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PROPRANOLOL IN MYOCARDIAL INFARCTION
643
Germany and Switzerland went into the " non-patent " column. Moreover, in calculating the 10 to 1 ratio itself, the authors of the report chose to ignore the 60 discoveries made by the United States-a quite incredible omission. As you undoubtedly suspected, the facts are really the reverse of those cited by Mr. Inglis-i.e., countries with patents have discovered many more drugs than countries without patents. One wonders why Mr. Inglis chose to accept so unquestioningly an erroneous bit of information from a Senate report of doubtful credibility. to
Smith Kline and French Laboratories, Philadelphia, Pennsylvania 19101.
FRANCIS BOYER.
∈-AMINOCAPROIC ACID IN ASTHMA SIR,-During the past year, we have studied possible methods of suppressing allergic manifestations in asthma. The complex formation of antigen, antibody, and complement activates enzymes (proteases and oc-chymotrypsin) on the cell surface, with consequent release of histamine and biological amines which produce increased secretion of the bronchial mucosa and, at times, transient bronchial spasm. In our first series of investigations we therefore attempted to demonstrate the therapeutic possibilities of e-aminocaproic acid (E.A.C.A.)an inhibitor of chymotrypsin. 16 patients who were having attacks of asthma and 28 patients with chronic asthmatic bronchitis were given E.A.c.A. (’ Epsamon’, Emser-Werke) in oral doses of 10 g., 8 g., and 5 g. per day. The therapeutic effect was judged by the subjective condition of these patients as well as by clinical and spirometric examination. Of the 20 patients on 10 g. of E.A.C.A. daily, 6 showed a very good effect which could be repeated in 4 of them after discontinuation and re-exhibition of the drug; in 1 patient the effect was uncertain, and in 13 patients there was no response to E.A.C.A.
Of the 12
patients on 8
g. of E.A.C.A.
daily, 3 responded very
well, and the effect could be reproduced in 2 of them; in 2 patients the improvement was only moderate or uncertain, and in another 7
patients there was no improvement. Of the 12 patients on 5 g. of E.A.C.A. daily, 3 showed a very good result which was reproducible in 1 of them; the effect was uncertain in 3 patients and in 6 the abnormal findings were unchanged. These results certainly justify further investigations and demonstrate that, even in severe cases, e-aminocaproic acid may exert a favourable effect. Patients suffering from attacks of asthma seem to respond better to the drug than chronic bronchitics with asthmatic dyspnaea and irreversible anatomical changes. e-aminocaproic acid had also a very good effect on 3 patients who had remained persistently unresponsive to steroids; in 2 further patients steroid treatment that had lasted for months could be discontinued. H. BUDELMANN H. BÜRGI J. REGLI.
Heiligenschwendi,
Berne, Switzerland.
PROPRANOLOL IN MYOCARDIAL INFARCTION SIR,-It is unfortunate that Dr. Snow’s article (Sept. 18) should illustrate not only the advances which have been made in the practice of clinical trials, but also
some
to use a straightforward y_z test, which gives a P of 5% with Yates’s correction, and 3% without. This means that, on the assumption that the two groups were randomly selected samples from the same population (i.e., that the special treatments had no effect), then the probability of finding discrepancies in the death-rate between the two groups as large as, or greater than, that found lies between 0-03 and
just
over
LOW-FAT DIET IN MYOCARDIAL INFARCTION SIR,-Dr. Ball and his colleagues, in their admirable article last week, have shown that the dietary control of bloodcholesterol does virtually nothing to reduce the chances of a further attack of cardiac ischxmia. But in the present state of our knowledge and investigations it is legitimate, and I think essential, to make a clear distinction between the man who has had a coronary and the man who may be going to have one. Atherosclerosis (and cardiac ischaemia) is best regarded as a process in which infarction is a terminal event. It is reasonable to postulate that as our knowledge of the pathology and natural history of the process grows, we may be able not only to halt but perhaps even to reverse it. Coronary thrombosis is clearly multifactorial in origin, and a raised blood-cholesterol level is equally clearly one of the major factors. What we need to know now is whether by " screening off " men with appreciably raised blood-levels of cholesterol, and lowering this by diet,Atromid’, and/or weight control, their chances of getting an infarction can be reduced. Only time and much more work will give the answer to this problem, but at present it is important to make a clear distinction between the precoronary and the postcoronary case. Although it was not within their " dietary terms of reference ", it would be interesting to know whether, in the series so well reported by Dr. Ball and his colleagues, there was any correlation between relapse-rate and cigarette smoking, and also perhaps between it and hypertension, and occupation. Institute of Directors, Medical Centre, London, S.W.1.
H. B. WRIGHT.
of the deficiencies
which still exist. Dr. Snow used a statistical test, based on differences between percentages, which showed a significance level of 2-5%. In view of the small numbers of cases it might be better
0-05. It is important to take notice of the proviso because, in fact, the experiment was done in such a way that this condition was not fulfilled, and therefore it is illegitimate to apply any statistical test to the data. From the point of view of the experimenter, the need for random selection arises from the requirement that there should be no bias in selection. Since Dr. Snow knew what treatment his patients were going to receive, bias may have occurred in the selection of cases for inclusion in the trial; and it is also possible, though not so likely, that bias may have arisen in rejecting them from the trial after investigation. The net result is that, although Dr. Snow’s investigation suggests that there is a case for investigating the value of propranolol, despite all the hard work he has put into it, he has " spoilt the ship for a ha’p’orth of tar ". In general, clinical investigators have tended recently to accept the need for controlled trials. They have lost their eagerness for asserting that, when deprived of the data from a control group, they have more information for evaluating a drug. Furthermore, they do not assert with quite so much enthusiasm that it is more ethical to expose all their patients to the risks of a new treatment than only half (and under circumstances where they will not obtain any information anyway), but there is still a tendency to hesitate before the last step and accept the need for randomisation. This is the critical point which determines the validity of a statistical test, and it is not a trivial one. Department of Psychiatry, School of Medicine, MAX HAMILTON. University of Leeds.
MYOCARDIAL INFARCTION FOLLOWING RADIATION SIR,-Dr. Dollinger and his colleagues (July 31) and Dr. Prentice (Aug. 21) reported the cases of patients, aged 41 and 19, who received radiation therapy to their thoraces for Hodgkin’s disease, and subsequently had myocardial infarctions. In my department there is a 69-year-old male patient who has been treated for 3 months by radiation therapy to his
Germany and Switzerland went into the " non-patent " column. Moreover, in calculating the 10 to 1 ratio itself, the authors of the report chose to ignore the 60 discoveries made by the United States-a quite incredible omission. As you undoubtedly suspected, the facts are really the reverse of those cited by Mr. Inglis-i.e., countries with patents have discovered many more drugs than countries without patents. One wonders why Mr. Inglis chose to accept so unquestioningly an erroneous bit of information from a Senate report of doubtful credibility. to
Smith Kline and French Laboratories, Philadelphia, Pennsylvania 19101.
FRANCIS BOYER.
∈-AMINOCAPROIC ACID IN ASTHMA SIR,-During the past year, we have studied possible methods of suppressing allergic manifestations in asthma. The complex formation of antigen, antibody, and complement activates enzymes (proteases and oc-chymotrypsin) on the cell surface, with consequent release of histamine and biological amines which produce increased secretion of the bronchial mucosa and, at times, transient bronchial spasm. In our first series of investigations we therefore attempted to demonstrate the therapeutic possibilities of e-aminocaproic acid (E.A.C.A.)an inhibitor of chymotrypsin. 16 patients who were having attacks of asthma and 28 patients with chronic asthmatic bronchitis were given E.A.c.A. (’ Epsamon’, Emser-Werke) in oral doses of 10 g., 8 g., and 5 g. per day. The therapeutic effect was judged by the subjective condition of these patients as well as by clinical and spirometric examination. Of the 20 patients on 10 g. of E.A.C.A. daily, 6 showed a very good effect which could be repeated in 4 of them after discontinuation and re-exhibition of the drug; in 1 patient the effect was uncertain, and in 13 patients there was no response to E.A.C.A.
Of the 12
patients on 8
g. of E.A.C.A.
daily, 3 responded very
well, and the effect could be reproduced in 2 of them; in 2 patients the improvement was only moderate or uncertain, and in another 7
patients there was no improvement. Of the 12 patients on 5 g. of E.A.C.A. daily, 3 showed a very good result which was reproducible in 1 of them; the effect was uncertain in 3 patients and in 6 the abnormal findings were unchanged. These results certainly justify further investigations and demonstrate that, even in severe cases, e-aminocaproic acid may exert a favourable effect. Patients suffering from attacks of asthma seem to respond better to the drug than chronic bronchitics with asthmatic dyspnaea and irreversible anatomical changes. e-aminocaproic acid had also a very good effect on 3 patients who had remained persistently unresponsive to steroids; in 2 further patients steroid treatment that had lasted for months could be discontinued. H. BUDELMANN H. BÜRGI J. REGLI.
Heiligenschwendi,
Berne, Switzerland.
PROPRANOLOL IN MYOCARDIAL INFARCTION SIR,-It is unfortunate that Dr. Snow’s article (Sept. 18) should illustrate not only the advances which have been made in the practice of clinical trials, but also
some
to use a straightforward y_z test, which gives a P of 5% with Yates’s correction, and 3% without. This means that, on the assumption that the two groups were randomly selected samples from the same population (i.e., that the special treatments had no effect), then the probability of finding discrepancies in the death-rate between the two groups as large as, or greater than, that found lies between 0-03 and
just
over
LOW-FAT DIET IN MYOCARDIAL INFARCTION SIR,-Dr. Ball and his colleagues, in their admirable article last week, have shown that the dietary control of bloodcholesterol does virtually nothing to reduce the chances of a further attack of cardiac ischxmia. But in the present state of our knowledge and investigations it is legitimate, and I think essential, to make a clear distinction between the man who has had a coronary and the man who may be going to have one. Atherosclerosis (and cardiac ischaemia) is best regarded as a process in which infarction is a terminal event. It is reasonable to postulate that as our knowledge of the pathology and natural history of the process grows, we may be able not only to halt but perhaps even to reverse it. Coronary thrombosis is clearly multifactorial in origin, and a raised blood-cholesterol level is equally clearly one of the major factors. What we need to know now is whether by " screening off " men with appreciably raised blood-levels of cholesterol, and lowering this by diet,Atromid’, and/or weight control, their chances of getting an infarction can be reduced. Only time and much more work will give the answer to this problem, but at present it is important to make a clear distinction between the precoronary and the postcoronary case. Although it was not within their " dietary terms of reference ", it would be interesting to know whether, in the series so well reported by Dr. Ball and his colleagues, there was any correlation between relapse-rate and cigarette smoking, and also perhaps between it and hypertension, and occupation. Institute of Directors, Medical Centre, London, S.W.1.
H. B. WRIGHT.
of the deficiencies
which still exist. Dr. Snow used a statistical test, based on differences between percentages, which showed a significance level of 2-5%. In view of the small numbers of cases it might be better
0-05. It is important to take notice of the proviso because, in fact, the experiment was done in such a way that this condition was not fulfilled, and therefore it is illegitimate to apply any statistical test to the data. From the point of view of the experimenter, the need for random selection arises from the requirement that there should be no bias in selection. Since Dr. Snow knew what treatment his patients were going to receive, bias may have occurred in the selection of cases for inclusion in the trial; and it is also possible, though not so likely, that bias may have arisen in rejecting them from the trial after investigation. The net result is that, although Dr. Snow’s investigation suggests that there is a case for investigating the value of propranolol, despite all the hard work he has put into it, he has " spoilt the ship for a ha’p’orth of tar ". In general, clinical investigators have tended recently to accept the need for controlled trials. They have lost their eagerness for asserting that, when deprived of the data from a control group, they have more information for evaluating a drug. Furthermore, they do not assert with quite so much enthusiasm that it is more ethical to expose all their patients to the risks of a new treatment than only half (and under circumstances where they will not obtain any information anyway), but there is still a tendency to hesitate before the last step and accept the need for randomisation. This is the critical point which determines the validity of a statistical test, and it is not a trivial one. Department of Psychiatry, School of Medicine, MAX HAMILTON. University of Leeds.
MYOCARDIAL INFARCTION FOLLOWING RADIATION SIR,-Dr. Dollinger and his colleagues (July 31) and Dr. Prentice (Aug. 21) reported the cases of patients, aged 41 and 19, who received radiation therapy to their thoraces for Hodgkin’s disease, and subsequently had myocardial infarctions. In my department there is a 69-year-old male patient who has been treated for 3 months by radiation therapy to his