intervention Strategies (Continued)

Clinical effect: Clinical effect: Health system effect: Health system effect: Health system effect:

Treatment side Disease course and Change in use of other Number of physician Tests used (yes/no

effects (spectrum) complications

(short and long I (short and long

medication (by type v is i ts / t ime per iod

I o f m e d i c a t i o n r e l a t e d

choice for each test

I I in each time period)

term).. term) 1 to change in clinical 1 I

Health system effect: I Health system effect: I Outcome. Health I Outcome: Resource

Hospitalization (in each Surgery (by type,I I

(for each strategy)I

costs (net, for each

time period) i n each time period) strategy)

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)rated only one “poor” —a record that comparedquite favorably with Chalmers, et al. ’s assess-ment of clinical trials of other treatments forulcer disease.

There is one important methodological differ-ence between the controlled studies of ulcer dis-ease done in the 1970’s and those done earlier. Inthe more recent studies, fiberoptic endoscopyreplaced gastrointestinal X-rays as the meansused to verify the presence and healing of ulcers.This direct visual confirmation of ulcer statuscan reduce diagnostic errors and consequentvariability in experimental results. As a result,endoscopy-controlled studies may be more like-ly to find statistically significant differences inthe clinical effectiveness of various treatments,

In addition to controlled studies, several sym-posia have been devoted to cimetidine (22,52,150), and a number of review articles have ap-peared in major medical journals (e.g., 48,126).This work has provided reliable informationthat can contribute to estimates of clinical bene-fits and risks in a CEA, but a number of impor-tant areas of uncertainty remain.

Short-Term Clinical Effects

HEALING

At least 10 double-blind, placebo-controlledstudies examining the short-term clinical effectsof cimetidine in patients with duodenal ulcershave been published in the English language.Together these 10 studies (see table 10) providecompelling evidence that cimetidine promoteshealing of duodenal ulcers. Overall, the rate ofhealing in 4 to 6 weeks among cimetidine-treated patients was approximately 70 percent,almost twice the level achieved by placebo-treated patients (36 percent). Similar resultswere obtained in a half-dozen additional studiesconducted in France, West Germany, Italy, andSpain (7).

One notable exception to the almost uniform-ly significant findings of cimetidine’s superiorityover placebo is the large, multicenter U.S. studyby Binder, et al. (11). Among outpatients assess-ed at the end of 4 and 6 weeks (57 on cimetidine;54 on placebo), no significant differences were

observed in the proportions healed (67 and 56percent, respectively). [t is evident that thestatistical conclusions from this study are dif-ferent from the others not because of worse per-formance of cimetidine, but because of a sub-stantially higher rate of healing within the pla-cebo group.

It is possible that the patients in the U.S. trialdiffered from those in the European studieseither because of differences in the naturalhistory of the disease in different countries orbecause the U.S. subjects tended to be at a dif-ferent stage of illness. For example, some of theearlier European studies were restricted to pa-tients who were considered candidates for sur-gery. The importance of criteria for patientselection and evaluation, as well as possiblevariation in the course of disease in differentcountries, was stressed in a Swiss study thatfound a very high proportion of patients withpeptic ulcer healing under placebo treatment(125).

It is possible that the discrepant results arepartly related to differences in antacid consump-tion. With one exception (108), all the con-trolled studies permitted ad libitum antacids forall patients. Patients in the European studieswere usually provided tablet antacids, whichare less potent than the type of liquid antacidused in the U.S. study (81,106). Overall, theU.S. patients consumed more antacid than theirEuropean counterparts. More to the point,among the subjects in the U.S. study, placebo-treated patients whose ulcers healed consumedmore antacid than those whose ulcers did notheal. (Mean antacid consumption was 12 per-cent higher among inpatients whose ulcer healedand 112 percent higher among outpatients thanin those whose ulcers failed to heal; differencesin median antacid consumption were 68 and 21percent, respectively. )

This raises the possibility that a partialtherapeutic effect was realized in the placebogroup in the U.S. study. Underlying this pos-sibility is the assumption that antacids promoteulcer healing. Antacids have been shown in atleast two endoscopy-controlled studies to have agreater effect than placebo on healing of duo-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 ● 2 9

Table 10.—Short-Term, Double-Blind, Placebo-Controlled Studies of Cimetidine:Effect on Duodenal Ulcer Healing

Study

D1

D2

D3

D4

D5 ‘

D6

D7

D8

D9

D10

CimetidineInvestigator a daily doseyear/country (grams)— .— — — . . — .Bank, et al. (6) 1.2

1976/South 1.6Africa

Bardhan, et al. (8)1979/UnitedKingdom

Binder. et-al. (11) ‘ -

1978/UnitedStates

Placebo

Duration Number of Number/o/.(weeks) patients b healed

6 19 (19) 8 (420/o)

14 46 (50) 13 (28°/0)

2

12 2 (inpatient) 49 (53) 18 (37%)

2 (outpat ient ) 27 7 (260/. )4 (outpatient) 27 (103) 13 (48°/0)6 (outpatient) 27 17 (63%)

Cimetidine v.

Cimetidineplacebo;

significantNumber of Number/o/o differencepatients b healed (ps0.05)

8 (8) 7 (86%) Yes (p< 0.01)

11 (11) 9 (82°/0)

70 (78) 43 (61 %) Yes (p< 0.001)

64 (72) 45 (70%)

43 (45) 24 (56%) Yes (p< 0.05)

26

}

12 (46%) Yes (p< 0.05)28 (107) 16 (570/’) No29 2 2 ( 7 6 % ) N o

— — B-lack wood, et al. (13) 1.6 - 6 12 (NA) d 3 (25%) 11 (NA)d 9(82%) Yes (p< 0.025)

1976/UnitedKingdomC

. —Bodemar and

Walan(15) 0.8 6 14 (15) 2(1 4°/0)15 (15) 12 (80°/0) Yes (p< 0.001)

19761 Sweden 1.2 15 (15) 14 (93°/0)

Gray, et al.West Germany 1 4 20 (20) 5 (20°/0) 20 (20) 17 (850/o) Yes (p< 0.0005)

Hetzel, et al, (76) 1.2 ‘- 6 42 (44) 16 (380/o) 43 (44) 36 (840A) Yes (p< 0,001)1978/Australia

Moshal, et al. (108) -

1977/South 0.8 6 19 (21) 8 (42°/0)I

‘g ( 4 0 ) 14 (74°/0)Africa Yes (p< 0.05)

1.2 17 11 (65%) —

Northfield and 6 21

)

4 (19°/0) 21 13 (620/o)Blackwood (1 10) 1.6

(NA)d (NA)d Yes (p< 0.05)

1977/UnitedKingdom e 12 15 4 (27%) 17 15 (88°/0)

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 availablebN “mbers , “ p’rerl~heses are numbers enterln9 study elncludes Patients from study D4cpatlents 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, bytients experienced ulcer healing after 4 weeks’ Peterson, et al. (116) in the United States, usedtreatment 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 36perienced 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). Astudy; Chinese patients have similar parietal cell recent British review, prompted by the lessermasses 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 antacidswere effective in promoting healing of duodenalulcer (106).

Notice that the rates of healing with antacidsin the Lam (93) and Peterson (116) studies (77and 78 percent, respectively) are much higherthan the healing rate (56 percent) in the placebogroup using ad libitum antacids in the multi-center U.S. trial of cimetidine (11). In fact, thehealing rates with antacids in the Lam and Pe-terson studies were even higher than the rate ofhealing with cimetidine (67 percent) in the U.S.multicenter trial (11)

This observation leads to an important ques-tion: Is cimetidine more effective than a con-certed antacid program in promoting ulcer heal-ing? The question is important because a CEAshould seek to compare the incremental effectsof competitive alternatives with one another, aswell as with a do-nothing strategy.

It is statistically unsound and maybe mislead-ing to compare selected groups from differentstudies. Fortunately, at least one randomized,double-blind study has compared cimetidinewith intensive antacid therapy in patients withduodenal ulcers (80). This multicenter trialfound that in 15 (52 percent) of 29 patients tak-ing antacids seven times daily, and in 40 (62 per-cent) of 65 patients taking cimetidine, ulcershealed after 4 weeks .13 The rate of healing in pa-tients taking cimetidine was not significantlybetter than the rate in patients taking antacid (p> 0.1), and the authors concluded that “800 and1,200 mg of cimetidine daily produced duodenalulcer healing and pain relief equivalent to 210ml of Al-Mg antacid daily” (80).

This conclusion should be qualified. Conven-tional tests of significance, as employed by theseinvestigators, are concerned with the risk offalsely rejecting the null hypothesis of “no dif-ference” between treatments (the a or type Ierror). In the Ippoliti study, the observed dif-ference did not justify a conclusion to reject thehypothesis of “no difference” at a 95-percent

IJThe Cimetidine patients were divided into two groups with dif-ferent dosage regimens: 33 patients received 1,200 mg daily and 21(64 percent) experienced healing; 32 patients received 800 mg dailyand 19 (59 percent) experience healing.

level of confidence. However, also of concern isthe complementary error, namely the failure toreject the null hypothesis when in fact a differ-ence in treatment outcomes in present (the B ortype 11 error) (49). This error, which may beclinically important, has been overlookedfrequently in trials of the treatment of duo-denal ulcer (27), as well as in other medical re-search (54).

We have estimated that if cimetidine trulyhealed 10 percent more ulcers than did antacids(62 V. 52 percent, the findings of the Ippolitistudy), then, given the number of patients in thetrial, there was less than one chance in three thatthe investigators would have found a statistical-ly significant difference.14 This would argue fora more tentative clinical conclusion. It argues aswell for more extensive research on the ques-tions of the relative clinical effectiveness ofcimetidine and antacids. 15

Several double-blind randomized trials havecompared cimetidine to placebo in patients withgastric ulcer. These are summarized in table 11.(A number of additional reports of interim re-sults (150) and studies without endoscopic as-sessment of healing (95) are excluded. ) Two ofthe European trials— one by Bader, et al. (5), theother by Frost, et al. (56)-—found a statisticallysignificant improvement in healing with cimeti-dine at 4 and 6 weeks, respectively. However,this finding was not borne out in the trials byCiclitira, et al. (28) and Dyck, et al. (40). Thelatter trials did tend to favor cimetidine (14 perc-ent more patients healed at 4 weeks in the Cicli-tira study (28) and 19 percent more at 6 weeks inthe Dyck study (40)), but these differences werenot statistically significant. The point madeabove concerning the chance of B-error appliesto the interpretation of these studies as well.Also pertinent is the earlier discussion of thetendency of U.S. patients to consume greater

ItMore Preclse]y, given the stated assumptions, the power of theexperiment (1 -~) is estimated to be 0.68.

‘51ppoliti has conducted a second, unpublished randomized trialof patients with duodenal ulcers, treating 65 patients withcimetidine and 62 patients with an intense antacid regimen. In thisstudy, the proportion showing healed ulcers at 4 and 6 weeks wasvirtually identical in the two groups. At 4 weeks, the proportionswith healed ulcers were 62 percent for patients taking cimetidineand 66 percent for patients taking antacids; at 6 weeks, the propor-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 Cimetidineplacebo;

Cimetidine significantInvestigatora 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 UnitedKingdom 1 4 25 13 (52%) 35 23 (66°/0) NO

G3 Dyck, et al. (40)19781United 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 ofStudies on the Treatment of Gastric Ulceration With C!met!dlne, 1978 (156)

amounts of antacid, which hinders comparisonamong studies done in the United States andEurope.

The effectiveness of antacids alone in thehealing of gastric ulcer is debatable, with con-trolled studies reaching conflicting conclusions(55). One multicenter, randomized study of pa-tients with gastric ulcer in the United Statescompared three treatment regimens: cimetidinealone, antacid alone, and cimetidine plus ant-acid (43). This study found no significant differ-ences in healing among these three groups at 12days or 6 weeks.

16 N. control group taking pla-cebo only was included, apparently because ofethical concerns about withholding a potentiallyeffective treatment (i. e., antacids) from all pa-tients (55). This omission, subsequently la-mented by at least some of the investigators(53), leaves open the question of whether treat-ment with either cimetidine or antacids is supe-rior to placebo in patients with gastric ulcer.

In summary, cimetidine has been shown con-clusively to promote healing of duodenal ulcer,and some evidence suggests it is more effective

than placebo in patients with gastric ulcer .17 Ingeneral, European studies have found more fa-vorable results with cimetidine than have U.S.trials. In patients with gastric ulcers, cimetidinehas not been shown convincingly to be more ef-fective than an intense course of antacids.Whether cimetidine is more effective than an in-tense antacid program in healing duodenalulcers is still open to question. Of course, pro-motion of healing is only one aspect of short-term clinical performance (see table 9, p. 26).

PAIN RELIEF

Seven of the 10 randomized, controlled stud-ies of duodenal ulcer listed in table 10 also com-pared cimetidine to placebo in terms of painrelief. Those findings are summarized in table12. Comparison across studies is complicated bythe variety and subjectivity of measures em-ployed. These measures include frequency ofpainful days and nights, number of pain-freeweeks, severity of pain, proportion of asympto-matic patients, and days of treatment requiredto achieve symptom relief. An additional com-plication arises because the time frame for meas-

‘OAfter 12 days, 16 percent of 67 patients taking antacids, 20 per-cent of 71 patients taking clmetldine, and 25 percent ot 65 patientstaking both experienced ulcer healing: after 6 weeks, the resultswere, respect ivei y, 61 percent (JI 62 pat]ents, 59 percent (If 68 pa-tients, and 70 percent (lt 60 patient+.

“In addition to cimetidine and antacids, three other drugs havebeen shown in controlled clinical trials to promote healing ofulcers better than a placebo: colloidal bismuth, carbenoxolone,and trimipramine (139). None is now used for this purpose in theUnited States.

32 ● Background Paper #2 Case .Studies of Medical Technolologies

Table 12.—Short-Term, Double-Blind,Placebo-Controlled Studies of Cimetidine:

Effect on Duodenal Ulcer Pain Relief

Study a Summary of results

D1

D2

D3

D4D5

D6

07Da

D9D10

Cimetidine group asymptomatic for mean of 4 outof 6 weeks; placebo group free of symptoms fora mean of 2.4 out of 6 weeks; in other words,the cimetidine group had a 44% reduction inthe mean number of weeks with some pain.(Statistical significance not reported.)

Cimetidine group experienced a 34% reduction indays with pain and a 36% reduction in nightswith pain compared to the placebo group. Dif-ferences in the frequency of pain were sig-nificant in each of the 4 weeks of the study (p< 0.005).

Inpatients: significantly more patients takingcimetidine than taking placebo had day andnight pain relief at the end of 3 days (61 v. 30%;p < 0.01); difference not significant at the endof 1 week (69 v. 55%).

Outpatients: significantly more patients takingcimetidine had day and night pain relief at theend of 1 week (45 v. 31 O/.; p < 0.05); differencenot significant after the first week.

Not reported.Cimetidine group had “significantly lower pain

score” (p range < 0.02 to < 0.1) both day andnight during the first 3 weeks (method of meas-urement and computation not fully explained).After 3 weeks, cimetidine group had “signifi-cantly” (p < 0.1) less day pain in weeks 5and 6.

Cimetidine group had significantly more pain-freedays each week of the study (p < 0.01).

Not reported.At the end of 6 weeks, cimetidine group had sig-

nificantly more asymptomatic patients (780/’)than did the placebo group (47°/0) (p < 0.025).

Not reported.Cimetidine group required significantly fewer days

to achieve symptom relief (8.1 ± 9.9 [S. D.]) thandid the placebo group (20.6 ± 9.1 [S.D.]) (p‹0.01).

asee table 10 for lnvestlgator, year, and country

urement varies from study to study. Nonethe-less, these studies fairly consistently repor tgreater pain relief with cimetidine than with pla-cebo. Again, the multicenter U.S. trial (11)shows less striking differences than the othertrials.

The Ippoliti study (80) comparing cimetidineto antacid found prompt symptom relief withboth treatments (55 percent of cimetidine-treated patients and 58 percent of antacid-treated patients became asymptomatic by day).

At the end of 4 weeks’ treatment, 63 percent ofpatients taking antacids and 80 percent of thosetaking cimetidine were asymptomatic, a differ-ence that was not statistically significant (p >0.1).

Placebo-controlled studies of patients withgastric ulcer varied in the extent to whichcimetidine-treated groups experienced morerapid or complete pain relief than those treatedwith antacids (see table 13). The Englert study(43) comparing antacids and cimetidine foundsimilar symptom response in all groups.

Investigators differ in their conclusions aboutthe correspondence between ulcer healing andpain relief. Several investigators report a poorcorrelation between healing and symptom relief(e.g., 6,62,108), and others say the correlation isgood (e.g., 8,61,80). Part of the reason for dif-fering assessments may be a difference in whatvarious investigators consider a good or a poorcorrelation. For example, Bardhan (8) found theassociation between healing and symptom reliefto be significantly different from what wouldhave been expected to occur by chance. On theother hand, the same data show that the ability

of pain relief to predict ulcer healing is not verystrong. 18

As in our discussion of B-error above, thispoints out the important distinction between theinterpretation of results based on statisticalcriteria and that based on clinical criteria:Results that fail a test of statistical significancemay still be clinically meaningful; conversely,statisticall y significant differences may not beparticularl y meaningful clinically. The degree ofassociation between healing and pain relief ispertinent to a cost-effectiveness assessment,because a patient’s decision to return to normalactivity depends at least as much on symptomsas on the physical repair of the ulcer. If esti-mates of a drug’s comparative effectiveness inreturnin g patients to work are based primarily

on healing, they may be misleading insofar as

‘“The probability (If ulcer healin g given symptc)m improvementIS 50 60 = 0.77, and the pr(~babi] I t y of nonhea] ing given noimprovement In symptc~ms is 42/72 = 0..58, These are n[)t ~lar.ticularly large predictive values. In the Ippoliti study (80), the cor-resp~~nding values are a bit lt]wer in the first case (42 ’60 = O 70)and somewhat h]gher in the second (18 20 = 0,90),

Table 13.—Short-Term, Double-Blind,Placebo.Controlled Studies of Cimetidine:

Effect on Gastric Ulcer Pain Relief

Study a Summary of results

G1 Patients taking cimetidine tended to have morerapid and greater relief of pain, but differenceswere not statistically significant.

G2 Cimetidine-based group had significantly fewerattacks of pain during each week of the study.

G3 No systematic or significant differences in theseverity or frequency of pain at 2 weeks or at 6weeks between the cimetidine-treated andplacebo-treated groups.

G4 Group taking cimetidine had fewer days of pain,but differences were not statisticallysignificant.

aSee table 11 for Investigator year and country

pain relief and healing do not correspond to oneanother, Almy (2) suggests a further possibilityif a patient returns to work after symptoms haveremitted but before healing has occurred: Work-days gained might be lost later on owing to lateconsequences of unhealed ulcer.

In summary, evidence from most controlled,double-blind studies suggests that cimetidinepromotes faster and more complete pain reliefthan does a placebo in duodenal ulcer, but notnecessarily in gastric ulcer. An intense antacidprogram appears to be about as effective ascimetidine, but more evidence on this questionis needed. The correspondence between healingand symptom relief is imperfect: The associa-tion is not random, but relief of symptoms is nota reliable clinical predictor of healing.

SAFETY AND ADHERENCE

No pharmacologic agent is perfectly safe. Adrug’s side effects depend on its toxicity, thedosage and duration of administration, and theindividual susceptibility of the patient. The im-portance of side effects of any one treatmentshould be judged in relation to the severity ofthe disease being treated and the risks of alter-native interventions.

Before turning to cimetidine, let us brieflyconsider the alternative of antacid therapy as abaseline. Unlike cimetidine, the Al-Mg antacidsuspensions usually prescribed are, for the most

part, not systemically absorbed. The most com-mon adverse side effect of these antacids is diar-rhea, which is related to the dose of magnesiumsalts. In studies with intense antacid regimens,27 percent (80) and 36 percent (43) of patientstaking antacids developed diarrhea. In thePeterson study (116) comparing antacids with aplacebo, 66 percent of the antacid group and 21percent of the placebo group were switched forat least 7 days to an alternative medicationbecause of diarrhea. Mild diarrhea may not bevery important medically, but this effect, alongwith the need for frequent administration, doesdiscourage patient adherence to high-dose an-tacid regimens. Aluminum salts bind phosphateions, and this may produce hypophosphatemiain patients who have intestinal malabsorptionproblems. This rare consequence may becountered by selecting a different type of an-tacid or giving phosphate supplements. 19

Cimetidine in short-term use has been associ-ated with a wide range of side effects. Themanufacturer instituted a formal, postmarkedsurveillance system that covered 9,907 ambula-tory patients and found a total of 577 adverseevents in 442 patients (4.4 percent of all pa-tients) (59). Only a fraction of the adverseevents were believed to be attributable to cimeti-dine; for example, 30 of 254 adverse gastrointes-tinal events occurred in circumstances thatstrongly suggested an association with cimeti-dine. No deaths were attributed to use of thedrug. An extensive review by Kruss and Littmanin 1978 (92) of publications, manufacturers’files, and submissions to FDA concluded thatcimetidine was safe enough to be used in pa-tients with duodenal ulcer disease for up to 8weeks, and indeed, this is the use currently ap-proved by FDA. A high proportion of patientsdevelops clinically insignificant elevations inserum creatinine which resolves promptly withcessation of therapy (92). Gynecomastia (ex-cessive development of breast tissue in males)has been reported in under 1 percent of patientson short-term treatment; the incidence increases

‘“A ditterent arr~y (Jt metabolic p r o b l e m s m a y Itlllow use ofcalclurn cdrbt~ndte antacid (which 1s abs~~rbed systemical [y ), but+1 nce this is nc~t usual]}’ presc rlbed hy physician+ in the UnitedState<. 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(102), reversible hepatitis (145), and severalcases of severe allergic reaction (33) have alsobeen reported. Agranulocytosis, the principalproblem with cimetidine’s predecessor, meti-amide, has been reported to occur transientlywith cimetidine (32,90). In addition, at least onefatality due to aplastic anemia has been reportedin association with cimetidine (26).

Recent bacteriological studies of the gastricjuice of patients before and after 4 weeks’ treat-ment with cimetidine found major increases intotal bacterial counts, including large numbersof fecal-type organisms, following treatment(122), This effect, noted after short-term use,would be of greater concern with long-term useof cimetidine, as explained below. The principaldeterminant of gastric flora in humans is theacidity of the stomach, and increases in fecaltypes of bacteria are found in the stomachs ofachlorhydric patients such as those with per-nicious anemia (38). Patients with perniciousanemia have long been recognized to have a sig-nificantly increased risk of developing gastriccancer (107). Possibly, the increased incidenceof cancer is related to the metabolic activity offecal-type bacteria that reduce nitrates and maylead to the development of carcinogenic N-ni-troso compounds in the stomach (123). At pres-ent, however, this long-term risk of cimetidine(or any agent that chronically reduces gastricacidity) is speculative.

In the past year, new evidence has accumu-lated concerning the effects of cimetidine on thereproductive function in males. Earlier animalstudies had clearly shown an antiandrogenic ef-fect of large doses of cimetidine administered for6 to 12 months (92). During the past year, atleast one case of reversible impotence has beenattributed to cimetidine (155). In addition, astudy of seven patients with ulcer disease, duo-denitis, gastritis, or esophagitis found a 30- per-cent reduction in mean sperm count after 9weeks of cimetidine treatment; the luteinizinghormone response to luteinizing hormone-releasing factor was also reduced (144).20 This

“’The m e a n iperrn c~mnts were 134.3 mllli(>n per ml bet(>recvmet tdine and 94.0 mlllif)n per ml at ter treat men t. The in ves-t ig~t{lrs state that the reduct Ion wa~ 43 percent, but this ~]ver-

study included no control group of ill patientsnot taking cimetidine. Sperm counts remainedwithin the wide fertile range, but the antiandro-genic side effects of cimetidine should be eval-uated further. 21

Thus, cimetidine used for up to 2 months ap-pears to be a relatively safe drug, but reportedincreases and shifts in gastric flora and en-docrinologic effects are disturbing. Cimetidineis more risky than antacids, but less trouble-some to the patient. The more extensively adrug is used, the more difficult it is to impute acausal relation to sporadically reported side ef-fects or case fatalities. On the other hand, trulyassociated but rare side effects can affect sub-stantial numbers of patients if a drug is verywidely prescribed, as is cimetidine. One’s at-titude toward the safety of cimetidine dependsin part on the weight placed on the possibility ofunanticipated and remotely occurring side ef-fects such as those that have occurred with othermedications like diethylstilbestrol (75).

COMPLICATIONS

The major complications of ulcer disease arebleeding from the base of the ulcer, obstructiondue to swelling or fibrosis, perforation throughthe intestinal wall into the peritoneal cavity,and penetration into the pancreatic bed. Asnoted previously, these complications are rela-tively uncommon and rarely occur as the initialmanifestation of ulcer disease.

The principal question of interest here iswhether short-term use of cimetidine alters thelikelihood of near-term complications. SeveralBritish investigators have reported patients whodeveloped perforation of peptic ulcers shortlyafter the cessation of cimetidine therapy(60,148). An increased risk of perforation fol-lowing cimetidine therapy is not substantiatedby controlled studies comparing longer term useof cimetidine and placebo following an initialcourse of cimetidine. These studies, discussed inthe section on long-term clinical effects below,

statement is apparently based on dividing the difference in meansperm count (40. 3 million per ml3) by the final, rather than the in-itial, count,

‘ ‘Additional studies are underw~y, accc~rding to FDA (5 I I.

assess whether maintenance doses of cimetidinecan reduce the likelihood of ulcer recurrence,

ULCER RECURRENCE FOLLOWING SURGERY

Cimetidine has been used to treat ulcers thatrecur following surgery for ulcer disease. We areaware of two randomized, controlled trials ofcimetidine’s effectiveness in preventing ulcera-tion after surgery (71,88). These studies reacheddifferent conclusions. In Britain, Kennedy andSpencer (88) compared cimetidine with placeboin patients who had undergone one of a varietyof surgical procedures (including gastrectomyand vagotomy with and without a drainage pro-cedure) and who, after surgery, had developedulcers at various locations (stomach, duo-denum, or jejunum). The 12 patients treatedwith 1 g of cimetidine daily did not show signifi-cantly more healing at 6 weeks than the 12 pa-tients treated with placebo.

A more recent study in West Germany (71)was restricted to patients who had undergonepartial gastrectomy and developed ulcers at ornear the site of the surgery. After 4 weeks oftreatment, ulcers had healed in six of seven pa-tients treated with 1 g of cimetidine daily, butnone of the eight treated with placebo had heal-ed (difference significant, p < 0.01). After 8weeks, all seven cimetidine-treated patients, butonly one of eight placebo-treated patients hadhealed (difference significant, p < 0.01). The in-cidence of relapse after cessation of cimetidineand effects of maintenance on preventing recur-rence after surgery have not yet been reported incontrolled trials.

RECOMMENDATIONS FOR TREATING NEWLYDIAGNOSED, UNCOMPLICATED ULCER

Gastroenterologists differ in their recom-mended treatment for patients with newly diag-nosed, uncomplicated duodenal ulcers. Some,stressing comparable rates of healing, long ex-perience with antacids, and uncertainties atten-ding any recently introduced drug, recommendan initial trial of intense antacid therapy (140).Others, impressed with cimetidine’s per-formance and concerned about lack of patientadherence to an antacid regimen, prefer to usecimetidine (98).

The choice between antacids and cimetidine isclearly closely balanced. Rather than adopt ei-ther approach exclusively, a conscientious clini-cian might better weigh the choice for each pa-tient individually, taking account of presentuncertainties as well as each patient’s personali-ty and preferences. For example, patients varyin their willingness to persevere with antacids inthe face of mild to moderately uncomfortableside effects. In addition, patients, as well as doc-tors, vary in their attitudes toward known andunknown risks. Thus, a young man trying tostart a family would surely view possible anti-androgenic effects differently than would awoman or elderly man.

As times goes on, new evidence may reducepresent uncertainties about the comparativebenefits and risks of cimetidine. Individual pa-tient characteristics and values might still makethe preferred treatment different for differentpatients who are all classified in the same gen-eral diagnostic category.

Long-Term Clinical Effects

The use of cimetidine beyond the short-termtreatment of ulcer may take two forms: 1 ) inter-mittent administration if symptoms or ulcera-tions recur, and 2) maintenance treatment withthe aim of preventing ulcer recurrence.

Cimetidine is probably very commonly usedfor intermittent treatment of ulcers (7), but weare aware of no controlled studies comparingcimetidine to alternative approaches. One study(64) suggests that with cimetidine, healing of asecond ulcer is slower than healing of an initialulcer. In 25 patients with recurrent ulcers, 5 2percent healed after 4 weeks of treatment withcimetidine compared to 76 percent who hadhealed within 4 weeks after diagnosis of theirfirst ulcer. Interpretation of the results of thisstudy, however, is clouded by differences in theinitial treatment history of these patients andambiguity in the report. For example, the 25 pa-tients with recurrent ulcers included a majoritywhose first ulcers had been treated with cimeti -dine and others whose first ulcers had healedspontaneously. In addition, most of the 25 pa-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 beenmaintained on low-dose cimetidine.

We are aware of no studies comparing main-tenance cimetidine to maintenance antacids.Perhaps it has been assumed that few patientswould adhere to long-term treatment with effec-tive doses of antacids. Grossman (67) suggeststhat this might be reconsidered in light of the re-cent study by Lam, et al. (93), who found thatrelatively small doses of antacids given in theform of tablets were effective in promoting thehealing of duodenal ulcers.

Most research on long-term use has comparedmaintenance doses of cimetidine to placebo(with antacids ad libitum). These studies formthe basis for the following discussion.

ULCER RECURRENCE

Table 14 summarizes the results of six double-blind controlled studies, published in English,comparing maintenance cimetidine to placebofor periods ranging from 80 days to 1 year. Pa-tients in these studies were given 400 or 800 mg

of cimetidine daily. Investigators consistentlyreport a statistically significant reduction insymptoms and recurrent ulceration during theperiod of treatment in the cimetidine-treatedgroup compared to those given placebo. Theconsistency of results is particularly strikinggiven the range of criteria used to selectpatients —with some studies including patientswith recently treated new ulcers (e. g., 70),others limited to chronically ill patients (e.g.,16), and others restricted to patients consideredcandidates for surgery (e. g., 64).

The conclusions from these studies are rein-forced by a recent review by Burland, et al. (23).These authors compiled results from 15 double-blind maintenance trials, either completed or inprogress, involving 695 patients. Overall, thenumber developing recurrent ulcers while tak-ing placebo appears to be twice that observedwith maintenance cimetidine. Approximately 10percent of patients treated with placebo and 50percent of cimetidine-treated patients remainedin remission during 12 months of treatment.

Table 14.—Controlled Trials of Maintenance Cimetidine in Peptic Ulcer

Ulcer recurrenceSymptomatic relapse (by endoscopy)

Initial Duration DifferenceInvestigator (premaint.) of maint. Maint. Number Number/% Number Number/% significant

Study year/country t reatment (months) t reatment ana lyzed 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

M2 Blackwood, et al.recurrence

(13) Not 6 P hs 24 12 (50%) 24 21 (88%) Yes1976/United specified C 800 mg hs 21 8 (380/. ) 21 5 (250/.) (p< 0.0005)Kingdom

M3 Bodemar & Walanrecurrence

(16)/ 65 cimetid. 12 P bid 36 30 (83%) 36 38 (83%) Yes1978/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%) YesKingdom 8 other C 400 mghs 26 11(42%) 22 7 (32%)

M5 Gudmand-Hbyer, Not 12 P bid 25 20(80%) — Yeset al. (70)

—specified C 400 mg 26 3(12%) – (p< 0,1301)

19781 Denmark—

bidM6 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 studybp = 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 ofcimetidine daily.

The performance of different maintenanceregimens may depend on the initial treatmentreceived by patients. Those whose ulcers havehealed initially with placebo, antacids, or cime-tidine may differ in their susceptibility to recur-rence. Consider the possibility that patientswith newly developed ulcers fall into two clini-cally indistinguishable subpopulations, one(type A) being more resistant to treatment andprone to relapse than the other (type B). Nowconsider the hypothetical experimental situationillustrated in table 15. Seventy patients in eachof two groups are assigned randomly to initialtreatment with cimetidine or with antacids. Ineach group of 70, 40 are type A and 30 are typeB. Both treatments produce healing in 75 per-cent of type A patients, but cimetidine is twiceas effective as antacids (67 v. 33 percent) in pro-ducing healing in type B patients.

After initial treatment, only those patientswho have healed are followed for possible re-lapse. (In the case of maintenance studies, onlypatients initially healed are tested with mainte-nance therapy. ) Assuming that a given propor-tion (one-third) of all type A patients and that alarger proportion (one-half) of all type B pa-tients both relapse within 6 months, then cimeti-dine-treated patients will appear to be moreprone to relapse (40 v. 38 percent). This can betrue even when, as shown in the last column oftable 15, cimetidine results in a greater fractionof the initial population of patients remainingasymptomatic.

Empirical evidence consistent with such anadverse selection of patients whose ulcers healinitially with cimetidine may be found in theresults collected by Burland, et al. (23). Amongpatients treated with maintenance placebo, 245(50 percent) of 290 patients initially treated withcimetidine developed symptomatic re-ulcera-tion, compared to 9 (30 percent) of 30 patientsinitially treated with placebo (difference signifi-cant, p c 0.05). On the other hand, there maynot be an adverse selection of patients who healfollowing cimetidine treatment as compared tothose who heal after antacid treatment. Ippolitifollowed patients with duodenal ulcer who hadbeen assigned randomly to treatment for up to 6weeks with a concerted antacid program or withcimetidine. 22 Among those whose ulcers healed,the rate of recurrence at 6 months (as deter-mined by endoscopic examination at 3 and 6months) was 54 percent among the 41 patientswho had been treated with cimetidine and 60percent among the 35 patients who had beentreated with antacids.

Following cessation of treatment, patientswho had been taking cimetidine begin to relapseat the same rate as the initial rate of relapseamong patients who were treated with mainte-nance placebo. This important finding is dem-onstrated in the study by Gudmand-Høyer, etal. (70). Once it is discontinued, maintenancecimetidine appears neither to accelerate recur-rence nor to effect any more permanent cure.

“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

Starting populationInitial treatment of patients

Cimetidine - Total = 70Type A = 40Type B = 30

Antacids Total = 70Type A = 40Type B = 30

Response to initialtreatment: Numberhealed (o/o of those

entered)

Total = 50 (71 O/. )Type A = 30 (75°/0)Type B = 20 (67%)

Total = 40 (570/. )Type A = 30 (750/. )Type B = 10 (33%)

Relapse in 6 monthsafter treatment

discontinued: Number Number remainingrelapsed (o/o of initially asymptomatic (0/0 of

healed) starting population)

Total = 20 (400/. ) 30 (43°/0)Type A = 10 (33°/0) 20 (50°/0)Type B = 10 (500/. ) 10 (33°/0)

Total = 15 (380/. ) 25 (36°/0)Type A = 10 (330/. ) 20 (50°/0)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 areless consistent than are the findings. To some in-vestigators, the high relapse rate after cessationof treatment “suggests that prolonged cimeti-dine therapy is necessary to retain most patientsin remission” (76). Others, cognizant of thepotential unknown risks in treatment for longerthan 12 months, wonder whether “those pa-tients would have been better off if surgery hadbeen advised at a much earlier stage. A year hasbeen wasted in which they have been taking tab-lets daily when the end-result was surgery afterall” (Wulff, quoted in 150). But not all patientswho relapse become candidates for surgery, anda key question is the likelihood of their healingwithout surgery. Even if maintenance cimeti-dine accomplished nothing more than a l-yeardelay in surgery, it might be worthwhile forsome patients to defer the small, but definite,mortality risk from surgery in favor of the risksof cimetidine for 12 months. Indeed, as a pa-tient’s surgical risk increases, cimetidine’s un-known consequences become more acceptable(29).

In summary, compared to placebo, mainte-nance treatment with cimetidine significantlyreduces the chance of ulcer recurrence. Oncecimetidine is discontinued, patients begin torelapse at the same rate as they would havewithout maintenance treatment. We found nocontrolled studies of maintenance cimetidinecomparing alternative treatments other thanplacebo and no published reports studying peri-ods longer than 1 year of maintenance therapy.

SAFETY

Long-term studies with cimetidine turn up noimportant new side effects other than thosementioned in relation to short-term treatment.The incidence of gynecornastia may be as highas 4 percent in patients treated for 2 months to 1year (131). Presumably, changes in the bacterialflora of the stomach found after 4 weeks ofcimetidine treatment would persist with long-term therapy (122). As discussed earlier, thisraises the possibility that patients takingmaintenance cimetidine might have an increasedrisk of developing gastric cancer. Experienced

clinicians express concern that rare, but severe,side effects may not be evident in relativelysmall controlled trials and that risk of toxicity isgreatly magnified if treatment continues for pro-longed periods of time (70).

COMPLICATIONS

Available controlled trials tell us very littleabout possible effects of cimetidine on long-term complications of ulcer disease (hemor-rhage, obstruction, perforation, and penetra-tion). The reasons rest mainly in the nature ofthe disease, absence of reliable estimates ofbaseline rates (no randomly selected populationof ulcer patients has been followed over manyyears), and the comparative rarity of severecomplications, believed to be not more than afew percent per year following initial diagnosis(140).

As stressed by Grossman (70), the size of astudy needed to detect clinically relevantchanges in complication rates would be enor-mous. If, as he posits, 5 per 1,000 recurrencesresult in perforation, and we wanted to detect ata 0.05 significance level a treatment that wouldhalve the rate of recurrence, we would needmore than 15,000 patients in each of two ex-perimental groups to have a 90-percent chanceof finding that difference (49).

It may be that insofar as a treatment such ascimetidine therapy can reduce or delay recur-rence, it will reduce or delay complications.However, insofar as patients at higher risk ofcomplications are also more resistant to treat-ment that delays recurrence, reductions in com-plication rates will be less than reductions inrecurrence. The reasons are analogous to the ad-verse-selection bias hypothesized above. Thereis little convincing evidence that cessation ofcimetidine treatment can promote complica-tions (see earlier discussion), and likewise, thereare no convincing data from clinical trials thatcimetidine reduces complications. Given the sizeof studies that would be required, it seems un-likely that compelling evidence on this questionwill be forthcoming from controlled clinicaltrials.

PENDING APPROVAL BY FDA

At the present time, FDA is considering ap-proval of cimetidine for use longer than 8 weeksin patients with duodenal ulcer disease. Its ad-visory committee reportedly recommended inOctober 1979 the approval of maintenancecimetidine for patients who are at “high risk” forsurgery (50). This probably includes both pa-tients who are more likely to require surgeryand patients who are less likely to survive sur-gery. We understand that final decisions on thisquestion, as well as revised limits on the ap-proved duration of treatment, are not yet for-mulated. The principal drawback to longer termuse is the risk of unknown side effects. Avail-able evidence supports the effectiveness of cime-tidine in delaying recurrence. Physicians andpatient attitudes toward the unknown risks ofcimetidine will vary, but for those with relative-ly large and tangible risks from surgery,cimetidine is likely to be judged as a less danger-ous course.

FDA has not yet approved cimetidine for usein patients with gastric ulcer. This is apparentlyrelated to the conflicting evidence about the ef-ficacy of cimetidine for gastric ulcer (see table11, p. 31) and to a more general policy concernabout the possible role of nitrosoaminated com-pounds in the development of cancer.

Health System Effects

Empirical data on the health system effects ofcimetidine are more sparse than available in-formation about clinical effects. Some pertinentinformation is available, and several studies arein progress that may shed more light on these ef-fects, but at the present time, available evidenceis suggestive rather than conclusive. As dis-cussed in the next part of this case study, thelack of empirical evidence to inform estimates ofcimetidine’s health system effects seriouslyhandicaps available benefit-and-cost analyses.

Medication

Eight of the 20 placebo-controlled studies ofcimetidine shown in table 16 (D1, D2, D3, D5,D6, G2, G3, M3) compared antacid consump-

tion among patients in the experimental andcontrol groups. Five (D2, D5, D6, G2, M3) ofthe eight studies were conducted in Europe andone (D1) in South Africa. In these six studies,cimetidine-treated patients consumed between47 and 84 percent less antacid. In the remainingtwo studies (D3 and G3), both done in theUnited States, differences were less marked, andthere were no consistent trends toward de-creased antacid consumption among cimetidine-treated patients.

Possible effects of cimetidine use on the con-sumption of other drugs have not been reported.

Diagnostic Tests

Insofar as persistent or recurrent ulcer symp-toms lead physicians to perform diagnostictests, and insofar as cimetidine reduces or delayssymptoms, the drug could result in fewer diag-nostic tests if used without the constraints ofcontrolled triail protocols. It is important to bearin mind that cimetidine’s effectiveness in long-term use has been tested against placebo, butnot, to our knowledge, against an antacid pro-gram or other regimen. To the extent that cime-tidine produces biochemical or other abnormal-ities that physicians choose to evaluate further,it could increase the number of laboratory testsperformed.

In addition, if physicians felt obliged to screenfor unlikely but potentially serious side effects,such as granulocytopenia, the number of diag-nostic tests in patients treated with cimetidinecould increase. The presence and extent of thesedifferent effects are currently matters for spec-ulation.

Physician Visits

The range of potential effects posited for diag-nostic tests applies as well to physician visits.Secondary induced effects are also possible: Ifphysicians are visited less often for a principalproblem of ulcer disease, then less medicationand fewer procedures may be used for a lesstroublesome problem, such as mild to moderatejoint pain, that in itself might not prompt a per-son to seek medical care.

40 ● Background Paper #2: Case Studies of Medical Technologies

Hospitalization and Surgery

Costs of hospitalization and surgery are thelargest single component of medical expendi-tures for ulcer disease (see table 6, p. 19). Hence,the effects of an intervention such as cimetidineon the rates of hospitalization and surgery areparticularly important to a CEA.

Because, as discussed earlier, cimetidine wasdisseminated widely in a short period of time, itseems possible that its effects might be reflectedin global trends of hospitalization and surgery.Data we have compiled and analyzed fromNCHS do indicate an unexpectedly sharp de-cline in surgery in the first calendar year (1978)following the introduction of cimetidine in theUnited States. According to data from CPHAcompiled by Elashoff and Grossman (42), how-ever, the decline was less precipitous. Hospital-related effects that are linked more directly tothe use of cimetidine may emerge in the next fewyears from several studies currently in progress,which we will describe briefly.

Table 16.—Short-Term, Double-Blind,Placebo-Controlled Studies of Cimetidine:

Effect on Antacid Consumption

Antacid consumption ofcimetidine group compared to

Study a Time period that of placebo group

D1 6 weeks 83% reductionD2 4 weeks “Significantly” fewer tabletsb

03 First weekc Inpatients: no differencesOutpatients: 40% reduction

D4 — Not reportedD5 6 weeks 84% reductionD6 4 weeks 47% reductionD7 — Not reportedD8 — No antacids permittedD9 — Not reportedD10 — Not reportedG1 — Not reportedG2 4 weeks 61% reductionG3 2 weeks No significant differences

6 weeksG4 — Not reportedM l — Not reportedM2 — Not reportedM3 12 months 700/. reduction (approximately)M4 — Not reportedM5 — Not reportedM6 — Not reported

asee tables 10, I 1, and 14 for Investigator, year, and cOuntrYbscatter PIOIS of antacid consumption presented, no numbers provided or sta.

tlstlcal tests reported.c Not reported for later weeks of study

Two principal sources of nationwide hospitaldata are the Hospital Discharge Survey ofNCHS and the Hospital Record Study ofCPHA. Data from both sources are used in thisanalysis. Unless otherwise stated, HospitalRecord Study data are taken from a review byElashoff and Grossman (42). Hospital DischargeSurvey data were obtained directly from NCHSand then compiled for this case study.

Information from NCHS and CPHA is not inperfect agreement. Estimates in both theHospital Record Study of CPHA and the Hos-pital Discharge Survey of NCHS are based onsamples of non-Federal, short-term hospitaldischarges, stratified by hospital size and loca-tion. The fraction of records sampled is inverse-ly proportional to hospital size, so that theoverall probability of selecting a particulardischarge is approximately the same for eachclass of hospital size. Both sources estimatedischarges, not patients, so multiple admissionsfor an individual patient are indistinguishablefrom one-time-only admissions.

One major distinction between the twosources is the difference in parent populations ofhospitals. For the Hospital Discharge Survey,NCHS selects a representative sample from allU.S. hospitals. CPHA draws its sample for theHospital Record Study from the more than 750hospitals in its parent file. These hospitals com-prise approximately 13 percent of all U.S. hos-pitals, but they account for nearly 40 percent ofall hospital discharges. Thus, large hospitals areoverrepresented in the CPHA parent file. Thesubset selected for the Hospital Record Studydata is chosen to represent the size distributionfor all U.S. hospitals, but the extent to whichany bias is introduced by the inclusion or exclu-sion of U.S. hospitals in the CPHA parent set isnot well defined .23

Table 4 (p. 16) showed NCHS Hospital Dis-charge Survey data for peptic ulcer disease forthe years 1966 and 1970 through 1978. The first-

z lone ind ica kc)r t~f tfle represen ta t iveness of Hospital Rec~)rd-Study based figures is a comparison of Hospital Record Study es-timated deaths from peptic ulcer and total counts (not pr(~jrcti(~ns)tabulated by the NCHS Division c)f Vital Statistics. Between 1970and 1978, Hospital Rec~~rd Study estimates of annual deaths frompeptic u]cer were 92 to 114 percent of U, S. \’itd] Statistics counts(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 forwhich one of the ulcer diseases was listed as theprimary diagnosis. These data, plotted in figure3 (p. 17), show a distinct downward trend overthe past decade for hospitalization of patientswhose first-listed diagnosis was ulcer disease.The CPHA Hospital Record Survey data show asimilar and significant downward trend, with aneven greater difference in the total decline from1970 to 1978 (42).24 According to both sets ofdata, the number of hospitalizations for ulcerdisease in 1978 is approximately what would beexpected by extrapolating the trend establishedthrough 1977.

Furthermore, both sets of data confirm thathospitalizations during the 1970’s have declinedfor duodenal ulcer and remained constant forgastric ulcer. Between 1970 and 1978, the ratioof hospitalizations for duodenal ulcer to thosefor gastric ulcer declined by 37 percent ac-cording to the Hospital Record Study and by 49percent according to the Hospital DischargeSurvey. This is further evidence for the epidemi-ologic distinction between duodenal and gastriculcer. The figures are incomplete because a rela-tively small number of diagnoses categorized as“peptic ulcer—site unspecified” is omitted, buttheir inclusion would not alter the trendsindicated.

Data from CPHA’s Hospital Record Studycan also be used to estimate the number of ad-

“Elashott and Grossman def]ne a trend as significant if: 1 ) theSpearman rank (}rder correlation is significant (p< O.OS), and 2)the difference between the 1970 and 1978 values exceeds the size ofthe Q5-percent c(~ntidence interval tor the med]an value (42).

missions for uncomplicated ulcer disease andthose for ulcer disease associated with hemor-rhage or perforation (42). Between 1970 and1978, uncomplicated duodenal ulcer admissionsdeclined by 46 percent; admissions for hemor-rhage declined by 37 percent; and admissionsfor perforation declined 24 percent, though fail-ing to reach statistical significance because ofthe small number of admissions for perforation.Uncomplicated gastric ulcer admissions showeda small, but significant, decline (18 percent). Noclear trend emerged for complicated gastriculcer admissions.

The number of surgical procedures for ulcerdisease has shown a decline during the 1970’sthat roughly parallels that for hospitalizations.Both NCHS and CPHA collect data on surgicalprocedures, but neither routinely relates oper-ations to discharge diagnoses. The principle sur-gical procedures used for ulcer disease are par-tial gastrectomy (excision of part of the stom-ach) and vagotomy (cutting of the vagus nerve),with pyloroplasty (enlargement of the pyloriccanal) or other drainage procedure (134). Thenumbers of these procedures performed duringselected years from 1966 through 1978 areshown in table 17 (NCHS data). During thisperiod, pyloroplasty and drainage procedureswere almost invariably performed in associationwith vagotomy. Virtually all vagotomies wereprobably undertaken for the treatment of ulcerdisease. Presumably, the great majority of par-tial gastrectomies were also done for ulcerdisease, but there are also several less commonindications for partial gastrectomy (e.g., gastriccarcinoma and trauma).

Table 17.—Number of Selected Surgical Procedures(Partial Gastrectomy, Vagotomy, Pyloroplasty and Drainage”) in the United States, 1966-78

Year

1966 . . . . . . . . . . . .1970 . . . . . . . . . . . .1972 ........, . . .1975. , ... , . . . . . .1976 . . . . . . . . . . . .1977 .., . . . . . . . .1978 . . . . . . . . . . . .

PyloroplastyPartial gastrectomy Vagotomy and drainage

74,500 61,000 56,80055,800 62,800 45,50063,300 59,300 42,00053,300 52,800 38,50054,200 48,300 31,20051,100 45,500 26,30039,700 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 andvagotomies can serve as a reasonable proxy forthe number of surgical operations done for pep-tic ulcer disease. Summing these two proceduresmay double count some patients who undergosurgery, because a patient who receives bothpartial gastrectomy and vagotomy is recordedunder both procedures. Despite the possibilityof some double counting, the trend over time inthe total of these two procedures would remaina useful index.

Estimates for the number of partial gastrec-tomies and vagotomies from NCHS tend to behigher than estimates from CPHA, but datafrom both sources show a distinct downwardtrend over time in the number of operations (seetable 8, p. 22). An acceleration (or deceleration)of this downward trend in surgery following theadvent of cimetidine might be ascribable to theintroduction of this new, widely used medica-tion.

We tested whether the number of surgicalprocedures performed in 1978 was differentfrom that which would be predicted by theprevious trend in the following way. First, wefitted a least-squares, linear regression line tothe surgical data available through 1977. Thepredicted number of procedures in 1978 is basedon a direct extension of the regression line. Thisis shown in figures 5 and 6, respectively, for theNCHS and CPHA surgery data. The NCHS es-timates of surgery are consistently higher thanthe CPHA estimates, but the rates of decline(slopes of the regression lines) are quite similar,within one standard error of each other .25 Theplots also show the 95- percent confidence inter-val about this regression line for individualestimates in each year for which data areavailable.

According to the NCHS data (figure 5), therate of surgery in 1978 is significantly (p< 0.01)below the rate that would have been predictedon the basis of the trend through 1977. The dropin 1978 is less striking in the CPHA data (figure6), but even here there is only about a 1 0 -percent chance that the estimated amount of

“Thr ~l(~pc (){ the regre~~lon line tor the’ NCHS data ts 0.33cII;that for the CPHA data is 0.3Q4s.

Figure 5.— NCHS Data on Number of SelectedSurgical Procedures (Partial Gastrectomy and

Vagotomy) in the United States, 1966.78

140

60,1965 1970 1975 1980

● Best fit computed by least-squares method. Confidence intervalsshown for curve fit to years 1966-77,

SOURCE Based on data from the Nat fonal Center for Health Stat[s ICS HyattsV1/1~ Md

Figure 6.—CPHA Data on Number of SelectedSurgical Procedures (Partial Gastrectomy and

Vagotomy) in the United States, 1966-78

40,000 JI 1 1 1 I E I I I I I J, --

1970 1975 1980

● Best fit computed by least-squares method. Confidence Intervalsshown for curve fit to years 1966-77.

SOURCE Based on data from the Comnllsslon on Professional and +ospltalActlvttles compiled by J D Ela Shoff and M I Grossman 1981)(42)

surgery in 1978 is in line with the precedingtrend. The number of surgical procedures in1978 was approximately 11,000 fewer than thepredicted number based on CPHA data, and26,000 fewer than the predicted number basedon NCHS data.

Further evidence for the apparent excessivedrop in surgery in 1978 compared to earlieryears comes from a comparison of the numberof surgical procedures as a proportion of hos-pitalizations for ulcer disease for various years(see table 18). Each year from 1966 to 1977, thenumber of operations was between 25 and 29percent of hospital admissions; in 1978, thenumber of operations for ulcer disease was 19percent of hospitalizations. Roughly speaking,for the decade before 1978, more than one infour patients hospitalized for peptic ulcer re-ceived surgery; in 1978, the proportion droppedbelow one in five.

If an unexpected decline in ulcer surgery did,in fact, occur in 1978, the question is, why? Didcimetidine play any role in the apparent drop?Are there other plausible explanations? Whatsorts of data might be obtained that couldanswer these questions?

Table 19 shows numbers and rates of surgicalprocedures for all abdominal surgery and forselected abdominal surgical procedures forselected years from 1970 through 1978. Therewas no general decline in abdominal surgeryover these years. Only surgery for peptic ulcerdisease shows a marked decline in 1978 com-pared with the rates in earlier years. Somesurgery for peptic ulcer is elective, and onemight imagine that part of the decline could berelated to a newly emerging, more cautious at-titude toward elective operations. This mightoccur, for example, as a result of more patientsseeking second opinions or of greater cost-con-

Table 18.— Proportion of Patients With First-Listed Diagnosisof Ulcer Disease Having Surgery, 1966-78

BA Number of patients

Number of surgical discharged withYear procedures diagnosis of ulcerb A/B— — .1 9 6 6 : : 135,500 526,000 0.2581970. ...., . . . . 118,600 438,000 0.2711 9 7 2 , 122,600 429,300 0.2861975 . . . . . . . . . . . . 106,100 411,700 0.2581976 . . . . 102,500 385,400 0.2671977 .., . . . . . . . 96,600 385,400 0.2511 9 7 8 68,900 360,400 0.191

al ~~1 udes part Ial gast rectom~ and va90t0mYblncludes 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 gastrectomyAll abdominal surgery and vagotomy Appendectomy Cholecystectomy a Herniorrhaphy b

—.Year Number RateC Number RateC Number RateC Number RateC Number RateC

—— —..1 9 7 0 2,440,000 122 119,000 6 325,000 16 367,000 18 496,000 251975 . . . . 2,894,000 138 106,000 5 319,000 15 442,000 21 549,000 261 9 7 6 . . . . , . , 2,809,000 133 102,000 5 306,000 14 442,000 21 507,000 241 9 7 7 2,937,000 139 97,000 4 342,000 16 446,000 21 533,000 251 9 7 8 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(erbsurglcal repa[r of a herniac 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,we find no parallel decline between 1977 and1978 in other abdominal surgery, such as her-niorrhaphy (surgical repair of a hernia), whichis probably more frequently elective than issurgery for ulcer disease.

A dramatic change in the criteria used todecide on surgery or use of a different type ofsurgery for patients with ulcer disease might ac-count for some decline. To our knowledge,however, neither the recognized indications forsurgery nor the types of operations havechanged dramatically in the past few years.Also we know of no changes in the standardcoding for operative procedures in 1978 thatmight account for the observed decline. Diag-nostic advances, such as fiberoptic endoscopy,may provide greater- assurance of benignity of aslowly healing gastric ulcer and thus avert somesurgery that would have been performedpreviously. Even if present, however, such ef-fects seem very unlikely to reach the propor-tions of the evident decline in 1978.

Results from at least one of the maintenancetrials comparing cimetidine with placebo sup-port the possibility that the decline in surgery in1978 is related to the availability of cimetidine.In a year of maintenance treatment, Bodemarand Walan (16) found that 1 patient in 32 whoreceived cimetidine and 15 in 36 who receivedplacebo underwent surgery because they hadtwo recurrences or because of severe symptomsat the first recurrence (difference significant,p < 0.0005). 26 Thus, one possible explanationfor the decline in surgery for ulcer disease in1978 is that the dramatic growth in the use ofcimetidine enabled more patients to be treatedsuccessfully medically. If cimetidine wereresponsible, the effect could be temporary. Pa-

‘@In a second maintena ace study that rept~rted sur~lcal e x -perience, p[wsible effects t~t cimetldine <~n ~urgery are obscured bythe 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 ‘placebofai lures” durtng the 6 months [~t the study (M ~ In thi~ ~tudy, 30patients wew treated in]t ially with Imaintenance p]acebt~, 24 re-l a p s e d , al! t~t wht~m were t h e n trc>a ted with c I met i dine, and ~

underwent surgery wit h In t Ilt, ~-m on t h period L)} t hc \t udv. Ot the26 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 the6-m(~nth perl(xi t~t the ~tudy

tients who were scheduled for an elective opera-tion may have decided with their physicians todelay surgery in order to try the new drug. Sincepatients appear to relapse at the same ratefollowing cessation of cimetidine, the decline insurgery might be followed by a compensatoryrebound, especially if more reports (e. g., 121)suggest increased risks or adverse side effectswith long-term use of cimetidine.

To date, only circumstantial evidence andargument by exclusion can make the case for therole of cimetidine in decreased rates of surgery.However, more direct evidence may be forth-coming from several sources. Murray Wylie ofthe University of Michigan is engaged in adetailed analysis of CPHA data on patients hos-pitalized with ulcer disease .27 Wylie has data onall patients discharged with a diagnosis of ulcerdisease from a cohort of 790 hospitals that par-ticipated continuously in the CPHA data systemfrom January 1974 through October 1978. Al-though the data do not specifically identify pa-tients who did and did not receive cimetidine, heis able to examine surgical rates on a month-to-month basis. Thus, he can test the corre-spondence between any accelerated decline insurgery and the introduction of cimetidine in theUnited States in August 1977.

Wylie’s preliminary impression is that the fre-quency of surgery began to drop even a fewmonths before the release of cimetidine. Hespeculates that this might be attributable to adelay in elective surgery in anticipation of thenew medication. It would be very informativeto compare changes in rates of surgery separate-ly for uncomplicated cases (presumably ad-mitted because of pain) and for those with hem-orrhage or perforation. If cimetidine is reducingsurgery by effecting a medical remission afterpatients are hospitalized, the largest drop insurgery as a proportion of admissions should befor patients hospitalized because of pain.

Wylie will also be able to analyze his dataseparately for surgical and medical admissions,including length of stay. This is of particular in-terest to a cost-effectiveness assessment of 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

{~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 besaved by cimetidine. Presumably, some fractionof the reduction in surgery that might be at-tributable to cimetidine is due to patients notbeing hospitalized, and another fraction is dueto hospitalized patients being treated medicallyonly. (The large drop in surgery in 1978 com-pared with the drop in hospitalizations suggeststhat the latter fraction may be the larger. ) Onthe average, surgical lengths of stay would beexpected to be longer than medical, and a shiftfrom surgical to medical care in a hospitalshould typically produce a reduction in hospitaldays. If a very large number of patients who areconsidered potential candidates for surgery arefirst treated medically, however, any failures onthe medical regimen would then undergo sur-gery after a delay, and this could add to theaverage length of stay for patients. In addition,successful medical treatment with cimetidinemight or might not take longer than a medicalregimen without the drug. A few points of datawould be preferable to a lot of speculation.

Another approach to assessing cimetidine’seffects on the health system has been undertakenby Professors Burton Weisbrod and JohnGeweke at the University of Wisconsin .28 Theyare analyzing patient records developed for ac-counting purposes by the Texas medicaid pro-gram. Weisbrod and Geweke aim first to recon-struct medicaid expense records on a patient-by-patient basis for all patients with a diagnosis ofulcer disease. They have identified 1,206 pa-tients with ulcers in a sample that begins inJanuary 1976 and will extend to August 1979.These investigators have conducted a pilotstudy with 81 patients randomly selected fromthis population, 36 with and 45 without a his-tory of cimetidine use. Their intent is to com-pare the health and expenditure history (includ-ing nearly 50 categories of various expenses forhospitalization, physicians, drugs, nursinghomes, etc. ) for patients treated with and with-out cimetidine.

Weisbrod and Geweke recognize some in-herent limitations in the available data. For ex-ample, approximately one-fifth of the medicaid

‘F\\’c’ are gratet UI to [’r(lfes~t~r Cewcke t(lr \harlng intt~rmatl(lnabc~u t t hcl r \t udy t or t h 1+ reptlrt

claims do not include the patient’s diagnosis;medicaid patients over 65 years old are alsocovered by medicare, about which the investi-gators have no information; and the data do notinclude information concerning patient status atdischarge or work history. The major difficultyWeisbrod and Geweke face, however, is con-trolling for selectivity bias in those patients whodo receive cimetidine. Their approach is tostratify patients according to demographic fac-tors and clinical history. Although it will be im-possible to overcome the aforementioned bar-riers completely, Weisbrod and Geweke’s studypromises to be the first large-scale, patient-based study providing data on the direct and in-duced health system effects of cimetidine. Thedata base can also be used to describe the diffu-sion of the drug in a given patient populationand the pattern of present use by medical practi-tioners in one State.

We are aware of a few additional studies ofthe health system effects of cimetidine that arein more preliminary stages of development. Atleast one of these involves a health maintenanceorganization (HMO); if the HMO’s populationis sufficiently stable, it may be a particularlyvaluable setting for study. Ideally, one wouldseek results from a long-term, randomized, con-trolled study of patients with ulcer disease whoare or are not treated with cimetidine, but forethical and practical reasons, such a study isunlikely to materialize.

In summary, hospitalization and surgery forpeptic ulcer disease have both declined signifi-cantly during the past decade. The decline inhospital admissions for 1978 is consistent withearlier trends. However, the fall in surgical pro-cedures for ulcer disease in 1978 is unexpectedlylarge, amounting to 11,000 to 26,000 fewer pro-cedures in 1978 than would be expected from thetrend leading up to that year. The introductionand widespread use of cimetidine is one plausi-ble explanation for this unexpected decline.More specific information from studies in prog-ress, including a month-by-month tracing ofsurgical rates and a comparison of healthresources used by patients who did and did notreceive cimetidine, would help strengthen orrefute this inference.

46 ● Background Paper #2: Case Studies of Medical Technologies

Outcome

The outcome effects of cimetidine are conse-quences of its clinical and health system effects.We have already discussed how clinical andhealth system effects interest and lead to the twocomponents of outcome: health status and re-source costs. In this section, we present addi-tional empirical evidence about cimetidine’spossible effect on outcome.

The available empirical evidence plus meth-odologic and other considerations raised in alater section entitled “Guidelines for Review ofHealth Care Benefit-and-Cost Analyses” serveas a basis for our review of published analysesof cimetidine’s benefits and costs in the next partof this case study.

Health Status

As we have already discussed, it is convenientand usual to think of health status in terms ofmortality and morbidity.

MORTALITY

We are aware of no empirical studies of theeffects of cimetidine on mortality from pepticulcer disease. This is not surprising, becausemortality from this disease is relatively low. Acontrolled cohort study would require enor-mous numbers of patients, for reasons presentedearlier in the discussion of possible effects of ci-metidine on complication rates. One mightargue that insofar as cimetidine delays or sup-plants surgical intervention and attendant sur-gical mortality and delays the development ofcomplications, it will forestall some deaths.However, it is conceivable that patients whowould naturally develop the more virulent com-plications of peptic ulcer might benefit less fromcimetidine or that complications followingcessation of the drug would be more severe thanthey might have been had cimetidine not beenadministered. Any of these circumstanceswould counter potential improvements in sur-vival related to cimetidine. In addition, anysevere and unanticipated side effects from long-term use would further compromise cimetidine’sbeneficial effects on mortality.

Table 3 (p. 16) shows that mortality fromulcer disease has been declining steadily over thepast 15 years. Figure 7 shows NCHS ulcer mor-tality statistics on a quarterly basis from 1976 tomid-1979. It shows both a continuing down-ward trend and a seasonal variation in mor-tality, No unexpected mortality reduction fol-lowing the introduction of cimetidine in August1977 is evident. If cimetidine has saved lives ofulcer patients, the lives saved are too few tohave a substantial effect on overall mortality todate. Of course, these figures are mute on thequestion of whether even more widespread andconsistent use of cimetidine might demonstrablydelay or prevent deaths from ulcer disease in thefuture.

In summary, there are some reasons to be-lieve cimetidine might have beneficial effects onulcer mortality and other reasons to doubt it. Ifcimetidine did have a small beneficial effect onmortality, it would be very difficult to detect incontrolled cohort studies or from national mor-tality trends.

Figure 7.— Number of Deaths in the United StatesFrom Ulcer Disease (Gastric, Duodenal, and Peptic—

Site Unspecified), 1976-79

January- April- July- October-March June September December

NOTE: 1978 and 1979 figures extrapolated from a 10-percentsample.

SOURCE Based on data from the Natlooal Center for Health Statistics, Dlvlslonof Vital Stat jstics, Iiyattsvllle, Md

MORBIDITY

From the perspective of BCA, in which thereis an effort to translate morbidity into socialresource costs, an important consideration is theeffect of cimetidine on disability and days lostfrom work. Cimetidine produces more promptand consistent relief from ulcer pain than doesplacebo. In the short-term treatment of pepticulcers, it is reasonable to expect that faster heal-ing and pain relief can mean earlier return towork. This potential benefit may be reduced in-sofar as doctors prescribe and patients follow“rest at home” for a set number of days or weeksfollowing diagnosis of a new ulcer, irrespectiveof the promptness of symptom remission. Thatpolicy would be reasonable, for example, ifclinicians believed that patients returning to thestress of work with unhealed ulcers would bemore likely to develop bleeding or other com-plications of ulcer disease.

A number of the randomized clinical trials ofcimetidine in the United States included a spe-cial protocol to assess time lost from work(118). A preliminary report presented results in64 outpatients, 37 treated with cimetidine and27 with placebo. (Many of the 217 potentialsubjects were disqualified because of uncertainemployment status, a problem that is being rec-tified with a revised protocol. ) Among the pa-tients analyzed, there was a striking tendency tobe absent full time or to work full time. Com-pared to the number of days lost from workduring the week prior to treatment, the groupreceiving cimetidine averaged significantly moredays of work in weeks one, two, and four(p< 0.001) and in week six (P< 0.05) followingthe initiation of treatment. This report isnotable not only for its results, but because itrepresents an admirable effort to collect datapertinent to the economic consequences of amedical practice in the context of a controlledclinical trial.

One of the trials comparing maintenance ci-metidine with placebo also reported on the workexperience of patients (15). During the year ofthe study, 1 of 32 patients taking cimetidine didnot report to work for 79 days, and 23 of 26 pa-tients taking placebo did not report to work fora total of 1,405 days because of symptoms.

Thus, the cimetidine-treated patients reported towork an average of approximately 36 more daysper patient during the year of the study (dif-ference significant, p < 0.001).

The effectiveness of cimetidine compared toother treatments, such as antacids, in enablingpatients to return to work is not addressed inany of the controlled trials we have reviewed.

Resource Costs

The economic implications of an interventionsuch as cimetidine include the costs of the in-tervention itself, the resource costs and savingsrelated to induced effects on the health caresystem, and indirect effects on productivity re-lated to change in mortality and morbidity. Inthis section, we offer a few observations on thedirect costs of cimetidine compared to alter-natives. We defer consideration of the resourcevalue attached to the induced and indirect ef-fects of cimetidine until the next part of thisstudy, in which we review some of the benefit-and-cost analyses that have been carried out.

The daily cost of cimetidine is less than thedaily cost of antacid in doses that have beenshown to be as effective in promoting the heal-ing of newly discovered duodenal ulcers (80).The retail cost of cimetidine is approximately$0.25 to $0.30 per 300-mg tablet.29 Assumingconsumption of four tablets daily, the daily costof cimetidine is $1.00 to $1.20.

Antacids vary in their compositions, neu-tralizing capacities, and costs (115). Two of themore popular blends of aluminum hydroxideand magnesium hydroxide are Maalox® andMylanta II®. 30 The latter was the antacid used inthe studies by Peterson, et al. (116) and Ippoliti,et al. (80). Mylanta II® has approximately 50-percent more neutralizing capacity than thesame quantity of Maalox® and costs approx-imately $3.80 per 12-ounce bottle compared to$1.80 for Maalox®.31

-“’Ba+wi (In inlc~rmati(ln pr{>vicjecj b} tour Bostf}n-area d r u gst(~res a nci ct~n~i~ten t w’i t h est im a tw (}} the man utacturer.

‘OMylanta 1 1 c(~ntains, in addltit~n to antacid, t h e det(~arningsi I ictlne a ncl a n t Itla t ulen t ~imeth ic(~nc.

‘lC~~st e~timatcs bawd on average charge> at tour B(wt(>n-areadrug St (}res.

If we assume administration of the sameamount of antacid as used in the studies citedabove (seven daily doses, each with approx-imately 120 mEq of buffering capacity), thedaily cost would be approximately $1.58 forMaalox® (seven 45-ml doses) and $2.22 forMylanta® (seven 30-ml doses). If patients whoare prescribed cimetidine consume three or fouradditional doses of antacid daily, their medica-tion costs would still be comparable to those ofpatients who follow an intense antacid regimen.Thus, a typical patient can expect to pay nomore, and possibly somewhat less, for ci-metidine than for a therapeutically equivalentcourse of popular, brand-name antacids .32

Summary

Organized according to the benefit-and-costmodel for medical interventions presented earli-er, this part of our case study has describedavailable information about the effects of cime-tidine—its clinical effects, its health system ef-fects, and its potential impact on outcome.

Numerous controlled studies of patients withduodenal ulcer confirm that cimetidine pro-motes healing and provides faster and morecomplete pain relief than placebo. Less con-clusive evidence suggests the drug may be moreeffective than placebo for patients with gastriculcer. An intense antacid program appears to beabout as effective as cimetidine for patients withduodenal ulcer, but more evidence on this mat-ter is needed. Clinical studies have also shownthat relief of symptoms is not a reliable in-dicator of healing. In general, European studieshave found more favorable results withcimetidine than have’ U.S. trials.

Cimetidine used for up to 2 months appearsto be a relatively safe drug. Most known side ef-fects are minor or reversible, but recently re-ported changes in gastric flora and endocrino-logic effects are disturbing. Available studies of

“It may be pos~ible to tind less expensive, generic brands (Jt an-tacids with equivalent neutralizing capacity, but the costs (ItMaalox ” and Mylanta ” are no more than thcwe CJ[ m~wt otherbrands (~f aluminum-magnesium antacids (63), Antacids are ~va]]-ablc wit h(~ut a presc rip t itm, and their use d(w>s nc~t nccessart 1 y en-tail the ctwt tlt a phys]clan visit, but in this dlscussl(~n we haveassumed that a high -cl(w .lnt~cid regimen (Ir clmet i dine would bc~consumed on I y tol Ic)wi ng a ph ys]cia n \ ad~r ict’.

maintenance cimetidine do not alter this assess-ment. As with any new drug, uncertainty existsas to possible long-term consequences of thedrug’s use.

Compared to an intense course of antacids,cimetidine is comparably effective, more risky,and less troublesome to the patient with duo-denal ulcer. Cimetidine plus a moderate amountof antacids costs no more than a therapeuticallyequivalent course of intense antacid therapy,Experts now differ in their recommendations forinitial therapy of duodenal ulcer, some favoringcimetidine and others antacids. A reasonableapproach is to select therapy based on each pa-tient’s preferences and personality.

Compared to placebo, maintenance treatmentwith cimetidine as long as 1 year significantlyreduces the chance of ulcer recurrence. Oncecimetidine is discontinued, patients appear torelapse at the same rate as they would havewithout maintenance treatment. We are awareof no controlled trials comparing maintenancecimetidine to treatments other than placebo.There is little empirical evidence either thatcimetidine prevents future complications ofulcer disease or that cessation of cimetidine pro-motes complications. At present, FDA is con-sidering approval of cimetidine for use longerthan 8 weeks in patients with duodenal ulcerswho are at high risk for surgery.

In European trials, but not in U.S. studies,cimetidine-treated patients tend to consume lessantacid than placebo-treated patients. Verylimited empirical data are currently available onthe possible effects of cimetidine on use of othermedication, on diagnostic tests, or on physicianvisits. Several studies are underway that mayshed light on these matters.

Data we have compiled from NCHS show anunexpectedly sharp decline in the rates of sur-gery for ulcer disease in 1978, the first full calen-dar year after the introduction of cimetidine.This drop occurred against a background of fall-ing rates of surgery and hospitalization for ulcerdisease over the previous decade. Other expla-nations are possible, but the widespread use ofcimetidine may have contributed to the mag-