1185 would have been resolved had indomethacm been given after the antihypertensive effect had been fully established. Birch Hill Hospital, Rochdale OL12 9QB
C. DAVIDSON
DISOPYRAMIDE IN MYOCARDIAL INFARCTION
SIR,—The natural history of myocardial infarction is very variable, and several hundred patients matched with an equal must be studied if a new form of treatment is to be accurately assessed. The paper by Dr Zainal and his colleagues (Oct. 29, p. 887) claiming that disopyramide lowers both mortality and the incidence of extension of infarction, ventricular tachycardia, and ventricular fibrillation could, if confirmed, represent a major advance, as stated in your accompanying editorial. However, only 30 patients were studied, with a similar number of controls. How and at what stage were the patients randomly selected? Mortality in the placebo group was unexpectedly high (30%) even after exclusion of patients who were unconscious or shocked and those in complete heart block or with arrhythmias. How were patients excluded for these reasons during the trial? Disopyramide has a place, among other drugs, in the control of arrhythmias, especially ventricular extrasystoles and tachycardia, but the data supplied do not support the claim that "until information is available to the contrary oral disopyramide should be given for the first seven days after myocardial infarction to all patients not managed in an intensive care unit".
number of controls
Royal Postgraduate Medical School, Hammersmith Hospital, London W120HS
C. T. DOLLERY D. M. KRIKLER J. P. SHILLINGFORD
not recorded. From the other figures, and the age of the disopyramide-treated patient who depending died, either 4 or 5 patients under 66 and 6 or 7 over 66 receiving placebo died. If the mortality in age-matched sub-groups is compared, the numbers involved become small and it is difficult to draw any definite conclusion, especially since mortality among the controls was so high. A further worry is that some patients on disopyramide had no drug detectable in their blood and that "development of arrhythmias did not correspond with low levels".
mide
died; his age is on
Whittingson Hospital, ROBERT GREENBAUM
London N19 3UA
The first
two
letters have been shown
to
Dr Kidner and his
colleagues, whose reply follows.-ED.L. SIR,-We thank
our colleagues for their comments on our hope that the additional information will clarify the points that they have raised. There were 30 patients from St Mary’s Hospital, W9, 19 from St Charles Hospital, W10, and 11 from Willesden General Hospital, NW10 (which closed during the study). There were almost equal numbers in the two groups at each hospital. There were no important differences in treatment policy. The data requested on re-infarction and death are shown in the table. We cannot definitely implicate sustained arrhythmias in the genesis of re-infarction because such data could only be obtained from 24 h tape electrocardiography. Unfortunately, in no patient was the recording available at the time of re-infarction. This problem is now being investigated. The variable drug levels are explained by the different times at which blood was taken after the patient’s first dose. The concentrations after the first day were in the therapeutic
paper and
range. RE-INFARCTION AND DEATH
SIR,-We were interested to read the paper by Dr Zainal and his colleagues on the use of oral disopyramide in patients with myocardial infarction managed on open wards. The results seem impressive, but many points require clarification, particularly in view of the far-reaching implications of the conclusions drawn. Further information on matching, the distribution of patients between hospitals, and the treatment policies of the three hospitals is needed. We need to know the causes of death and the timing of death or infarct extension. Zainal et al. state that disopyramide may reduce the incidence of infarct extension by preventing sustained arrhythmias. Were sustained arrhythmias implicated in infarct extension in their placebo
group? An unspecified number of patients in the treated group had no disopyramide detectable in plasma. Was this a reflection of patient compliance or sampling-time, and can such patients be properly considered to be part of the disopvramide group? University Department Royal Infirmary, Edinburgh EH3 9YW
of Therapeutics,
A. POTTAGE S. PICKENS R. H. ROBSON
SIR,—DR Zainal and his colleagues recommend that "oral disopyramide should be given for the first seven days after myocardial infarction to all patients not managed in an intensive-care unit". I would question their optimism on the effect of the drug on mortality and its ability to protect against lifethreatening arrhythmias. There were 35 patients aged 65 or less and 25 aged 66 or 2 patients were admitted twice. The patients were age matched so that of 29 in each group it would seem 17 were under 66 and 12 were over 66 years. 1 patient receiving disopyramore.
P=placebo; D=disopyramide; v.F.=ventricutar fibrillation; C.H.B.=complete heart block. The initial comments from our colleagues at the Royal Postgraduate Medical School are based on what could be a false premise. The number of patients required to investigate any therapeutic intervention depends not only on the condition under review but also upon the efficacy of the treatment. If a therapeutic intervention is effective, then it might not be necessary to test several hundred patients. Moreover, our report does show how patients were selected. All patients under the age of 80 admitted to the hospitals within 36 h of the onset of chest pain and with a presumptive diagnosis of acute myocardial infarction were included in the trial, save the exceptions mentioned in detail. The patients were then allocated to
1186
disopyramide or placebo in a randomised double-blind manner before therapy was started. During the trial, patients were excluded as treatment failures if they were noted by the nursing or medical staff to have heart block or arrhythmias requiring treatment. If the patients had any degree of cardiogenic shock they were also taken out of the study group-as possible complications of the therapy. of opinion whether the evidence presented in our report is "slender". Our experience with the use of disopyramide in the coronary-care unit’ suggested that this agent could prevent development of ventricular irritability after myocardial infarction and also seemed to affect the incidence of extension of myocardial infarction. When the drug was tested in clinical circumstances where cardiac monitoring was less than ideal, the difference between the active and placebo groups was even more apparent with regard to the development of myocardial irritability and extension of myocardial infarction. Indeed, the analysis of the 24 h tapes led us to suppose that, on the open ward, cardiac monitoring was far less than ideal and under no circumstances could be assumed even to approximate the monitoring within the coronary-care unit. It was also apparent to us that, under these circumstances, extension of myocardial infarction was associated with mortality. If there is any likelihood at all that development of myocardial irritability is in any way associated with extension of myocardial infarction, then it is important, we feel, to prevent arrhythmias. This is especially so when such a development is likely to be missed by the monitoring staff-for example, in the circumstances of the open ward. We therefore recommend the use of disopyramide in patients following infarction managed on the open ward. We are very well aware of the difficulties of assessing the efficacy of any intervention under these circumstances, and we wholeheartedly support the setting up of a multicentre trial looking specifically towards the prevention of extension of myocardial infarction and mortality by the prophylactic use of disopyramide. Such a trial is in preparation. We would like to acknowledge a regrettable oversight and apologise to the Guy’s poisons unit: without their help it would have been impossible to estimate the blood levels of disopyramide. D. J. S. CARMICHAEL It
must
be
a matter
Waller Cardio-pulmonary Unit, St Mary’s Hospital, London W2 1NY
E. M. M. BESTERMAN P. H. KIDNER
I have
a
further 4 patients in atrial fibrillation who do not take
digoxin. Does Dr Hull’s practice have a much larger proportion of fibrillators who do not receive digoxin? If so, perhaps many patients in atrial fibrillation could be taken off digoxin as well as those in sinus rhythm. Alton Health Alton, Hants
Centre,
H.
J. N. BETHELL
STROKES: A COMPLICATION OF MITRAL-LEAFLET PROLAPSE
SIR,—From the pathologist’s viewpoint the relationship
prolapse of the mitral valve and embolic disease is complex than either the paper by Dr Kostuk and his colleagues (Aug. 13, p. 313) or the subsequent correspondence (Oct. 27, p. 923) would suggest. Potentially embolic lesions are common with prolapsed mitral valves. Very careful naked-eye examination reveals thrombotic areas in about a third of cases. These appear as yellow, irregular, roughened areas on the atrial face of the abnormal part of the leaflet, as "jet" lesions on the opposite cusp or the base of atrial septum, and, as illustrated by Kostuk et al., as thrombi at the junction of abnormal cusp and related atrial wall.1,2 Histologically all these lesions show thrombus, usually superimposed on superficially damaged subendothelium, and abnormal valves with no naked-eye lesions will frequently show microscopic thrombi. In our experience of several hundred cases with prolapsing mitral valve, with and without atrial fibrillation, these thrombotic lesions are invariably small, unless infective endocarditis has developed. Although these thrombotic lesions might be responsible for retinal-artery occlusion or transient neurological symptoms it seems unlikely they could be a source of emboli large enough to cause serious strokes. Where the mitral-valve prolapse is between more
associated with atrial fibrillation the risk of cerebral embolism from this source is clear and, we suspect, no different from that in atrial fibrillation of ther causes. Harefield and Mount Vernon Pathology Laboratories, Mount Vernon Hospital, Northwood, Middlesex HA6 2RN
A. POMERANCE
Pathology Department, St. George’s Hospital Medical School, London
M. J. DAVIES
DISCONTINUATION OF MAINTENANCE DIGOXIN
SIR,—Ican confirm Dr Hull and Dr Mackintosh’s finding that, in general practice, maintenance digoxin therapy can be discontinued in most patients in sinus rhythm (Nov. 19, p.
1054). Over the past
18 months I have reviewed all the
patients in my practice who have taken long-term digoxin. In a practice of 3000 there were 44 patients on maintenance digoxin. 25 were in atrial fibrillation, 3 had paroxysmal atrial fibrillation, 1 had recurrent supraventricular tachycardia, and 15 were in sinus rhythm. Of the patients in sinus rhythm, 11 have been taken off digoxin with no ill-effects. 2 patients with intractable heart-failure were left on digoxin as was 1 old lady who was reluctant to stop her "heart tablets". 1 patient went into pulmonary oedema when the dose of digoxin was reduced. There were 2 deaths in the sinus-rhythm group, both in patients who continued with digoxin. It would seem prudent to tail off the dose of digoxin gradually rather than stop it suddenly. I was interested by the discrepancy in the number of patients in atrial fibrillation on digoxin therapy in the two practices. In Dr Hull’s practice, there were 7 ouf of 4630 (0.15%) and in my practice there were 25 out of 3000 (0.83%). 1.
Jennings, G., and others. Lancet, 1976, i, 51.
CARBAMAZEPINE IN RAYNAUD’S DISEASE SIR,—Raynaud’s disease is characterised by digital blanching which may be triggered by exposure to cold, by smoking, or by anxiety, or it may have no obvious cause. It must be distinguished from a variety of other peripheral vascular diseases. We have been treating with carbamazepine a 31-year-old woman with nocturnal complex partial seizures who also has migraine headaches and Raynaud’s disease. On carbamazepine, 300 mg a day (blood level 6-8 ug/ml) her symptoms of Raynaud’s disease have disappeared. She is not taking propranolol or ergot compounds and does not smoke. If this finding can be reproduced it may have interesting implications for the pathogenesis of this disorder. Many clinicians have noted an association between "nervous instability" and Raynaud’s disease. Psychiatric Institute and Clinic, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, U.S.A. Western
JAMES R. MERIKANGAS RALPH AUCHENBACH
1. Pomerance, A. Br. Heart. J. 1969, 31, 343. 2. Pomerance, A., Davies, M. J. Pathology of the Heart.
Oxford, 1975.
C. DAVIDSON
DISOPYRAMIDE IN MYOCARDIAL INFARCTION
SIR,—The natural history of myocardial infarction is very variable, and several hundred patients matched with an equal must be studied if a new form of treatment is to be accurately assessed. The paper by Dr Zainal and his colleagues (Oct. 29, p. 887) claiming that disopyramide lowers both mortality and the incidence of extension of infarction, ventricular tachycardia, and ventricular fibrillation could, if confirmed, represent a major advance, as stated in your accompanying editorial. However, only 30 patients were studied, with a similar number of controls. How and at what stage were the patients randomly selected? Mortality in the placebo group was unexpectedly high (30%) even after exclusion of patients who were unconscious or shocked and those in complete heart block or with arrhythmias. How were patients excluded for these reasons during the trial? Disopyramide has a place, among other drugs, in the control of arrhythmias, especially ventricular extrasystoles and tachycardia, but the data supplied do not support the claim that "until information is available to the contrary oral disopyramide should be given for the first seven days after myocardial infarction to all patients not managed in an intensive care unit".
number of controls
Royal Postgraduate Medical School, Hammersmith Hospital, London W120HS
C. T. DOLLERY D. M. KRIKLER J. P. SHILLINGFORD
not recorded. From the other figures, and the age of the disopyramide-treated patient who depending died, either 4 or 5 patients under 66 and 6 or 7 over 66 receiving placebo died. If the mortality in age-matched sub-groups is compared, the numbers involved become small and it is difficult to draw any definite conclusion, especially since mortality among the controls was so high. A further worry is that some patients on disopyramide had no drug detectable in their blood and that "development of arrhythmias did not correspond with low levels".
mide
died; his age is on
Whittingson Hospital, ROBERT GREENBAUM
London N19 3UA
The first
two
letters have been shown
to
Dr Kidner and his
colleagues, whose reply follows.-ED.L. SIR,-We thank
our colleagues for their comments on our hope that the additional information will clarify the points that they have raised. There were 30 patients from St Mary’s Hospital, W9, 19 from St Charles Hospital, W10, and 11 from Willesden General Hospital, NW10 (which closed during the study). There were almost equal numbers in the two groups at each hospital. There were no important differences in treatment policy. The data requested on re-infarction and death are shown in the table. We cannot definitely implicate sustained arrhythmias in the genesis of re-infarction because such data could only be obtained from 24 h tape electrocardiography. Unfortunately, in no patient was the recording available at the time of re-infarction. This problem is now being investigated. The variable drug levels are explained by the different times at which blood was taken after the patient’s first dose. The concentrations after the first day were in the therapeutic
paper and
range. RE-INFARCTION AND DEATH
SIR,-We were interested to read the paper by Dr Zainal and his colleagues on the use of oral disopyramide in patients with myocardial infarction managed on open wards. The results seem impressive, but many points require clarification, particularly in view of the far-reaching implications of the conclusions drawn. Further information on matching, the distribution of patients between hospitals, and the treatment policies of the three hospitals is needed. We need to know the causes of death and the timing of death or infarct extension. Zainal et al. state that disopyramide may reduce the incidence of infarct extension by preventing sustained arrhythmias. Were sustained arrhythmias implicated in infarct extension in their placebo
group? An unspecified number of patients in the treated group had no disopyramide detectable in plasma. Was this a reflection of patient compliance or sampling-time, and can such patients be properly considered to be part of the disopvramide group? University Department Royal Infirmary, Edinburgh EH3 9YW
of Therapeutics,
A. POTTAGE S. PICKENS R. H. ROBSON
SIR,—DR Zainal and his colleagues recommend that "oral disopyramide should be given for the first seven days after myocardial infarction to all patients not managed in an intensive-care unit". I would question their optimism on the effect of the drug on mortality and its ability to protect against lifethreatening arrhythmias. There were 35 patients aged 65 or less and 25 aged 66 or 2 patients were admitted twice. The patients were age matched so that of 29 in each group it would seem 17 were under 66 and 12 were over 66 years. 1 patient receiving disopyramore.
P=placebo; D=disopyramide; v.F.=ventricutar fibrillation; C.H.B.=complete heart block. The initial comments from our colleagues at the Royal Postgraduate Medical School are based on what could be a false premise. The number of patients required to investigate any therapeutic intervention depends not only on the condition under review but also upon the efficacy of the treatment. If a therapeutic intervention is effective, then it might not be necessary to test several hundred patients. Moreover, our report does show how patients were selected. All patients under the age of 80 admitted to the hospitals within 36 h of the onset of chest pain and with a presumptive diagnosis of acute myocardial infarction were included in the trial, save the exceptions mentioned in detail. The patients were then allocated to
1186
disopyramide or placebo in a randomised double-blind manner before therapy was started. During the trial, patients were excluded as treatment failures if they were noted by the nursing or medical staff to have heart block or arrhythmias requiring treatment. If the patients had any degree of cardiogenic shock they were also taken out of the study group-as possible complications of the therapy. of opinion whether the evidence presented in our report is "slender". Our experience with the use of disopyramide in the coronary-care unit’ suggested that this agent could prevent development of ventricular irritability after myocardial infarction and also seemed to affect the incidence of extension of myocardial infarction. When the drug was tested in clinical circumstances where cardiac monitoring was less than ideal, the difference between the active and placebo groups was even more apparent with regard to the development of myocardial irritability and extension of myocardial infarction. Indeed, the analysis of the 24 h tapes led us to suppose that, on the open ward, cardiac monitoring was far less than ideal and under no circumstances could be assumed even to approximate the monitoring within the coronary-care unit. It was also apparent to us that, under these circumstances, extension of myocardial infarction was associated with mortality. If there is any likelihood at all that development of myocardial irritability is in any way associated with extension of myocardial infarction, then it is important, we feel, to prevent arrhythmias. This is especially so when such a development is likely to be missed by the monitoring staff-for example, in the circumstances of the open ward. We therefore recommend the use of disopyramide in patients following infarction managed on the open ward. We are very well aware of the difficulties of assessing the efficacy of any intervention under these circumstances, and we wholeheartedly support the setting up of a multicentre trial looking specifically towards the prevention of extension of myocardial infarction and mortality by the prophylactic use of disopyramide. Such a trial is in preparation. We would like to acknowledge a regrettable oversight and apologise to the Guy’s poisons unit: without their help it would have been impossible to estimate the blood levels of disopyramide. D. J. S. CARMICHAEL It
must
be
a matter
Waller Cardio-pulmonary Unit, St Mary’s Hospital, London W2 1NY
E. M. M. BESTERMAN P. H. KIDNER
I have
a
further 4 patients in atrial fibrillation who do not take
digoxin. Does Dr Hull’s practice have a much larger proportion of fibrillators who do not receive digoxin? If so, perhaps many patients in atrial fibrillation could be taken off digoxin as well as those in sinus rhythm. Alton Health Alton, Hants
Centre,
H.
J. N. BETHELL
STROKES: A COMPLICATION OF MITRAL-LEAFLET PROLAPSE
SIR,—From the pathologist’s viewpoint the relationship
prolapse of the mitral valve and embolic disease is complex than either the paper by Dr Kostuk and his colleagues (Aug. 13, p. 313) or the subsequent correspondence (Oct. 27, p. 923) would suggest. Potentially embolic lesions are common with prolapsed mitral valves. Very careful naked-eye examination reveals thrombotic areas in about a third of cases. These appear as yellow, irregular, roughened areas on the atrial face of the abnormal part of the leaflet, as "jet" lesions on the opposite cusp or the base of atrial septum, and, as illustrated by Kostuk et al., as thrombi at the junction of abnormal cusp and related atrial wall.1,2 Histologically all these lesions show thrombus, usually superimposed on superficially damaged subendothelium, and abnormal valves with no naked-eye lesions will frequently show microscopic thrombi. In our experience of several hundred cases with prolapsing mitral valve, with and without atrial fibrillation, these thrombotic lesions are invariably small, unless infective endocarditis has developed. Although these thrombotic lesions might be responsible for retinal-artery occlusion or transient neurological symptoms it seems unlikely they could be a source of emboli large enough to cause serious strokes. Where the mitral-valve prolapse is between more
associated with atrial fibrillation the risk of cerebral embolism from this source is clear and, we suspect, no different from that in atrial fibrillation of ther causes. Harefield and Mount Vernon Pathology Laboratories, Mount Vernon Hospital, Northwood, Middlesex HA6 2RN
A. POMERANCE
Pathology Department, St. George’s Hospital Medical School, London
M. J. DAVIES
DISCONTINUATION OF MAINTENANCE DIGOXIN
SIR,—Ican confirm Dr Hull and Dr Mackintosh’s finding that, in general practice, maintenance digoxin therapy can be discontinued in most patients in sinus rhythm (Nov. 19, p.
1054). Over the past
18 months I have reviewed all the
patients in my practice who have taken long-term digoxin. In a practice of 3000 there were 44 patients on maintenance digoxin. 25 were in atrial fibrillation, 3 had paroxysmal atrial fibrillation, 1 had recurrent supraventricular tachycardia, and 15 were in sinus rhythm. Of the patients in sinus rhythm, 11 have been taken off digoxin with no ill-effects. 2 patients with intractable heart-failure were left on digoxin as was 1 old lady who was reluctant to stop her "heart tablets". 1 patient went into pulmonary oedema when the dose of digoxin was reduced. There were 2 deaths in the sinus-rhythm group, both in patients who continued with digoxin. It would seem prudent to tail off the dose of digoxin gradually rather than stop it suddenly. I was interested by the discrepancy in the number of patients in atrial fibrillation on digoxin therapy in the two practices. In Dr Hull’s practice, there were 7 ouf of 4630 (0.15%) and in my practice there were 25 out of 3000 (0.83%). 1.
Jennings, G., and others. Lancet, 1976, i, 51.
CARBAMAZEPINE IN RAYNAUD’S DISEASE SIR,—Raynaud’s disease is characterised by digital blanching which may be triggered by exposure to cold, by smoking, or by anxiety, or it may have no obvious cause. It must be distinguished from a variety of other peripheral vascular diseases. We have been treating with carbamazepine a 31-year-old woman with nocturnal complex partial seizures who also has migraine headaches and Raynaud’s disease. On carbamazepine, 300 mg a day (blood level 6-8 ug/ml) her symptoms of Raynaud’s disease have disappeared. She is not taking propranolol or ergot compounds and does not smoke. If this finding can be reproduced it may have interesting implications for the pathogenesis of this disorder. Many clinicians have noted an association between "nervous instability" and Raynaud’s disease. Psychiatric Institute and Clinic, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, U.S.A. Western
JAMES R. MERIKANGAS RALPH AUCHENBACH
1. Pomerance, A. Br. Heart. J. 1969, 31, 343. 2. Pomerance, A., Davies, M. J. Pathology of the Heart.
Oxford, 1975.
