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Round table discussion on duodenal ulcer
00165085/78/7402-0407$02.00/O GABTROENTEROLOGY ‘74:407-409,1978 Copyright 0 1978by the American Gastroenterological Association
ROUND TABLE
DISCUSSION
Vol.74,
No. 2, Part 2
Printed in U.S.A.
ON DUODENAL
ULCER
J. I. ISENBERG, CHAIRMAN, W. P. BEST, G. GILLESPIE, R. R. GILLIES, A. F. IPPOLITI, J. E. MCGUIGAN, C. E. RUBIN, D. J. C. SHEARMAN, AND D. H. WINSHIP
(Chicago): First of all, I would like to say that it is a real pleasure to see a number of well designed trials available this early in the use of this drug. There are a number of features that characterize a good clinical trial. One is a clear statement of the question of just what is being studied. I think that we have clear questions in all of these five trials. There are probably six questions in these five trials, but that is the nature of the game. Each one has a slightly different thing that is being studied. The big danger, of course, that we are trying to avoid in designing any trial, is bias, and we have repeatedly heard the words “randomization” and “double blindness,” which are two of the requisites of good unbiased study. Sometimes I think that these words are thrown off a little bit loosely, and people go through the motions. The real question is, were the motions successful? Was it really a blind study? The question, can you identify the difference between a placebo and the cimetidine, is a key question in this regard. The answer that, yes, they taste different, could be an unblinding factor, but then we would like to get data on how many patients tried chewing the tablets. DR. C. E. RUBIN (Seattle): We have been talking here at great length about rate of healing. And I have not seen anybody show anything about rate of healing. They have shown the percentage that heal. One cannot presume that you are comparing two similar groups, when you do not know whether some have larger and others have smaller ulcers. You do not really know the rates of healing. It amazes me that we have even been able to find a difference, when we are using essentially subjective criteria in a spontaneously remittent disease. I will be the first to recognize that it is technically very difficult to put out a measuring stick against all ulcers in the duodenal cap, but it can be done. It implies, of course, that you will have a variety of instruments available to you, both side viewing and end viewing, and that you will take photographs, with the measuring stick lying across the ulcer. The other thing that distresses me about the studies is that, in most instances, the one area that really was not controlled was what was called placebo. In many instances it is not placebo at all, it is antacid. DR. A. M. CONNELL (Cincinnati): I would like more discussion about the differences which have, in fact, emerged in the percentage of patients healed. In the United States studies, the difference between DR. W. P. BEST
the placebo and the cimetidine response is less than 20%. In other words, less than 1 person in 5 got additional advantage from the cimetidine over what he would have got with the placebo alone, whereas in the British studies the difference is consistently around 40% or 2 persons in 5. There is a 100% difference. Does this mean that ulcer disease is different in the two countries or does it mean that there is a fundamental difference in the conducting of the trials? Is it because Americans are more suspicious and chew the tablets? DR. J. E. MCGUIGAN (Gainesville): The incidence of ulcer healing in the patients receiving cimetidine in the worldwide studies and in the United States studies is virtually identical. But your point is well made that the difference is the fact that the percentage of ulcer healing in patients receiving PRN (as required) antacids in the United States is higher than that worldwide. We do not have a final explanation, but I did review this subject when this material was being considered for presentation to the United States Food and Drug Administration some 6 months back. The amount of antacid consumed on a PRN basis in the United States, in terms of neutralizing capacity, was at least 5 times that of the mean amount consumed abroad. I think that this is a function, perhaps, of the customs in the United States and the emphasis that we place on the use of antacids. However, the amount consumed on a PRN basis in the United States by no means approaches the amount that we would select and propose for patients on a vigorous antacid program. The average amount consumed in the United States patients receiving antacid PRN was about 50 ml of Maalox per day. DR. CONNELL: I think that that may be one factor, but it still does not explain the difference at the other end of the scale. The British studies are coming through with cimetidine responses of the order of 75% and indeed as high as 85%, and in the United States, results are coming through at 57% at 4 weeks in a multicenter study and 65% in the Los Angeles study. DRI. D. J. C. SHEARMAN (Adelaide, South Australia): The Australian trial that we conducted had antacid given only for pain- the patient had to have pain. I think that our placebo response fits in with the European results on this basis. I would agree with the previous questioner that the amount of antacid is likely to be very important. An analysis of this could be made in the various trials because we all have recorded the doses of antacid taken. 407
408
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TABLE
DR. A. P. DOUGLAS(Los Angeles): I am glad that Dr.
Rubin has brought up the point about healing rate. I think that it is a misuse of the English language when people talk about rate. They really mean incidence. It is important to realize that no one actually measured rate, in spite of the words on the slides. In Dr. Ippoliti’s study there appear to be something like 3 times as many women in the group that was studied with cimetidine as in those that were studied with placebo. This might mask or bring out differences that we otherwise might be missing. DR. N. CHOUHDRY (Karachi, Pakistan): I should like to know whether, at this stage, it is possible to say in what way cimetidine is going to influence the natural history of peptic ulcer disease. We know that this disease has spontaneous remissions and relapses and, if I understood correctly from the last paper, the incidence or relapses is about the same in patients who are healed with cimetidine and those who are on placebo. The crux of the matter is, by attaining a short term healing of the ulcer, are we attaining anything? DR. G. GILLESPIE(Glasgow, Scotland): There may be some clues from the kind of selected group of patients that we studied, namely, the severe end of the duodenal ulcer spectrum. It seems that, judging from the natural periods of remission that these patients had before entry to the cimetidine studies, the interval of freedom thereafter was somewhat longer. The impression is that cimetidine may have conferred some protection for some time thereafter. DR. T. M. VOGT(Los Angeles): I am disturbed by some of the comparisons that have been made. It seems to me that, in introducing a new drug like this, there are two relevant considerations. The first is, is it safe and is it effective? I think that that has been addressed. The second is, is it sufficiently better than what is available to justify the additional cost? I do not think, except for the single study which was small, that that issue has been addressed. I would like to hear somebody’s comment on the panel as to why we have not addressed the issue of whether cimetidine is better than a rigorous antacid therapeutic regimen. Comparing it to a PRN antacid regimen is not fair. You should compare PRN cimetidine to PRN antacid. DR. D. H. WINSHIP(Columbia, MO.): I think that we must remember that the first studies which have shown real efficacy for anything in the treatment of duodenal ulcer have occurred only very recently. The information on antacids was presented for the first time at the American Gastroenterological Association meeting in Toronto this spring. When cimetidine was getting off the ground, there really was not any standard treatment that had been clearly shown to be effective. DR. VOGT:But do we have any cost effective data at the present time? DR. WINSHIP:I do not know of any.
DISCUSSION
Vol. 74, No. 2, Part 2
DR. R. R. GILLIES(Ottawa, Ontario): The entry characteristics of our patients may have been different from others. in that the centers involved were all referral centers. The patients that we saw had longstanding ulcer disease, which had been so symptomatic under standard therapy that they were referred. They were taking full doses of antacids and, obviously, were still in enough trouble to be referred. Less than 15% of these patients reported the taking of any antacids after entering on the study. DR. F. KERN,JR. (Denver): I would like to ask Dr. Best and other members of the panel to comment about the scientific and ethical dilemmas that are posed by interrupting long term studies to examine the results. DR. BEST: This is something that we have tried to avoid in the cooperative studies in which we have been involved. The reasoning is more or less as follows. Usually the interim data are not conclusive. In certain cases, investigators get nervous and sometimes they will say let’s quit because we are almost there. Well, almost there is not very convincing. You have got a problem of convincing the medical population at large that you have shown something definitively. I think that the investigators should be really blind to the results. We get over the ethical dilemmas involved by having a group of experts who are not investigators in the study take periodic looks at the data. These periodic looks should be taken with a slightly different (Y risk. It is significantly changed when you take multiple looks at the data. DR. KERN:Then when you find that significant probability value, is it ethical to continue giving placebo to one group of patients? If you do not continue giving placebo, you lose the opportunity to collect a lot of information. DR. BEST:These are real dilemmas, and the operations committee, which is the name that the Veterans Administration has given to this overseeing group, sometimes has some very tough decisions on what should be done in the best interest of the patient. I think that, as I have seen these groups work, they have done very well in making wise decisions under these circumstances. DR. A. R. COOKE(Kansas City, Kans.): I would like to come back to the question of smoking. The literature indicates that patients who smoke heal their gastric ulcers more slowly than people who do not smoke and that smokers have a higher morbidity and a higher mortality rate than nonsmokers. Now, although all of these trials seem to address the problem of age and sex distribution, one trial at least mentioned that they did not look into the question of who smoked and who did not. The other trial, the multicenter trial, said that they advised their patients not to smoke. Now, does the panel believe that smoking has no role in duodenal ulcer. If they do not believe that, why was this
February 1978
ROUND
TABLE
factor not taken into consideration in the design of these trials? DR. GILLESPIE:In our Glasgow study we did look at those patients who smoked and who consumed alcohol. There were no differences in the behavior patterns in either group. But, then, again, everybody drinks in Glasgow. DR. SHEARMAN: Everybody drinks in Australia, as well. We looked at the smoking aspect and found that the two groups had comparable numbers of smokers. Furthermore, smoking did not affect the healing rate in either placebo group or cimetidine group. But, of course, that is not a satisfactory conclusion because, if you are going to look at smoking, you need to randomize your patients from that point of view right at the beginning. All that we say is that our two groups were comparable for the amount that they smoked. You would need to do a separate trial to look at the factory of smoking and ulcer healing. DR. A. F. IPPOLITI(Los Angeles): In Peterson’s study, in the antacid-treated patients it made no difference in terms of ulcer healing whether one smoked or not. But in the placebo-treated patients, failure of ulcer healing was significantly more common among smokers than nonsmokers, suggesting that with no or minimal treatment smoking may have a deleterious effect in duodenal ulcer disease. DR. M. SCHAPIRO (Los Angeles): I recently had a disappointing experience reviewing the endoscopic photographs from many of these United States studies. I found them uninterpretable. I agree with Dr. Rubin’s comments on the advancements of our technology today to document what we are seeing. I think that many of these studies have been performed with instruments that are somewhat outdated. Marked improvements can be made to try to satisfy these problems of ulcer healing rate and to determine whether there is independent observer variation in what we are seeing through these instruments. With the improvement of films, cameras, and automatic exposure systems, I think that we should be able to document photographically. Such documentation is an absolute must if
DISCUSSION
409
we are going to put so much reliance upon the percentage of healing. We seem to spend a lot of time with titration for acid and not enough time with documentation of what we have seen. My question is, were the observers the same throughout the study and were the numbers of observers throughout the study large or were they mostly based on a few individuals? DR. GILLESPIE: In the Glasgow study, there were two endoscopists at every endoscopy, as it were, two independent observers. Also, the question of ulcer size-we did get some index of the size by measuring with the biopsy forceps straddled across the ulcer base. DR. SHEARMAN:We used the same endoscopist before and after. We have a lot of data on ulcer size in this study and on concomitant duodenitis and so on. It is impossible to present this in this time, but it is available. DR. IPPOLITI:It was the same endoscopist at each hospital. In our study we had multiple hospitals. DR. MCGUIGAN:In the United States study there were 12 centers, and it was the same endoscopist for the first and follow-up studies, with one to two endoscopists at each center. I would like to ask whether there was any correlation between relief of ulcer symptoms and ulcer healing? DR. IPPOLITI:In our study there was a very strong correlation between complete symptom relief and healing of the duodenal ulcer. DR. GILLESPIE: And the same in Glasgow. DR. WINSHIP:It is highly variable, and in some of the studies there was very little correlation between healing and symptom relief. DR. BEST:I have to take this opportunity to say a word about type 2 error. Because this is an error frequently made in the literature, I think that it is well to take every opportunity to say a word about it. In most cases, this is related to the relatively small numbers. In other words, if you say there is a certain amount of difference which could be clinically significant if it were really there, you have to have enough numbers or you are not going to show it up.
ROUND TABLE
DISCUSSION
Vol.74,
No. 2, Part 2
Printed in U.S.A.
ON DUODENAL
ULCER
J. I. ISENBERG, CHAIRMAN, W. P. BEST, G. GILLESPIE, R. R. GILLIES, A. F. IPPOLITI, J. E. MCGUIGAN, C. E. RUBIN, D. J. C. SHEARMAN, AND D. H. WINSHIP
(Chicago): First of all, I would like to say that it is a real pleasure to see a number of well designed trials available this early in the use of this drug. There are a number of features that characterize a good clinical trial. One is a clear statement of the question of just what is being studied. I think that we have clear questions in all of these five trials. There are probably six questions in these five trials, but that is the nature of the game. Each one has a slightly different thing that is being studied. The big danger, of course, that we are trying to avoid in designing any trial, is bias, and we have repeatedly heard the words “randomization” and “double blindness,” which are two of the requisites of good unbiased study. Sometimes I think that these words are thrown off a little bit loosely, and people go through the motions. The real question is, were the motions successful? Was it really a blind study? The question, can you identify the difference between a placebo and the cimetidine, is a key question in this regard. The answer that, yes, they taste different, could be an unblinding factor, but then we would like to get data on how many patients tried chewing the tablets. DR. C. E. RUBIN (Seattle): We have been talking here at great length about rate of healing. And I have not seen anybody show anything about rate of healing. They have shown the percentage that heal. One cannot presume that you are comparing two similar groups, when you do not know whether some have larger and others have smaller ulcers. You do not really know the rates of healing. It amazes me that we have even been able to find a difference, when we are using essentially subjective criteria in a spontaneously remittent disease. I will be the first to recognize that it is technically very difficult to put out a measuring stick against all ulcers in the duodenal cap, but it can be done. It implies, of course, that you will have a variety of instruments available to you, both side viewing and end viewing, and that you will take photographs, with the measuring stick lying across the ulcer. The other thing that distresses me about the studies is that, in most instances, the one area that really was not controlled was what was called placebo. In many instances it is not placebo at all, it is antacid. DR. A. M. CONNELL (Cincinnati): I would like more discussion about the differences which have, in fact, emerged in the percentage of patients healed. In the United States studies, the difference between DR. W. P. BEST
the placebo and the cimetidine response is less than 20%. In other words, less than 1 person in 5 got additional advantage from the cimetidine over what he would have got with the placebo alone, whereas in the British studies the difference is consistently around 40% or 2 persons in 5. There is a 100% difference. Does this mean that ulcer disease is different in the two countries or does it mean that there is a fundamental difference in the conducting of the trials? Is it because Americans are more suspicious and chew the tablets? DR. J. E. MCGUIGAN (Gainesville): The incidence of ulcer healing in the patients receiving cimetidine in the worldwide studies and in the United States studies is virtually identical. But your point is well made that the difference is the fact that the percentage of ulcer healing in patients receiving PRN (as required) antacids in the United States is higher than that worldwide. We do not have a final explanation, but I did review this subject when this material was being considered for presentation to the United States Food and Drug Administration some 6 months back. The amount of antacid consumed on a PRN basis in the United States, in terms of neutralizing capacity, was at least 5 times that of the mean amount consumed abroad. I think that this is a function, perhaps, of the customs in the United States and the emphasis that we place on the use of antacids. However, the amount consumed on a PRN basis in the United States by no means approaches the amount that we would select and propose for patients on a vigorous antacid program. The average amount consumed in the United States patients receiving antacid PRN was about 50 ml of Maalox per day. DR. CONNELL: I think that that may be one factor, but it still does not explain the difference at the other end of the scale. The British studies are coming through with cimetidine responses of the order of 75% and indeed as high as 85%, and in the United States, results are coming through at 57% at 4 weeks in a multicenter study and 65% in the Los Angeles study. DRI. D. J. C. SHEARMAN (Adelaide, South Australia): The Australian trial that we conducted had antacid given only for pain- the patient had to have pain. I think that our placebo response fits in with the European results on this basis. I would agree with the previous questioner that the amount of antacid is likely to be very important. An analysis of this could be made in the various trials because we all have recorded the doses of antacid taken. 407
408
ROUND
TABLE
DR. A. P. DOUGLAS(Los Angeles): I am glad that Dr.
Rubin has brought up the point about healing rate. I think that it is a misuse of the English language when people talk about rate. They really mean incidence. It is important to realize that no one actually measured rate, in spite of the words on the slides. In Dr. Ippoliti’s study there appear to be something like 3 times as many women in the group that was studied with cimetidine as in those that were studied with placebo. This might mask or bring out differences that we otherwise might be missing. DR. N. CHOUHDRY (Karachi, Pakistan): I should like to know whether, at this stage, it is possible to say in what way cimetidine is going to influence the natural history of peptic ulcer disease. We know that this disease has spontaneous remissions and relapses and, if I understood correctly from the last paper, the incidence or relapses is about the same in patients who are healed with cimetidine and those who are on placebo. The crux of the matter is, by attaining a short term healing of the ulcer, are we attaining anything? DR. G. GILLESPIE(Glasgow, Scotland): There may be some clues from the kind of selected group of patients that we studied, namely, the severe end of the duodenal ulcer spectrum. It seems that, judging from the natural periods of remission that these patients had before entry to the cimetidine studies, the interval of freedom thereafter was somewhat longer. The impression is that cimetidine may have conferred some protection for some time thereafter. DR. T. M. VOGT(Los Angeles): I am disturbed by some of the comparisons that have been made. It seems to me that, in introducing a new drug like this, there are two relevant considerations. The first is, is it safe and is it effective? I think that that has been addressed. The second is, is it sufficiently better than what is available to justify the additional cost? I do not think, except for the single study which was small, that that issue has been addressed. I would like to hear somebody’s comment on the panel as to why we have not addressed the issue of whether cimetidine is better than a rigorous antacid therapeutic regimen. Comparing it to a PRN antacid regimen is not fair. You should compare PRN cimetidine to PRN antacid. DR. D. H. WINSHIP(Columbia, MO.): I think that we must remember that the first studies which have shown real efficacy for anything in the treatment of duodenal ulcer have occurred only very recently. The information on antacids was presented for the first time at the American Gastroenterological Association meeting in Toronto this spring. When cimetidine was getting off the ground, there really was not any standard treatment that had been clearly shown to be effective. DR. VOGT:But do we have any cost effective data at the present time? DR. WINSHIP:I do not know of any.
DISCUSSION
Vol. 74, No. 2, Part 2
DR. R. R. GILLIES(Ottawa, Ontario): The entry characteristics of our patients may have been different from others. in that the centers involved were all referral centers. The patients that we saw had longstanding ulcer disease, which had been so symptomatic under standard therapy that they were referred. They were taking full doses of antacids and, obviously, were still in enough trouble to be referred. Less than 15% of these patients reported the taking of any antacids after entering on the study. DR. F. KERN,JR. (Denver): I would like to ask Dr. Best and other members of the panel to comment about the scientific and ethical dilemmas that are posed by interrupting long term studies to examine the results. DR. BEST: This is something that we have tried to avoid in the cooperative studies in which we have been involved. The reasoning is more or less as follows. Usually the interim data are not conclusive. In certain cases, investigators get nervous and sometimes they will say let’s quit because we are almost there. Well, almost there is not very convincing. You have got a problem of convincing the medical population at large that you have shown something definitively. I think that the investigators should be really blind to the results. We get over the ethical dilemmas involved by having a group of experts who are not investigators in the study take periodic looks at the data. These periodic looks should be taken with a slightly different (Y risk. It is significantly changed when you take multiple looks at the data. DR. KERN:Then when you find that significant probability value, is it ethical to continue giving placebo to one group of patients? If you do not continue giving placebo, you lose the opportunity to collect a lot of information. DR. BEST:These are real dilemmas, and the operations committee, which is the name that the Veterans Administration has given to this overseeing group, sometimes has some very tough decisions on what should be done in the best interest of the patient. I think that, as I have seen these groups work, they have done very well in making wise decisions under these circumstances. DR. A. R. COOKE(Kansas City, Kans.): I would like to come back to the question of smoking. The literature indicates that patients who smoke heal their gastric ulcers more slowly than people who do not smoke and that smokers have a higher morbidity and a higher mortality rate than nonsmokers. Now, although all of these trials seem to address the problem of age and sex distribution, one trial at least mentioned that they did not look into the question of who smoked and who did not. The other trial, the multicenter trial, said that they advised their patients not to smoke. Now, does the panel believe that smoking has no role in duodenal ulcer. If they do not believe that, why was this
February 1978
ROUND
TABLE
factor not taken into consideration in the design of these trials? DR. GILLESPIE:In our Glasgow study we did look at those patients who smoked and who consumed alcohol. There were no differences in the behavior patterns in either group. But, then, again, everybody drinks in Glasgow. DR. SHEARMAN: Everybody drinks in Australia, as well. We looked at the smoking aspect and found that the two groups had comparable numbers of smokers. Furthermore, smoking did not affect the healing rate in either placebo group or cimetidine group. But, of course, that is not a satisfactory conclusion because, if you are going to look at smoking, you need to randomize your patients from that point of view right at the beginning. All that we say is that our two groups were comparable for the amount that they smoked. You would need to do a separate trial to look at the factory of smoking and ulcer healing. DR. A. F. IPPOLITI(Los Angeles): In Peterson’s study, in the antacid-treated patients it made no difference in terms of ulcer healing whether one smoked or not. But in the placebo-treated patients, failure of ulcer healing was significantly more common among smokers than nonsmokers, suggesting that with no or minimal treatment smoking may have a deleterious effect in duodenal ulcer disease. DR. M. SCHAPIRO (Los Angeles): I recently had a disappointing experience reviewing the endoscopic photographs from many of these United States studies. I found them uninterpretable. I agree with Dr. Rubin’s comments on the advancements of our technology today to document what we are seeing. I think that many of these studies have been performed with instruments that are somewhat outdated. Marked improvements can be made to try to satisfy these problems of ulcer healing rate and to determine whether there is independent observer variation in what we are seeing through these instruments. With the improvement of films, cameras, and automatic exposure systems, I think that we should be able to document photographically. Such documentation is an absolute must if
DISCUSSION
409
we are going to put so much reliance upon the percentage of healing. We seem to spend a lot of time with titration for acid and not enough time with documentation of what we have seen. My question is, were the observers the same throughout the study and were the numbers of observers throughout the study large or were they mostly based on a few individuals? DR. GILLESPIE: In the Glasgow study, there were two endoscopists at every endoscopy, as it were, two independent observers. Also, the question of ulcer size-we did get some index of the size by measuring with the biopsy forceps straddled across the ulcer base. DR. SHEARMAN:We used the same endoscopist before and after. We have a lot of data on ulcer size in this study and on concomitant duodenitis and so on. It is impossible to present this in this time, but it is available. DR. IPPOLITI:It was the same endoscopist at each hospital. In our study we had multiple hospitals. DR. MCGUIGAN:In the United States study there were 12 centers, and it was the same endoscopist for the first and follow-up studies, with one to two endoscopists at each center. I would like to ask whether there was any correlation between relief of ulcer symptoms and ulcer healing? DR. IPPOLITI:In our study there was a very strong correlation between complete symptom relief and healing of the duodenal ulcer. DR. GILLESPIE: And the same in Glasgow. DR. WINSHIP:It is highly variable, and in some of the studies there was very little correlation between healing and symptom relief. DR. BEST:I have to take this opportunity to say a word about type 2 error. Because this is an error frequently made in the literature, I think that it is well to take every opportunity to say a word about it. In most cases, this is related to the relatively small numbers. In other words, if you say there is a certain amount of difference which could be clinically significant if it were really there, you have to have enough numbers or you are not going to show it up.