Cough and angiotensin II receptor antagonists: cause or confounding?

AIMS: Cough is one of the most frequent side effects associated with angiotensin converting enzyme inhibitors (ACEIs) but is not thought to be associated with losartan, an angiotensin II receptor antagonist (ARA). This study compares reports of cough with losartan and three ACEIs used in general practice. METHODS: Studies have been conducted for losartan, and three ACEIs enalapril, lisinopril and perindopril, using the technique of Prescription-Event Monitoring. Patients were identified using dispensed prescription data. Questionnaires were sent to patients' general practitioners 6 months after the date of first prescription. Cases of cough within the first 60 days of treatment with losartan resulting in withdrawal of the drug were followed up with additional questionnaires. Incidence rates for reports of cough were calculated. In order to reduce the impact of carry-over effects, rate ratios were calculated for first reports of cough between days 8 and 60 using losartan as the index drug. RESULTS: The cohort for each drug exceeded 9000 patients. Age and sex distributions and indications for prescribing the four drugs were similar. Cough was the most frequent reason for discontinuation of losartan and the most frequently reported event in the first month of treatment with this drug. When reports of cough between days 1-7 were excluded, rates of cough were significantly higher for the three ACEIs when compared with losartan (rate ratios 1.5, 4.8 and 5.7, all P<0.03). 101 patients had discontinued losartan due to cough. 91% of these had previously been prescribed an ACEI and 86% had previously experienced ACEI cough. CONCLUSIONS: Carry-over accounted for the observed excess of reports of cough with losartan. Rates of cough between days 8 and 60 were significantly higher for the three ACEIs compared with losartan. Confounding factors associated with comparative observational cohort studies are discussed.

Antidepressants and the serotonin syndrome in general practice.

BACKGROUND: As a consequence of the greater use of agents affecting the serotonergic system, a syndrome of serotonin hyperstimulation has been recognized more frequently. The serotonin syndrome is characterized by a constellation of symptoms that include mental status changes, agitation, myoclonus, hyperreflexia, sweating, shivering, tremor, diarrhoea, lack of coordination, and fever. Deaths have been reported. AIM: To identify cases of the serotonin syndrome among patients prescribed a new antidepressant in general practice, and to determine doctors' awareness of the syndrome. METHOD: Patients who were dispensed nefazodone in England between 1996 and 1997 were identified using dispensed prescription data. Prescribing doctors were sent questionnaires as part of a post-marketing surveillance study. Patients reported to have experienced two or more features of the serotonin syndrome were identified, and specific questionnaires were sent to their general practitioners. RESULTS: There was a 96.2% return rate of serotonin syndrome questionnaires. Nineteen cases met criteria for the syndrome (incidence = 0.4 cases per 1000 patient-months of treatment with nefazodone). Eight patients developed symptoms while taking nefazodone alone. Serotonergic symptoms were reported to a similar degree with five other antidepressants studied by the same method. In total, 85.4% of responding general practitioners were unaware of the serotonin syndrome. CONCLUSION: Improved awareness of the syndrome is needed within general practice. There is a need to distinguish the relatively minor serotonergic symptoms from those of a severe, life-threatening serotonin syndrome.

Nefazodone in community use: the results of prescription-event monitoring.

PURPOSE: This study was a pharmacovigilance exercise which aimed to determine the post-marketing event profile of nefazodone, a newly marketed antidepressant, in community use. METHODS: Information was collected on patients included in a non-interventional observational cohort study conducted by means of Prescription-Event Monitoring in England. Incidence densities were calculated for all reported events. RESULTS: Information was obtained for 11 834 patients. Nausea and dizziness were the most frequent adverse events that led to stopping nefazodone and the most frequently reported events during the first month of treatment. Unsteadiness and falls were reported more frequently in the elderly. Hepatic events, involuntary movements, thrombocytopenia, hallucinations and withdrawal reactions were reported rarely but were possibly associated with nefazodone. Eight overdoses involving nefazodone alone were reported with no serious clinical sequelae. Two premature births, one low birth weight term baby and two babies with renal abnormalities were outcomes in 38 pregnancies exposed in the first trimester to nefazodone. One death in a woman aged 71 years followed an illness with serotonergic features. CONCLUSIONS: Event data are presented for patients dispensed nefazodone in the community. The findings are discussed.

Post-marketing studies: the work of the Drug Safety Research Unit.

The Drug Safety Research Unit (DSRU) is the centre for prescription-event monitoring (PEM) in England. PEM studies are noninterventional observational cohort studies which monitor the safety of newly marketed drugs. The need for post-marketing surveillance is well recognised in the UK and general practice is an ideal source of data. PEM studies are general practitioner (community)-based and exposure is based on dispensed prescription data in England. To date, 65 PEM studies have been completed with a mean cohort size of 10 979 patients and the DSRU database has clinical information on over 700000 patients prescribed new drugs. Unlike spontaneous reporting schemes, PEM produces incidence rates for events reported during treatment. Comparative studies can be conducted for drugs in the same class. The DSRU aggregates outcome data for pregnancies exposed to new drugs. Data for children and the elderly can also be specifically examined. PEM data have a number of advantages over data from computerised general practice databases in the UK. PEM is the only technique within the UK capable of monitoring newly marketed drugs in such a comprehensive and systematic way.

The outcomes of pregnancy in women exposed to newly marketed drugs in general practice in England.

OBJECTIVE: To determine the proportion and nature of congenital anomalies in babies born to women exposed to newly marketed drugs during the first trimester. DESIGN: Non-interventional observational cohort studies. METHODS: The women were identified in confidence by the Prescription Pricing Authority. The doctor was sent a questionnaire to determine clinical events, including pregnancy, occurring after the drug was dispensed. A supplementary questionnaire determined the outcome of each reported pregnancy. SETTING: General medical practice in England. POPULATION: Women exposed to newly marketed drugs in whom pregnancy was recorded. MAIN OUTCOME MEASURES: Outcomes of pregnancies, the proportion and nature of congenital anomalies in the babies born. RESULTS: 2511 pregnancies were reported. In 831 of these pregnancies a newly marketed drug had been taken during the first trimester and in 74 during the second/third trimester. The outcome was ascertained for 780 (94%) of these 831 pregnancies: 547 (66%) births; 10 (1%) ectopic pregnancies; 94 (11%) spontaneous miscarriages; 5 (< 1%) missed abortions; 120 (14%) legal abortions; and 4 (< 1%) intrauterine deaths. 557 infants were born, of whom 14 (2.5%) had congenital anomalies. CONCLUSIONS: The proportion of live infants with a congenital abnormality born to mothers exposed to newly marketed drugs in the first trimester was similar to the percentage of congenital anomalies estimated by the Office for National Statistics. These data add valuable information to the safety database of these drugs.

United Kingdom experience with alendronate and oesophageal reactions.

Alendronate is indicated for the treatment of osteoporosis in post-menopausal women. Although the drug has been associated with reports of severe oesophagitis, there have been no studies establishing the incidence of such reactions. Information was collected on 1523 patients included in a study conducted by means of prescription-event monitoring. Dyspepsia, nausea/vomiting, and abdominal pain were the most frequently reported events in the first month of treatment. After follow-up, 20 patients (1.3%) experienced oesophageal events that were considered to be possibly related to alendronate.

Safety of long-term lamotrigine in epilepsy.

PURPOSE: To examine the safety of lamotrigine (LTG) used in general practice to treat epilepsy. METHODS: Information was collected on 11,316 patients who were included in a noninterventional observational cohort study conducted by means of Prescription-Event Monitoring (PEM). A follow-up study provided information on the first 3,994 patients who had taken LTG for > or = 6 months. Incidence density (ID) measurements were used to rank the frequency of the reported events. RESULTS: Rash was the most frequently reported nonepileptiform event (ID, 19.7/1,000 patient-months) in the first month of treatment and resulted in LTG being stopped in 2% of the 11,316 patients. Rash was reported more frequently among children aged 2-12 years (ID, 29.4/1,000 patient-months) than adults. Other events associated with the use of LTG included headache, drowsiness, nausea, vomiting, malaise, and lassitude. Rare serious events possibly associated with LTG included 12 cases reported as Stevens-Johnson syndrome, four cases of neutropenia, three cases of thrombocytopenia, and two cases of disseminated intravascular coagulation. There were also individual cases of leucopenia, a meningitic reaction, acute renal failure, hepatotoxicity, and a "lupus-like" reaction possibly associated with the drug. No foetal abnormalities were specifically associated with the use of the drug in pregnancy. No death was attributed to LTG. CONCLUSIONS: Patients had severe epilepsy, inadequately controlled by other antiepileptic agents. The results of these two studies suggest that LTG is acceptably safe when used for the treatment of refractory epilepsy.

A comparison of fluvoxamine, fluoxetine, sertraline and paroxetine examined by observational cohort studies.

OBJECTIVE: To compare the safety and side-effect profiles of the four selective serotonin reuptake inhibitor antidepressants (SSRIs), fluvoxamine, fluoxetine, sertraline and paroxetine. METHODS: The results from four observational cohort studies of the four SSRIs were compared. Each of these studies was conducted by Prescription-Event Monitoring (PEM). The exposure data were derived from general practitioner (GP) prescriptions confidentially supplied by the Prescription Pricing Authority (PPA) in England. Outcome data were obtained from questionnaires (green forms) on which the prescribing doctor recorded event data. The main findings comprised demographic information, including patients' date of birth and sex; the indication for prescribing the monitored drug; the effectiveness of the drug as perceived by the GP; the reasons for stopping treatment and all events recorded during and after treatment. RESULTS: The final cohort for each of the four SSRIs exceeded 10,000 patients. The sex, age distributions and indications for prescribing the four SSRIs were very similar. Only 36% of the GPs expressing an opinion reported fluvoxamine as effective, compared with approximately 60% for fluoxetine, sertraline and paroxetine. Fluvoxamine was associated with a higher incidence of adverse events than the other three SSRIs. Nausea/vomiting was both the most frequent clinical reason for stopping all four SSRIs and the most frequently reported clinical event. Adverse events reported in patients aged 70 years and over were comparable with the events reported for the total cohorts. Differences were identified between the four SSRIs for less frequently reported adverse events. Withdrawal symptoms were significantly more frequent with paroxetine than the other three SSRIs. CONCLUSIONS: The data from the four studies were comparable in terms of age distribution, sex of patients and indication for prescribing the drugs. Fluvoxamine had a considerably higher incidence of side-effects associated with its use than the other three SSRIs. The side-effect profiles of the four SSRIs were comparable for frequently reported events. Important differences were identified between the four SSRIs in respect of less frequently reported events. This study suggests that fluvoxamine compares unfavourably with fluoxetine, sertraline and paroxetine, both in terms of reported effectiveness and the incidence of adverse events. Biases possibly affecting the comparisons involved in this study are unlikely to account for the observed differences between fluvoxamine and the other three SSRIs.