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ANTICOAGULANT THERAPY FOR MYOCARDIAL INFARCTION
1112 then a (tris-hydroxy-methyl-aminomethane), rise in serum-potassium.7 LeVeenhas postulated that, in the experimental animal, cardiac arrest during acidosis may be due to hepatic potassium release, secondary to adrenaline secretion, and not to the stance T.H.A.M.
high Pecs does
not cause a
direct effect of the acidosis. It seems incorrect to conclude that a high Pc02, in the absence of a metabolic acidosis, does not alter myocardial contractility. It may well be that a high Pc02, associated with an uncompensated respiratory acidosis, as well as a metabolic acidosis, does indirectly depress myocardial function, but that a high PC02’ in the absence of acidaemia (either respiratory or metabolic) does not. Anæsthetic Department, Little Bromwich Hospital,
Birmingham.
J. M. MANNERS.
POLYPS OF THE LARGE BOWEL "
SIR,-In your annotation of Oct. 27 you said: It is high time that surgeons became aware of the real nature of most large-bowel polyps. Patients are still being subjected to needlessly radical operations." We do not believe that anyone knows the real nature of adenomas or that any comfort can be extracted from the fact that an adenoma is " only a tumour on a stalk ". We doubt whether your charge that surgeons are performing needlessly radical operations for large-bowel polyps is either fair or necessary. Who is treating benign large-bowel polyps by radical operations in this country ? You also state very dogmatically (Nov. 17) that familial polyposis is a distinct entity. It is unfortunately true that our only method of distinguishing the genetic nature of familial polyposis is the clinical detection of a family history. Just because this method is so crude, it is wrong at present to make a clear-cut distinction between frankly familial forms of polyposis and patients with many polyps or a few scattered or solitary polyps with no detectable genetic cause. The number of polyps found in a patient with or without a family history can
vary from
a
very few to many hundreds.
genetic analysis of the material at St. Mark’s Hospital has suggested that there may well be a hereditary factor in all A
isolated adenomas and that the distinction between these lesions and those in polyposis may be only a matter of number and the detail of the underlying genetic mechanism. For these reasons we believe that familial intestinal polyposis cannot be omitted from any serious discussion of the relationship between adenomas and carcinoma. Your final remark that familial polyposis should not be linked with the problems of the treatment or precancerous nature of adenomatous polyps is unjustifiably dogmatic. Research Department, St. Mark’s Hospital, London, E.C.1.
A. M. O. VEALE BASIL C. MORSON.
ENTERIC-COATED PREDNISOLONE TABLETS
SiR,ŅIn recent months the supply of enteric-coated prednisolone tablets was put out to tender by a hospital group. A pharmaceutical firm was given a contract because the price quoted was less than that of the then available enteric-coated tablets. The tablets supplied were made to fulfil the requirements for enteric coating laid down in the British Pharmacopaeia. Patients transferred to the tablets suffered considerable distress because they were largely ineffective. Enteric-coated prednisolone tablets were developed to help deal with prednisolone induced, or aggravated, peptic ulceration, and it is known that the rate of dissolution of the coating is an important factor in determining how much of the prednisolone is absorbed.9 7. 8. 9.
Nahas, G. G., Rosen, H. Fed. Proc. 1959, 18, 111. LeVeen, H. H. et al. Surgery, 1962, 51, 360. West, H. F. Brit. med. J. 1959, ii, 680.
Enteric-coated prednisolone tablets should not be used unless it is known that they are absorbed adequately. At this centre we find in adults with normal intestinal function that the enteric-coated prednisolone tablets of Pfizer Ltd. are a little less effective than plain tablets and that both are less effective than soluble prednisolone-phosphate tablets. For children and for adults who have had partial gastrectomy operations, we find the phosphate tablets desirable.10 Rheumatism Research Unit, Nether Edge Hospital, Sheffield.
H. F. WEST.
FUSIDIC ACID
SIR,-The correspondence has convinced me that fusidic acid does not act as an antiflammatory hormone. However, Dr. Crosbie (Nov. 17) has found that it does produce gastric irritation. My object in reporting the case in my letter of Oct. 6 was mainly the empirical one of drawing attention to the possible relationship between the administration of fusidic acid and the occurrence of gastric ulceration. Fulham Chest Clinic, Western Hospital, London, S.W.6.
J. VAHRMAN.
ANTICOAGULANT THERAPY FOR MYOCARDIAL INFARCTION
SIR,-Professor Wright (Sept. 29), in evaluating on the value of anticoagulant therapy in acute myocardial infarction, compared the 55 deaths during the first 48 hours in the treated group with the 101 deaths in the control group. The number of patients should read 161, not 101. In the control group there Hilden’s data
58 deaths that deserve further attention. These 58 patients had originally been assigned to the treatment group but died before treatment could be given and were transferred to the untreated cases, giving a total of 161 deaths in this group during the first 48 hours. This fact was pointed out in subsequent correspondence." The omission of these deaths from the treatment group has weighted the results in favour of treatment. Presumably there was a comparable group of deaths in the untreated group who died in this early period. Taking all the failures of the treated group that occurred in the pre-treatment period and adding them to the failures in the control group is unfair. It has resulted in approximately twice as many early deaths being shown in the control group as there were
should be. Dr. Wright’s analysis of the results of the study carried out the American Heart Association posed a similar problem. When the results of that study were analysed a correction was applied to allow for patients who had originally been assigned to the control group but who later were given anticoagulants for humane reasons when further thromboembolic complications developed. Some of these patients died and the deaths were recorded in the treatment group. It was assumed that if anticoagulants had been withheld from these patients more of them would have died. For this reason a number of hypothetical deaths were added to the control series. Without this correction the difference in mortality between control and treated patients was less impressive. Wright believes that the mortality-rate of 40% in acute myocardial infarction, reported by Hilden, to be excessively high. A similar rate has been found at the Toronto General Hospital where "modern medicine is available ". Our mortalityrate for the first 48 hours is 15%. This added to Dr. Wright’s mortality-rate of 24% for control patients dying after the first 48 hours approaches closely the value recorded by Hilden. A perfect study of the value of a drug is not solely prevented by the variables being too great, as Dr. Wright states. The
by
10. 11.
Bailey, E., Murphy, D., West, H. F. Arch. Dis. Childh. (in the press). Lancet, 1961, ii, 1041.
1113
method of handling the data may be very important. The best determine the value of a treatment is during this enthusiasm and false clinical impressions After the first trial. a make repetition of the original study difficult. Hilden’s may study is a commendable attempt after 15 years to examine the value of anticoagulant therapy in myocardial infarction objectively. The results should not be discredited because they differ from the earlier work. This discrepancy emphasises the urgent need to see whether there is a rational way to select patients who will benefit from this treatment and if there are better methods for controlling therapy. If these cannot be found, anticoagulant therapy should be abandoned in the treatment of acute myocardial infarction.
opportunity
to
Blood and Vascular Research Unit,
Department of Medicine, University of Toronto.
K. W. G. BROWN R. L. MACMILLAN J. F. MUSTARD.
SPIRONOLACTONE AND GYNÆCOMASTIA SIR,-In reply to Dr. W. G. Smith (Oct. 27), and by kind permission of Dr. William Evans and Dr. Lawson McDonald, I should like to describe the following case from the cardiac department of the London Hospital. A stock-taker, aged 60 years, first attended in December, 1958, with heart-failure of 10 months’ duration, which had followed an influenza-like illness. He gave no history of chest and after excluding the commoner varieties of heartdisease a diagnosis of cardiomyopathy was made. He responded poorly to digitalis, mersalyl, and hydrochlorothiazide, and was admitted in May and again in December, 1959, on the second occasion with gross cedema and ascities. In January, 1960, 7 litres of oedema fluid was removed by acupuncture, but he was still in congestive failure when discharged at the end of three months. On April 19, 1960, spironolactone (’Aldactone’) 100 mg. six-hourly was prescribed, and when he was seen again four weeks later the patient complained of swelling and discomfort in the right breast. The breast was firmly enlarged, and a diagnosis of carcinoma was considered, but by the end of another month it was obvious that the condition was bilateral. The accompanying figure was taken on July 12,1960, and on Aug. 9,
pain,
after further measured 4-7
hypertrophy of
breast tissue, the right breast and the left breast 5-0 cm. x 5-7 cm. There were now no signs of heart-failure, and on Aug. 23 the dose of spironolactone was halved, but for four months the gynaecomastia remained unchanged. The patient attended again on Jan. 31, 1961, having discontinued spironolactone 15 days earlier. He still complained of breast tenderness, and while both breasts were noted to be smaller in size I did not, unfortunately, make an exact record. (Edema had recurred and treatment with spironolactone was restarted. The patient, a married man with two childrer., when examined on Aug. 9, 1960, showed no evidence of testicular atrophy or neoplasm, though impotence had been a symptom for about two years. The urine on Aug. 23 contained 17-ketosteroids 16.5 mg. per 24 hours, and 17-ketogenic steroids 16.5 mg. per 24 hours. At this time the liver was impalpable, and liver-function tests had also been repeatedly normal, cm. x
5-5
cm.
cirrhosis as the cause of gynaecomastia. Bronchial carcinoma and hyperthyroidism could also be ruled out.! Furthermore, it is unlikely that heart-failure was responsible, the condition being most prominent when failure was controlled. It seems reasonable therefore to relate the gynxcomastia to the use of spironolactone.
eliminating
Pembroke County Hospital, Haverfordwest.
EIRIAN WILLIAMS.
GIVING UP SMOKING
SIR,-The suggestion made by your correspondent (Oct. 13, p. 776) of how to interest people in giving up smoking seems to me very sensible. In an issue of the Saskatchewan Health Newsletter (Nov. 15, 1959) there appeared an anti-smoking message of this type. A girl is shown in telephone conversation with a young man. She says: statement matters.
"
I never smoke on a date ! " We added the that fastidious women were careful about these
Department of Public Health, Regina, Saskatchewan.
CHRISTIAN SMITH Director of Health Education.
TREATMENT OF HIATUS HERNIA
SIR,-In retrospect, I have suffered from hiatus hernia thirty years, although the diagnosis was confirmed by X-ray only about ten years ago. I have an average-
for
hernia and after much trial and error I am able to live with it with a minimum of discomfort. I hope that some of my experiences may be of help to others. I am convinced that the epigastric pain is not caused as often size
sliding
now
by reflux of food into the oesophagus as by oesophageal spasm holding some food which cannot pass into the stomach. It
requires only the smallest amount of food to set up acute indigestion, and even the taking of considerable amounts of alkali will not relieve it, unless the spasm can be overcome and the food passed into the stomach. If this cannot be achievedand experience will soon tell you-then the simplest and most efficacious treatment is a couple of fingers at the back of the throat, and the regurgitation of this food will give immediate relief. A dose of alkali after this, and you can expect to sleep comfortably through the night. The spasm at the lower end of the oesophagus may be caused by regurgitation, or a stimulus from a distended hernia, or, from what I believe to be more common, loss of rhythm in the oesophageal contractions. The act of swallowing is complementary to that of mastication and the whole process should be a rhythmic one, starting with the muscles of mastication, continued with the muscles of deglutition, when the smooth bolus of food is accepted by the oesophagus, and carried on down to the stomach. Bad mastication, giving rise to an ill-formed bolus, will certainly cause a spasm in the oesophagus and an arrest of some of the food at its lower end. No medical treatment for hiatus hernia can be considered adequate unless an inspection of the mouth is carried out to make sure that there are sufficient teeth present, and that they are properly opposed to give a good bite, so that mastication is thorough and free from too much effort. Early fatigue of the muscles of mastication is bound to predispose to an ill-formed bolus and loss of rhythm in the act of swallowing.
The guiding principle in any advice must be that it should be easy to carry out and produce quick improvement. I think the following points are all that are necessary: (1) Meals should always be small in bulk, and it is quite remarkable how little of this is necessary to satisfy one’s physical needs. Plates filled with vegetables or stodge cause a lot of trouble. Avoid taking meals late at night. If you can have your stomach reasonably empty an hour of two before retiring there is practically no danger of indigestion. 1.
Stokes, J. F. Lancet, Nov. 3, 1962, p. 911.
high Pecs does
not cause a
direct effect of the acidosis. It seems incorrect to conclude that a high Pc02, in the absence of a metabolic acidosis, does not alter myocardial contractility. It may well be that a high Pc02, associated with an uncompensated respiratory acidosis, as well as a metabolic acidosis, does indirectly depress myocardial function, but that a high PC02’ in the absence of acidaemia (either respiratory or metabolic) does not. Anæsthetic Department, Little Bromwich Hospital,
Birmingham.
J. M. MANNERS.
POLYPS OF THE LARGE BOWEL "
SIR,-In your annotation of Oct. 27 you said: It is high time that surgeons became aware of the real nature of most large-bowel polyps. Patients are still being subjected to needlessly radical operations." We do not believe that anyone knows the real nature of adenomas or that any comfort can be extracted from the fact that an adenoma is " only a tumour on a stalk ". We doubt whether your charge that surgeons are performing needlessly radical operations for large-bowel polyps is either fair or necessary. Who is treating benign large-bowel polyps by radical operations in this country ? You also state very dogmatically (Nov. 17) that familial polyposis is a distinct entity. It is unfortunately true that our only method of distinguishing the genetic nature of familial polyposis is the clinical detection of a family history. Just because this method is so crude, it is wrong at present to make a clear-cut distinction between frankly familial forms of polyposis and patients with many polyps or a few scattered or solitary polyps with no detectable genetic cause. The number of polyps found in a patient with or without a family history can
vary from
a
very few to many hundreds.
genetic analysis of the material at St. Mark’s Hospital has suggested that there may well be a hereditary factor in all A
isolated adenomas and that the distinction between these lesions and those in polyposis may be only a matter of number and the detail of the underlying genetic mechanism. For these reasons we believe that familial intestinal polyposis cannot be omitted from any serious discussion of the relationship between adenomas and carcinoma. Your final remark that familial polyposis should not be linked with the problems of the treatment or precancerous nature of adenomatous polyps is unjustifiably dogmatic. Research Department, St. Mark’s Hospital, London, E.C.1.
A. M. O. VEALE BASIL C. MORSON.
ENTERIC-COATED PREDNISOLONE TABLETS
SiR,ŅIn recent months the supply of enteric-coated prednisolone tablets was put out to tender by a hospital group. A pharmaceutical firm was given a contract because the price quoted was less than that of the then available enteric-coated tablets. The tablets supplied were made to fulfil the requirements for enteric coating laid down in the British Pharmacopaeia. Patients transferred to the tablets suffered considerable distress because they were largely ineffective. Enteric-coated prednisolone tablets were developed to help deal with prednisolone induced, or aggravated, peptic ulceration, and it is known that the rate of dissolution of the coating is an important factor in determining how much of the prednisolone is absorbed.9 7. 8. 9.
Nahas, G. G., Rosen, H. Fed. Proc. 1959, 18, 111. LeVeen, H. H. et al. Surgery, 1962, 51, 360. West, H. F. Brit. med. J. 1959, ii, 680.
Enteric-coated prednisolone tablets should not be used unless it is known that they are absorbed adequately. At this centre we find in adults with normal intestinal function that the enteric-coated prednisolone tablets of Pfizer Ltd. are a little less effective than plain tablets and that both are less effective than soluble prednisolone-phosphate tablets. For children and for adults who have had partial gastrectomy operations, we find the phosphate tablets desirable.10 Rheumatism Research Unit, Nether Edge Hospital, Sheffield.
H. F. WEST.
FUSIDIC ACID
SIR,-The correspondence has convinced me that fusidic acid does not act as an antiflammatory hormone. However, Dr. Crosbie (Nov. 17) has found that it does produce gastric irritation. My object in reporting the case in my letter of Oct. 6 was mainly the empirical one of drawing attention to the possible relationship between the administration of fusidic acid and the occurrence of gastric ulceration. Fulham Chest Clinic, Western Hospital, London, S.W.6.
J. VAHRMAN.
ANTICOAGULANT THERAPY FOR MYOCARDIAL INFARCTION
SIR,-Professor Wright (Sept. 29), in evaluating on the value of anticoagulant therapy in acute myocardial infarction, compared the 55 deaths during the first 48 hours in the treated group with the 101 deaths in the control group. The number of patients should read 161, not 101. In the control group there Hilden’s data
58 deaths that deserve further attention. These 58 patients had originally been assigned to the treatment group but died before treatment could be given and were transferred to the untreated cases, giving a total of 161 deaths in this group during the first 48 hours. This fact was pointed out in subsequent correspondence." The omission of these deaths from the treatment group has weighted the results in favour of treatment. Presumably there was a comparable group of deaths in the untreated group who died in this early period. Taking all the failures of the treated group that occurred in the pre-treatment period and adding them to the failures in the control group is unfair. It has resulted in approximately twice as many early deaths being shown in the control group as there were
should be. Dr. Wright’s analysis of the results of the study carried out the American Heart Association posed a similar problem. When the results of that study were analysed a correction was applied to allow for patients who had originally been assigned to the control group but who later were given anticoagulants for humane reasons when further thromboembolic complications developed. Some of these patients died and the deaths were recorded in the treatment group. It was assumed that if anticoagulants had been withheld from these patients more of them would have died. For this reason a number of hypothetical deaths were added to the control series. Without this correction the difference in mortality between control and treated patients was less impressive. Wright believes that the mortality-rate of 40% in acute myocardial infarction, reported by Hilden, to be excessively high. A similar rate has been found at the Toronto General Hospital where "modern medicine is available ". Our mortalityrate for the first 48 hours is 15%. This added to Dr. Wright’s mortality-rate of 24% for control patients dying after the first 48 hours approaches closely the value recorded by Hilden. A perfect study of the value of a drug is not solely prevented by the variables being too great, as Dr. Wright states. The
by
10. 11.
Bailey, E., Murphy, D., West, H. F. Arch. Dis. Childh. (in the press). Lancet, 1961, ii, 1041.
1113
method of handling the data may be very important. The best determine the value of a treatment is during this enthusiasm and false clinical impressions After the first trial. a make repetition of the original study difficult. Hilden’s may study is a commendable attempt after 15 years to examine the value of anticoagulant therapy in myocardial infarction objectively. The results should not be discredited because they differ from the earlier work. This discrepancy emphasises the urgent need to see whether there is a rational way to select patients who will benefit from this treatment and if there are better methods for controlling therapy. If these cannot be found, anticoagulant therapy should be abandoned in the treatment of acute myocardial infarction.
opportunity
to
Blood and Vascular Research Unit,
Department of Medicine, University of Toronto.
K. W. G. BROWN R. L. MACMILLAN J. F. MUSTARD.
SPIRONOLACTONE AND GYNÆCOMASTIA SIR,-In reply to Dr. W. G. Smith (Oct. 27), and by kind permission of Dr. William Evans and Dr. Lawson McDonald, I should like to describe the following case from the cardiac department of the London Hospital. A stock-taker, aged 60 years, first attended in December, 1958, with heart-failure of 10 months’ duration, which had followed an influenza-like illness. He gave no history of chest and after excluding the commoner varieties of heartdisease a diagnosis of cardiomyopathy was made. He responded poorly to digitalis, mersalyl, and hydrochlorothiazide, and was admitted in May and again in December, 1959, on the second occasion with gross cedema and ascities. In January, 1960, 7 litres of oedema fluid was removed by acupuncture, but he was still in congestive failure when discharged at the end of three months. On April 19, 1960, spironolactone (’Aldactone’) 100 mg. six-hourly was prescribed, and when he was seen again four weeks later the patient complained of swelling and discomfort in the right breast. The breast was firmly enlarged, and a diagnosis of carcinoma was considered, but by the end of another month it was obvious that the condition was bilateral. The accompanying figure was taken on July 12,1960, and on Aug. 9,
pain,
after further measured 4-7
hypertrophy of
breast tissue, the right breast and the left breast 5-0 cm. x 5-7 cm. There were now no signs of heart-failure, and on Aug. 23 the dose of spironolactone was halved, but for four months the gynaecomastia remained unchanged. The patient attended again on Jan. 31, 1961, having discontinued spironolactone 15 days earlier. He still complained of breast tenderness, and while both breasts were noted to be smaller in size I did not, unfortunately, make an exact record. (Edema had recurred and treatment with spironolactone was restarted. The patient, a married man with two childrer., when examined on Aug. 9, 1960, showed no evidence of testicular atrophy or neoplasm, though impotence had been a symptom for about two years. The urine on Aug. 23 contained 17-ketosteroids 16.5 mg. per 24 hours, and 17-ketogenic steroids 16.5 mg. per 24 hours. At this time the liver was impalpable, and liver-function tests had also been repeatedly normal, cm. x
5-5
cm.
cirrhosis as the cause of gynaecomastia. Bronchial carcinoma and hyperthyroidism could also be ruled out.! Furthermore, it is unlikely that heart-failure was responsible, the condition being most prominent when failure was controlled. It seems reasonable therefore to relate the gynxcomastia to the use of spironolactone.
eliminating
Pembroke County Hospital, Haverfordwest.
EIRIAN WILLIAMS.
GIVING UP SMOKING
SIR,-The suggestion made by your correspondent (Oct. 13, p. 776) of how to interest people in giving up smoking seems to me very sensible. In an issue of the Saskatchewan Health Newsletter (Nov. 15, 1959) there appeared an anti-smoking message of this type. A girl is shown in telephone conversation with a young man. She says: statement matters.
"
I never smoke on a date ! " We added the that fastidious women were careful about these
Department of Public Health, Regina, Saskatchewan.
CHRISTIAN SMITH Director of Health Education.
TREATMENT OF HIATUS HERNIA
SIR,-In retrospect, I have suffered from hiatus hernia thirty years, although the diagnosis was confirmed by X-ray only about ten years ago. I have an average-
for
hernia and after much trial and error I am able to live with it with a minimum of discomfort. I hope that some of my experiences may be of help to others. I am convinced that the epigastric pain is not caused as often size
sliding
now
by reflux of food into the oesophagus as by oesophageal spasm holding some food which cannot pass into the stomach. It
requires only the smallest amount of food to set up acute indigestion, and even the taking of considerable amounts of alkali will not relieve it, unless the spasm can be overcome and the food passed into the stomach. If this cannot be achievedand experience will soon tell you-then the simplest and most efficacious treatment is a couple of fingers at the back of the throat, and the regurgitation of this food will give immediate relief. A dose of alkali after this, and you can expect to sleep comfortably through the night. The spasm at the lower end of the oesophagus may be caused by regurgitation, or a stimulus from a distended hernia, or, from what I believe to be more common, loss of rhythm in the oesophageal contractions. The act of swallowing is complementary to that of mastication and the whole process should be a rhythmic one, starting with the muscles of mastication, continued with the muscles of deglutition, when the smooth bolus of food is accepted by the oesophagus, and carried on down to the stomach. Bad mastication, giving rise to an ill-formed bolus, will certainly cause a spasm in the oesophagus and an arrest of some of the food at its lower end. No medical treatment for hiatus hernia can be considered adequate unless an inspection of the mouth is carried out to make sure that there are sufficient teeth present, and that they are properly opposed to give a good bite, so that mastication is thorough and free from too much effort. Early fatigue of the muscles of mastication is bound to predispose to an ill-formed bolus and loss of rhythm in the act of swallowing.
The guiding principle in any advice must be that it should be easy to carry out and produce quick improvement. I think the following points are all that are necessary: (1) Meals should always be small in bulk, and it is quite remarkable how little of this is necessary to satisfy one’s physical needs. Plates filled with vegetables or stodge cause a lot of trouble. Avoid taking meals late at night. If you can have your stomach reasonably empty an hour of two before retiring there is practically no danger of indigestion. 1.
Stokes, J. F. Lancet, Nov. 3, 1962, p. 911.