World J. Surg. 7, 372-377, 1983

W orldJoun l r,ge

�9 1983 by the Societ6 lnternationale de Chirurgie

Surgery or Cimetidine? I. Comparison of Two Plans of Treatment: Operation or Repeated Cimetidine

Daniel Andersen, M.D., Ph.D., Erik Amdrup, M.D., Ph.D., Finn Hanberg SCrensen, M.D., Ph.D., and Kurt Birger Jensen, M.D., Ph.D.

University Departments of Surgical Gastroenterology, Kommunehospitalet and Amtssygehuset, Aarhus, and University Departments of Surgical and Medical Gastroenterology, Odense Hospital, Odense, Denmark

The aim of this study was to compare the effect of 2 different treatment plans on the definitive treatment in a group of duodenal ulcer patients with symptoms severe enough to indicate surgery after pre-cimetidine criteria.

The patients were randomized to either 8 weeks of cimetidine 1 g per day followed by operation in case of symptomatic recurrence, or to repeated 8-week courses of cimetidine 1 g a day in case of recurrence. Many patients wanted to change their treatment plan, which was allowed and used as evidence of their value judgments.

After 3 years the cumulative operation rate was 74% in the Full dose/Stop cimetidine group and 60 % in the Repeat- ed cimetidine group. During the first year the probability of operation was highest in the group with only 1 course of cimetidine, but after this time the patients came to surgery with equal probabilities. Eight percent of the patients had no relapse and, therefore, had not undergone surgery after 3 years.

The study suggests that patients with severe ulcer disease usually have to undergo surgery, even after the advent of cimetidine, but surgery is delayed. It makes little difference whether cimetidine is offered once or in several courses. The economic consequences of the 2 schemes are very similar. Intermittent treatment with cimetidine, thus, can- not be expected to have much influence on the indications for surgery in severe duodenal ulcer disease. All patients should have 1 course of cimetidine, but additional courses make no material difference in the end result and usually can be avoided.

Until recently, only surgery was able to heal the crater of duodenal ulcer and to give lasting symp- tomatic relief. Now medical treatment, e.g., with H2-blockers, is in a position to achieve the same

Reprint requests: Dr. Daniel Andersen, Department K of Surgical Gastroenterology, Odense University Hospi- tal, DK-5000 Odense C, Denmark.

result, either when given as intermittent courses or in a maintenance dose. This new state of affairs must have some impact on the indications for elective surgery. Is it at all necessary to operate anymore, except in a minority of patients with an unsatisfactory response to medical treatment? It will require some time of adjustment before a new and balanced view can mature, and comparative studies of medical versus surgical treatment schemes will be necessary. This, however, is not straightforward, since the 2 kinds of treatment are fundamentally different. To compare 2 operative techniques is relatively simple because hard data such as mortality, recurrence rate, and frequency of severe side effects can be quantitated. When com- paring medical and surgical treatments, risks and discomforts are not of the same kind and must be weighed qualitatively by the patient's judgment of real or imagined values. As far as possible, econom- ic evaluations also should be considered in the comparison.

The purpose of this paper is to compare the results of 2 plans of treatment, one based on early surgery, and the other based on repeated courses of the H2-blocker cimetidine. This kind of study in- volves the difficulty that the patients have to be informed about the alternative treatment schemes, and it is to be expected that many will demand a deviation from their allocated treatment. If these patients should be left out of the study, a very artificial clinical situation would result without any parallel to real life, where the patient's wishes are followed as far as possible. We, therefore, decided to use the adherence to or deviation from the treatment scheme as an important parameter indi- cating the patient's value judgment of the options at his or her disposal. As a result of this principle, a patient stays in a group no matter what treatment he

D. Andersen et al.: Surgery or Cimetidine 373

Table 1. The patient material.

Age (years)

Number DU PU/PPU Male Female Median Range

Full dose/Stop cimetidine group 145 115 30 106 39 50 21-83 Repeated cimetidine group 148 123 25 111 37 51 20-82

or she actually receives. The comparison between groups is thus based on a combination of the effect of the treatment and the patient's attitude toward the treatment. As a matter of fact, we compare treatment policies rather than surgically and medi- cally treated patients.

Materials and Methods

Eligible for the study were only patients with endo- scopically proven ulcer in the duodenal bulb (DU), pyloric ring (PU), or prepyloric zone (PPU) includ- ing ulcers with their anal margin 2 cm or less from the pylorus. We wanted to include only patients who would have been operated on if cimetidine had not been available [1]. Therefore, the severity of disease had to warrant surgical treatment after pre- cimetidine criteria, and only patients who accepted operation in case of recurrence after cimetidine were included. Patients who had received cimeti- dine before the trial were excluded.

Three hundred patients entered the study. Four patients have not been seen after the first course of cimetidine, 2 patients had extragastric malignancies discovered soon after entrance to the study, and 1 patient had the first course of cimetidine interrupted because of progression of pre-existing mental de- pression. This leaves 293 patients for study (Table l). New patients were taken in from January 1, 1978, to the end of February, 1979.

The patients were allocated by random numbers to 1 of 2 treatment schemes. One group of 145 patients was randomized to cimetidine 1 g per day for 8 weeks and operation was suggested in case of symptomatic recurrence, no effect of treatment, or side effects. Endoscopic confirmation of an active ulcer recurrence was often obtained, but it was not an indispensable requirement if symptoms were of the usual type and severity. This group is referred to as Full dose~Stop cimetidine group.

The second group of 148 patients was also given a full dose course of cimetidine ! g per day for 8 weeks, but in case of symptomatic recurrence an- other course of cimetidine was suggested, and the same was done after subsequent recurrences. Oper- ation was advised if cimetidine did not relieve symptoms or if side effects appeared. This group is

referred to as Repeated cimetidine group. We ad- ministered cimetidine for 8 weeks because we antic- ipated that the severity of the cases might necessi- tate a longer than usual treatment for some patients.

The patients had regular clinical examinations at the end of each course of cimetidine, 3 months and 12 months later, and after that once a year. They were instructed to call in case of recurrent ulcer symptoms, other dyspeptic symptoms, or suspect- ed side effects. The same program was used for patients after surgery.

The operative methods used were parietal cell vagotomy without drainage (PCV) for DU and either PCV with a pyloroplasty (PCV+D) or selec- tive gastric vagotomy with a pyloroplasty (SGV + D) for PU and PPU. Earlier experience [2] had indicat- ed a very high recurrence rate when PCV was used for PU or PPU. The patients in this material, therefore, were treated as part of a larger series comparing PCV+D and SGV+D for these ulcers.

The patients were explained the treatment scheme for which they were assigned, but they were also told about the alternative scheme. At the onset, they all accepted their allocated scheme; but during the course of the treatment many deviations took place, as expected, because the patients de- sired a change. Since the medication was free, there was no economic incentive to change treatment, and the patients were not encouraged to do so; but on the other hand, no pressure was put on them in either direction. Patients who did not follow their schedule were, as already explained, not excluded, but their preference was included in the evaluation of the treatment policies. The final treatment was thus a result of randomization with consequent therapeutic suggestion and a certain amount of self- selection by the patients. By this method the main elements guiding general therapeutic practice are included in the trial, and it avoids the usual some- what artificial comparison of rigid schemes. There is a cost, however, in respect to strict statistical comparability between groups, since chance is only one factor among others determining the final treat- ment.

Cumulated rates of symptomatic recurrence and surgical treatment were calculated by a life-table method and illustrated by Kaplan-Meier plots [2-4]. Differences between groups of patients were evalu-

374 World J. Surg. Vol. 7, No. 3, May 1983

Table 2. Treatment of 145 patients in the Full dose/Stop cimetidine group.

No. Treatment patients

No recurrence and no operation 13 Recurrence and immediate operation 81 No effect of cimetidine and operation 7 Side effects of cimetidine and operation 2

Total adhering to plan 103 (71%) Repeated courses of cimetidine 16 Repeated courses of cimetidine and operation 18 Repeated courses of cimetidine and low-dose

cimetidine 8 Total deviating from plan 42 (29%)

Table 3. Treatment of 148 patients in the Repeated cimetidine group.

No, Treatment patients

No recurrence and no operation 9 Repeated cimetidine 31 No effect of cimetidine and operation 10 Side effects of cimetidine and operation 3

Total adhering to plan 53 (36%) Recurrence and immediate operation 4 Repeated courses of cimetidine and operation 71 Repeated courses of cimetidine and low-dose

cimetidine 16 Emergency operation 4

Total deviating from plan 95 (64%)

ated by the log-rank test [5]. The data for patients with DU, PU, and PPU were analyzed separately, but after it had been found that they were similar in every respect, data for all ulcer sites were pooled for this presentation. In order to estimate the proba- bility of future operation and its variation with time, plots of integrated operation intensity are present- ed. The slopes of the lines indicate the probabilities, as explained elsewhere [2].

Results

The patients' adherence to or deviation from the assigned treatment is shown in Tables 2 and 3.

In the Full dose/Stop cimetidine group, 42 pa- tients (29%) deviated from assignment. Sixteen wanted more than 1 course of cimetidine and have so far not undergone surgery. Eighteen wanted more than 1 course of cimetidine before they even- tually were operated on, and 8 wanted to continue with cimetidine in a maintenance dose 0.4 g per day after several full-dose courses.

Among the patients who followed the scheme, 2 were operated on because of side effects (dizziness in 1, and headache in 1).

In the Repeated cimetidine group, 95 patients (64%) deviated from assignment. Four patients wanted operation after the first symptomatic recur- rence and 71 patients wanted surgery after more than 1 course of cimetidine. Sixteen patients want- ed to shift to cimetidine in a maintenance dose 0.4 g per day after several full-dose courses with short lasting remissions. Four patients had emergency operation (perforation 1, hemorrhage 3) during or after the first full-dose course.

Among the patients who followed the scheme, 3 were operated on because of side effects (gyneco- mastia in 2, dizziness in 1).

Apart from the few patients operated on because of side effects, the cimetidine was very well tolerat-

ed, and there were only minor changes in the regularly performed tests of liver and renal function and hematological status.

The cumulative recurrence rate after the first full- dose course of cimetidine could be evaluated for all 293 patients and amounted to 51% after 3 months, 72% after 6 months, and 92% after 2 years. There was no difference in recurrence rate between DU, PU, and PPU. In the Repeated cimetidine group, no significant differences were found between the cu- mulative recurrence rates after the first, second, and third courses of cimetidine.

The patients in the 2 groups were operated on at a rate which in the Full dose/Stop cimetidine group depended mainly on the recurrence rate, and in the Repeated cimetidine group mainly on the patient's willingness to have several cimetidine courses after recurrence of symptoms. Many patients wanted surgery after 2 or 3 courses of cimetidine, especially if the periods of remission were brief. The cumula- tive operation rates for the 2 groups are seen in Fig. 1. As expected, patients in the Full dose/Stop cimetidine group were operated on earlier and in a higher percentage than the Repeated cimetidine group (p < 0.0001). After 3 years 74% and 60%, respectively, had undergone surgery. Figure 2 shows the integrated operation intensity. The slopes of the lines express the probability for a patient who had not undergone surgery to be oper- ated on during the next month. During the first year of study, this probability was 8.9% for patients in the Full dose/Stop cimetidine group and 3.6% in the Repeated cimetidine group. In the following years, these probabilities were equal for the 2 groups, 1.1%.

The patients in both groups were kept materially free from symptoms and sick leave. The benefits from the treatments, thus, were approximately identical. The costs for most of the patients in one group were cancelled by similar cost in the other

D. Andersen et al.: Surgery or Cimetidine 375

%

100

80

60

40

20

FULL DOSE/STOP CIMETIDINE GROUP

r a -

r - J

j.. j. ,.r ~J'-J

,r r ' !

REPEATED EIMETIDINE GROUP !

!

1 ,.e i

!

0

@

r

[ I I l

0 12 24 36 l+8 Monfhs

Fig. 1. Cumulative operation rate (percent) for patients in the Full dose/Stop cimetidine group and the Repeated cimetidine group.

group, including discomforts and complications of surgery since the numbers of surgically treated patients were almost equal. Eighteen patients, 9 in each group, had recurrence of ulcer symptoms after operation, and active ulcers were endoscopically verified. Seven were treated by antrectomy and 11 by cimetidine for shorter or longer periods. ThUs, the burden of recurrent ulcers and their treatment was equal for the groups. The calculations of differ- ence in costs between the gi~oups could be limited to the small difference in the number of patients oper- ated on and a difference in the number of courses of cimetidine. In the Full dose/Stop cimetidine group, 108 patients were operated on and the consumption of cimetidine after the initial full-dose course was 77 full-dose courses and 230 months of maintenance dose. In the Repeated cimetidine group, 92 patients were operated on, and 275 full-dose courses and 320 months of maintenance dose were given. Sixteen operations are thus equivalent to 12,200 g of cimeti- dine. One extra operation in one group corresponds to 760 g extra cimetidine in the other group.

1.5

1.0 �84

0.5

0 '~ 0

FULL DOsE/STOP CIMETIDIN[ GROUP

~ : 1.1%/monl'h

~s ~S~ i'):B 9% Imonfh . ~ ^

81 x,X ~ . Al~): l .1% lmonfh

/, X#

gA(f):3.6% /month

g REPEATED CII'4E.TIOINE GROUP

' ' 3'6 ' 12 48 Honfhs

Fig. 2. The operation intensity [k (t)] expresses the probability for a patient who has not undergone surgery to be operated on during the next month. It is calculated as the slope of the lines fitting the points of integrated recurrence intensity [[3 (t)]. For further explanation the reader is referred to reference numbers 2 and 4.

Discuss ion

This study was started early in the H2-blocker era, and no patients had received cimetidine before entrance to the trial. All patients had ulcer histories severe enough to warrant operation, and all had accepted surgery in case of recurrence after cimeti- dine. The high percentage of patients actually fol- lowing the plan in the Full dose/Stop cimetidine group bears witness to their determination. Atti- tudes, however, do change, and the results of a study like this may be different in the future. Patients probably will never be allowed to have recurring long periods of symptoms year after year because effective medical treatmerit will be institut- ed early in symptomatic relapses. Their motivation for operation, therefore, can be expected to be less than that of the patients in this study.

One important result was that 8% of the patients for whom indication for operation was present have

376 World J. Snrg. Vol. 7, No. 3, May 1983

been free of recurrence for at least 3-4 years after one course of cimetidine, and operation accordingly has not been contemplated. If not for other reasons, all ulcer patients Should have at least one course of effective medical treatment before operation is con- sidered. At the opposite end of the scale, 8% of patients were not benefited by the treatment or had side effects which made operation necessary. In- crease of the dose beyond 1 g a day was not attempted.

Most of the patients experienced excellent, but temporary, relief from symptoms. The cumulative recurrence rate after the first course of cimetidine was in accordance with the findings in many studies [6,7].

The rather high percentage (60% after 3 years) of patients who eventually came to surgery in the Repeated cimetidine group probably indicates that patients with a heavy ulcer history are reluctant to accept repeated recurrences, however short, that remind them of the basic chronicity of their disease, which they realize has not been cured. The reduc- tion in the number of operations found in this material is comparable to the result in another study [81.

To the extent this kind of patients still will be found after the advent of H2-blockers and other effective medical treatments, it can be expected that the effect of such treatment will be only a modest delay of surgery. From Fig. 2 it can be seen that, after the first year, the probability of future surgery is equal and rather high for patients on intermittent cimetidine treatment and patients who were offered only one course of cimetidine. This suggests that different dose schedules for the conservative treat- ment will make only a small difference in the total operation rate. The temporary pattern of the effect on surgery has also been observed in other studies [1, 9, 10].

The inconspicuous differences in the final treat- ment of the 2 groups of patients mean that the economic and social consequences of the treatment schemes are very similar, and the actual difference can be evaluated by considering a small number of excess operations in one group and a small excess in cimetidine consumption in the other group, The costs of 1 extra operation including a period of postoperative recreation may be estimated to be about double the cost of the excess amount of cimetidine in the most conservative scheme. At the present time, therefore, a conservative attitude with repeated courses of cimetidine before operation seems justified on economic grounds on a short- term basis; but as time elapses the modest net gain by a conservative treatment policy probably will decrease, since the amount of cimetidine consumed as well as the number of eventual operations will be expected to grow.

Acknowledgment

Smith Kline & French International Co. generously supplied the cimetidine for this study.

R~sum6

Le but de cette 6tude est de comparer les r6sultats de deux modalit6s diff6rentes de traitement m6dical par la cim6tidine appliqu6e aux malades atteints d'ulc6re duod6nal s6v6re.

Les patients furent randomis6s en deux groupes. Dans le premier groupe, les malades requrent un gramme par jour de cim6tidine pendant huit se- maines et furent op6r6s seulement en cas de r6ci- dive des troubles ulc6reux; dans le second groupe, ils furent soumis en cas de r6cidive ulc6reuse h la reprise 6pisodique du traitement pr6c6dent. De nombreux patients d6cid~rent de changer de type de traitement, leur d6sir ayant 6t6 accept6 de ma- ni6re g 6valuer la valeur de leurjugement. Au terme de trois ans, le taux d'intervention fut de 74% dans le premier groupe et de 60% darts le second. Au cours de la premi6re ann6e, la fr6quence de l'inter- vention fut plus grande dans le premier groupe mais apr6s ce laps de temps, la fr6quence de l'interven- tion devint 6gale pour les deux groupes. Au total, au bout de trois ans 8% des malades seulement ne pr6sentSrent pas de r6cidive et ne furent pas op6r6s. Cette 6rude sugg6re que l'ulcSre duod6nal grave relive de l'intervention chirurgicale malgr6 le traite- ment par la cim6tidine. Ce dernier ne fait que retarder l'6ch6ance chirurgicale, que le recours aux anti-H2 soit unique ou r6p6t6, les cons6quences 6conomique s des deux m6thodes 6tant tr~s voi- sines. Le traitement m6dical s6quentiel n'a que peu d'influence sur les indications de la chirurgie en cas d'ulc6re duod6nal s6v6re, Certes, si tous les ma- lades doivent drabord 6tre trait6s pendant huit semaines par un gramme quotidien de cim6tidine, il est inutile de r6p6ter ce traitement car le r6sultat final est identique pour les deux modalit6s th6ra- peutiques.

Abstracto

E1 prop6sito de este estudio es el de Comparar el efecto de 2 planes diferentes de terapia sobre el tratamiento definitivo en un grupo de pacientes con talcera duodenal con sfntomas suficientemente se- veros para la indicaci6n de cirugia segt~n criterios pre-cimetidina.

Los pacientes fueron asignados al azar a 8 se- manas de cimetidina en dosis de 1 g por dia seguidas de operaci6n en casos de recurrencia sintomfitica, o a cursos repetidos de 8 semanas de cimetidina en

D. Andersen et al.: Surgery or Cimetidine 377

dosis de 1 g por dfa en caso de recurrencia. Muchos pacientes desearon cambiar el plan, lo cual fue permitido y utilizado como evidencia de sus juicios de valor.

Despu6s de 3 an6s la tasa acumulativa de opera- ci6n rue de 74% en el grupo de dosis completa de cimetidina/descontinuar, y de 60% en el grupo de cimetidina repetida. En el primer afio la probabili- dad de operaci6n fue mgts alta en el grupo que recibi6 s61o un curso de cimetidina, pero despu6s de este perfodo de t iempo los pacientes vinieron a cirugfa con iguales posibilidades. Ocho po t ciento de los pacientes no presentaron relapso y no fueron operados, por consiguiente, despu6s de 3 afios.

El estudio sugiere que pacientes con enfermedad ulcerosa severa vienen a operaci6n, atin despu~s del advenimiento de la cimetidina, pero la cirugia resulta pospuesta. Hace muy poca diferencia el que la cimetidina les sea administrada en uno o en varios cursos. Las consecuencias econ6micas de los dos regfmenes son muy similares. Por consi- guiente, no puede esperarse que el tratamiento intermitente con cimetidina tenga mayor influencia sobre las indicaciones para cirugfa en filcera duode- nal severa. Todos los pacientes deben recibir un curso de cimetidina, pero cursos adicionales no ejercen diferencia material sobre el resultado final y usualmente pueden ser evitados.

Hasta una 6poca reciente s61o la cirugfa era capaz de cicatrizar el crfiter de la tilcera duodenal y de proveer mejor[a sintomgttica continuada. Actual- mente el t ratamiento m6dico, con bloquadores H2, se encuentra en posici6n de lograr los mismos resultados, bien sea mediante cursos intermitentes o en dosis de mantenimiento. Esta nueva situaci6n debe tener algfin impacto sobre las indicaciones para cirugfa electiva. +Serfi necesario realmente operar, a menos que sea en una minorfa de pa- cientes con una respuesta insatisfactoria al trata- miento m6dico? Se requerirfi algfin t iempo de ajuste antes de que una nueva y equilibrada visi6n pueda madurar, y serfin necesarios estudios comparat ivos de esquemas m~dicos versus quirt~rgicos. Esto, sin embargo, no es tan claro, puesto que los 2 tipos de tratamiento son fundamentalmente diferentes. Comparar 2 tipos de t6cnicas operatorias es relati- vamente simple, porque se pueden cuantificar datos s61idos tales como mortalidad, tasa de recurrencia y frecuencia de efectos colaterales. Cuando se com- paran tratamientos m6dicos y quirdrgicos, los ries- gos y las incomodidades no son de la misma clase, y deben ser estimados cuali tat ivamente por el juicio de valores reales o imaginarios del paciente. En lo posible, las evaluaciones econ6micas tambi6n de- ben ser consideradas en la comparaci6n.

El prop6sito de este artfculo es el de comparar los resultados de 2 planes de tratamiento, el uno basado en circugfa precoz, y el otro basado en cursos

repetidos del b loqueador H2, la cimetidina. Esta clase de estudio implica la dificultad de que los pacientes sean informados sobre los esquemas al- ternativos de tratamiento, y se debe esperar que muchos habrfin de demandar una desviacidn del tratamiento que les haya sido asignado. Si estos pacientes son exclu/dos del estudio, se producir/a una situacidn clfnica muy artificial sin paralelo con la vida real, en la cual los deseos de los pacientes son seguidos hasta donde sea posible. Por consi- guiente, nosotros decidimos utilizar la adherencia o la desviaci6n del esquema de tratamiento como un parfimetro de importancia que indica el juicio de valor del paciente en cuanto a l a s opciones a su disposicidn. Como resultado de este principio, un paciente se mantiene en su grupo, no importa qu6 tipo de tratamiento realmente recibe. En esta forma la comparaci6n entre grupos se basa en una combi- naci6n del efecto del tratamiento y de al actitud del paciente hacia el tratamiento. En la pr~ictia, com- paramos pol/ticas de tratamiento en vez de pa- cientes operados y tratados m6dicamente.

R e f e r e n c e s

I. Clark, C.G., Boulos, P.B.: Cimetidine and the gastric surgeon. World J. Surg. 3:745, 1979

2. Andersen, D., Amdrup, E., HCstrup, H., SCrensen, F.H.: The Aarhus county vagotomy trial: Trends in the problem of recurrent ulcer after parietal cell vagotomy and selective gastric vagotomy with drain- age. World J. Surg. 6:86, 1982

3. Kaplan, E.L., Meier, P.: Nonparametric estimation from incomplete observations. J. Am. Statist. Assoc. 53:457, 1958

4. Andersen, D., Amdrup, E., HCstrup, H., SCrensen, F.H.: The Aarhus county vagotomy trial. Recurrent ulcer after vagotomy. In Gastrins and the Vagus, J.F. Rehfeld and E. Amdrup, editors, New York, Aca- demic Press, 1979, pp. 223-231

5. Peto, R., Pike, M.C., Armitage, P., Breslow, N.E., Cox, D.R., Howard, S.V., Mantel, N., McPherson, K., Peto, J., Smith, P.G.: Design and analysis of randomized clinical trials requiring prolonged obser- vation of each patient. Br. J. Cancer 35:1, 1977

6. Bardhan, K.D.: The medical treatment of duodenal ulcer. Trop. Gastroenterol. 2:4, 1981

7. Bardhan, K.D., Cole, D.S., Hawkins, B.W., Franks, C.R.: Does treatment with cimetidine extended be- yond initial healing of duodenal ulcer reduce the subsequent relapse rate? Br. Med. J. 284:621, 1982

8. Wyllie, J.H., Clark, C.G., Alexander-Williams, J., Bell, P.R., Kennedy, T.L., Kirk, R.M., MacKay, C.: The effect of cimetidine on surgery for duodenal ulcer. Lancet 1:1307, 1981

9. Fineberg, H.V., Pearlman, L.A.: Surgical treatment of peptic ulcer in the United States. Lancet 1:1305, 1981

10. Kj~ergaard, J., Thomsen, F., Jensen, H.-E.: Cimeti- dine treatment of patients with duodenal ulcer re- ferred to a surgical clinic. Acta Chir. Scand. 147:151, 1981