Zomepirac and cardiovascular deaths.
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Biomedical subjects
Publications and source records attributed to W H Inman.
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Using prescription-event monitoring to determine whether erythromycin estolate was a more frequent cause of jaundice than erythromycin stearate or tetracycline 12 208 patients, for whom 5343 doctors had prescribed one of the three drugs, were identified by the Prescription Pricing Authority. Of the questionnaires sent to general practitioners about the possible occurrence of jaundice, 76% were returned. There were 16 reports of jaundice, of which four were attributable to gall stones, three to cancer, six to viral hepatitis, and only three were possibly related to an antibiotic. All three patients, in whom the antibiotic was a possible cause, had been treated with erythromycin stearate. No case was attributable to the estolate which had previously been suspected of being a more frequent cause of jaundice. Although the incidence is unknown, it is very unlikely to be more than one in 100.
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An independent, non-regulatory drug surveillance research unit has been established at the University of Southampton. Its first task will be to set up a prescription-event monitoring scheme in general practice to enable the pattern of adverse events, as distinct from suspected adverse reactions associated with new drugs to be compared with that of older medicines. Prescriptions for selected drugs will identify patients and a simple questionnaire, designed to be completed in under five minutes, will be used to obtain the required information. Medical opinions about causation need not be given, and the scheme will not interfere with normal prescribing practice.
Spontaneous reporting of suspected adverse drug reactions through the yellow card system provides an effective means of early warning of potentially serious drug effects but occasionally fails because of under-reporting. Since more than 80% of medicines are prescribed by general practitioners we look to them to support new methods of postmarketing surveillance. No single method will be appropriate for all drugs, and yellow cards will always be required to detect rare events. It is proposed that adverse events experienced by the first 10 000 patients who receive certain new medicines should be recorded and transmitted to a monitoring centre and that a realistic target, which should be reached early in the market life of a new medicine, is the detection of any adverse event that occurs in more than in 1000 patients.
A case-control study was conducted of the deaths from subarachnoid haemorrhage (SAH) in women aged 15-44 in England and Wales in 1976. There was a small excess of oral contraceptive use by the women who died from SAH compared with their generally healthy practice-matched controls; this was not, however, statistically significant. Out of 134 women who died from SAH, 34 had a history of hypertension compared with only six of their controls. Renal disease and pre-eclamptic toxaemia were more commonly associated with hypertension in the dead women than in controls. No change in the annual mortality from SAH has been observed in the past 20 years such as might have been expected if the risks were high. Although current or past use of oral contraceptives may have increased the blood pressure and risk of SAH in a few women, the most important factor in determining this risk was hypertension. SAH should thus probably not be regarded as serious cause for concern in healthy non-hypertensive women using oral contraceptives.
Aanalysis of data derived from 170 reports of jaundice developing after anaesthesia with halothane received after January 1974 confirmed the relations between multiple exposure to halothane and jaundice and between the number of exposures and the rapidity with which jaundice develops after exposure. When these reports were combined with 130 received earlier complete anaesthetic histories were available for 251 patients, 205 (82%) of whom had been exposed to halothane more than once; of these patients, 154 (75%) had been exposed more than once within 28 days. Altogether 139 (46%) of the 300 patients died.
We obtained drug histories for the first trimester of pregnancy for 836 mothers of congenitally malformed babies and for an equal number of control mothers of normal babies from the same doctors' practices. There was an association between the use of a hormonal pregnancy test and the subsequent birht of a malformed baby. There was also a greater use of barbiturates by mothers of affected children compared with mothers of control babies, mainly accounted for by treatment of epileptic mothers with phenobarbitone. For all other drugs usage was similar in both sets of mothers.
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The histories of 269 patients whose death certificates did not mention a drug as the cause of aplastic anaemia or agranulocytosis were investigated. Eighty-three deaths were probably caused by drugs, the most common cause of aplastic anaemia being treatment with phenylbutazone (28 deaths) and oxyphenbutazone (11 deaths). Thirteen out of 17 deaths from agranulocytosis were attributed to co-trimoxazole treatment. A separate survey of general practitioners' prescriptions enabled the mortality to be estimated. With the addition of one death due to oxyphenbutazone and four deaths due to phenylbutazone that were reported independently to the committee, the mortality from oxyphenbutazone was 3-8 per 100 000 and from phenylbutazone 2-2 per 100 000. With phenylbutazone the rates varied from under 1 death per 100 000 for men aged under 65 years to 6 per 100 000 for women aged 65 and over. Small numbers precluded estimates for oxyphenbutazone in these subgroups, although a similar trend was suggested. No particular indication for treatment seems to carry a higher risk, the main concern being the use of these two drugs in elderly patients.
A previous study of women who had died from myocardial infarction and of a control group of women matched with them for age suggested a fivefold increase in the risk of death from myocardial infarction among users of oral contraceptive aged 40-44 years compared with women not using such preparations. Only a small proportion of women in the infarction and control groups had used oral contraceptives, however, so the margin of error was wide. We therefore investigated a further 54 women in this age group who died from myocardial infarction and compared their oral contraceptive histories with those of age-matched, living controls. Combination of the findings from the present investigation with the previous results have enabled a revised estimate of a threefold increase in risk to be made. Although this risk estimate is similar to that previously shown for a younger age group, the total mortality attributable to complications associated with the use of oral contraceptives remained considerably greater among women over the age of 40.
We investigated 219 deaths from myocardial infarction in women under the age of 50. Their histories were compared with those of living age-matched controls selected from the same general practices. The frequency of use of oral contraceptives during the month before death was significantly greater in the group with infarction than during the corresponding month in the control group and the average duration of use was longer. No information of cigarette smoking was available but the proportion of women being treated for hypertension or diabetes was greater among those who died than among the controls. This did not alter the overall conclusion that the risk of fatal myocardial infarction was greater in the women using oral contraceptives, particularly in the older age groups.
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Analysis of data derived from 130 reports of jaundice occurring after anaesthesia with halothane showed a significant relation between the number of exposures to this anaesthetic and the rapidity with which jaundice develops after exposure. This is considered to provide strong evidence of a cause-effect relationship between the use of halothane and jaundice. Out of 114 patients with complete anaesthetic histories 94 (82%) had been exposed more than once; of those so exposed 80% had been anaesthetized with halothane more than once within 28 days. Altogether 66 (51%) of the 130 patients died.
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An adverse drug-reaction monitoring system based on spontaneous reporting to a central register of adverse reactions has been in operation for eight years. As a test of the validity of the reports and of the probability of causal relationship between drug and reaction a random sample of 82 cases were followed up in detail. The sample included 17 deaths, 26 serious reactions, and 39 reactions of moderate or only minor severity. Altogether 78% of the reactions were considered to be "probably" drug related and 13% "possibly" drug related. It is concluded that the reports are of value in the detection and evaluation of drug safety.