Laura E. Derby

Risk of hospital admission for idiopathic venous thromboembolism among users of postmenopausal oestrogens

BACKGROUND At the request of researchers in the UK, we conducted a case-control study to explore the relation between use of postmenopausal oestrogen hormone replacement therapy (HRT) and idiopathic venous thromboembolism (VTE). METHODS The study was based on information derived from Group Health Cooperative of Puget Sound for the period 1980 to 1994. Women aged 50-74 years admitted to hospital for idiopathic VTE were identified from hospital records. The diagnosis of idiopathic VTE was validated from the clinical record. Women who had medical conditions predisposing to VTE (a history of VTE or cancer, recent trauma, or surgery) were excluded as cases. Four control subjects matched to each case by age, duration of Cooperative membership, and calendar time were identified from the base population. Various potential risk factors were recorded based on record review. FINDINGS An initial analysis of 42 cases and 168 matched controls yielded a matched relative risk estimate of 3.6 (95% CI 1.6-7.8) for current users of oestrogens compared with non-users. There was a substantial effect of daily oestrogen dose. The matched relative risk estimates for oestrogen users of 0.325 mg, 0.625 mg, and 1.25 mg or more daily were 2.1, 3.3, and 6.9, respectively. Body-mass index was independently associated with the risk of VTE but did not materially confound the relation of oestrogen and VTE. The absolute risk of idiopathic VTE is estimated to be low (0.9 x 10(-4) woman-years) in non-users of oestrogen; the risk in current users is estimated at 3.2 x 10(-4) woman-years. INTERPRETATION The risk of idiopathic VTE is about three times higher among current users of replacement oestrogens than among non-users. However, the absolute risk is low for both groups and accounts for only a modest increase in morbidity.

Acute respiratory-tract infections and risk of first-time acute myocardial infarction

BACKGROUND There is growing interest in the role of infections in the aetiology of acute myocardial infarction (AMI). We undertook a large, population-based study to explore the association between risk of AMI and recent acute respiratory-tract infection. METHODS We used data from general practices in the UK (General Practice Research Database). Potential cases were people aged 75 years or younger, with no history of clinical risk factors, who had a first-time diagnosis of AMI between Jan 1, 1994, and Oct 31, 1996. Four controls were matched to each case on age, sex, and the practice attended. The date of the AMI in the case was defined as the index date. For both cases and controls the date of the last respiratory-tract infection before the index date was identified. We also did a case-crossover analysis of cases who had an acute respiratory-tract infection either before the index date or before an arbitrarily chosen date (1 year before AMI). FINDINGS In the case-control analysis of 1922 cases and 7649 matched controls, significantly more cases than controls had an acute respiratory-tract infection in the 10 days before the index date (54 [2.8%] vs 72 [0.9%]). The odds ratios, adjusted for smoking and body-mass index, for first-time AMI in association with an acute respiratory-tract infection 1-5, 6-10, 11-15, or 16-30 days before the index date (compared with participants who had no such infection during the preceding year) were 3.6 (95% CI 2.2-5.7), 2.3 (1.3-4.2), 1.8 (1.0-3.3), and 1.0 (0.7-1.6); (test for trend p<0.01). The case-crossover analysis showed a relative risk of 2.7 (1.6-4.7) for AMI in relation to an acute respiratory-tract infection in the 10 days before the index date. INTERPRETATION Our findings suggest that in people without a history of clinical risk factors for AMI, acute respiratory-tract infections are associated with an increased risk of AMI for a period of about 2 weeks. We cannot, however, completely exclude the possibility of misdiagnosis bias, if prodromal symptoms of AMI were mistaken for respiratory-tract infection.

A Population-Based Study of Appetite-Suppressant Drugs and the Risk of Cardiac-Valve Regurgitation

BACKGROUND Recent case reports suggest that a combination of the appetite suppressants fenfluramine and phentermine is associated with an increased risk of cardiac-valve regurgitation. There are also reports of valvular disorders in persons taking fenfluramine or dexfenfluramine alone, particularly for more than three months. METHODS We conducted a population-based follow-up study and a nested case-control analysis of 6532 subjects who received dexfenfluramine, 2371 who received fenfluramine, and 862 who received phentermine to assess the risk of a subsequent clinical diagnosis of a valvular disorder of uncertain origin. For comparison, we identified a group of 9281 obese subjects who had not taken appetite suppressants who were matched to the treated subjects for age, sex, and weight. All subjects were free of diagnosed cardiovascular disease at the start of follow-up. The average duration of follow-up for all subjects was about four years. RESULTS There were 11 cases of newly diagnosed idiopathic valvular disorders, 5 after the use of dexfenfluramine and 6 after the use of fenfluramine. There were six cases of aortic regurgitation, two cases of mitral regurgitation, and three cases of combined aortic and mitral regurgitation. There were no cases of idiopathic cardiac-valve abnormalities among the subjects who had not taken appetite suppressants or among those who took only phentermine. The five-year cumulative incidence of idiopathic cardiac-valve disorders was 0 per 10,000 subjects among those who had not taken appetite suppressants (95 percent confidence interval, 0 to 15.4) and among those who took phentermine alone (95 percent confidence interval, 0 to 76.6), 7.1 per 10,000 subjects among those who took either fenfluramine or dexfenfluramine for less than four months (95 percent confidence interval, 3.6 to 17.8; P=0.02 for the comparison with subjects who had not taken appetite suppressants), and 35.0 per 10,000 subjects among those who received either of these medications for four or more months (95 percent confidence interval, 16.4 to 76.2; P<0.001). CONCLUSIONS The use of fenfluramine or dexfenfluramine, particularly for four months or longer, is associated with an increased risk of newly diagnosed cardiac-valve disorders, particularly aortic regurgitation.

Calcium-channel blockers and risk of cancer.

Summary Background Previous studies have been interpreted as suggesting an increase in risk of cancer among users of calcium-channel blockers compared with users of β-blockers. To explore this issue further, we studied a large group of hypertensive patients to investigate the relation of calcium-channel blockers and cancer. Methods In cohorts of users of calcium-channel blockers, angiotensin-converting-enzyme (ACE) inhibitors, and β-blockers, we identified all cases of cancer diagnosed in 1995. We used a nested case-control analysis to estimate the risk of cancer among users of calcium-channel blockers and ACE inhibitors, with users of β-blockers as a reference group. The study was based on information taken from the General Practice Research Database, and the study population was restricted to patients with at least 4 years of medical history recorded on computer. Findings The study was based on 446 cases of cancer and 1750 controls. The relative risk estimates for all cancers combined were 1·27 (95% CI 0·98–1·63) and 0·79 (0·58–1·06) for users of calcium-channel blockers and ACE inhibitors, respectively, relative to users of β-blockers. There was little difference in risk estimates with duration of use of calcium-channel blockers of less than 1·0 year (relative risk 1·46), 1·0–3·9 years (1·26), and 4·0 years or more (1·23). Interpretation The small positive association between calcium-channel blockers and risk of cancer is unlikely to be causal since there is no increase in risk with increasing duration of calcium-channel blocker use.

Incidence of first-time idiopathic seizures in users of tramadol.

Study Objective. To assess the risk of idiopathic incident seizures among patients who ever took tramadol.

Sudden Unexplained Death Among Subjects with Refractory Epilepsy

Summary: Purpose: To address concerns about possible increases in rates of sudden unexplained death (SUD) after use of new anticonvulsants, more information on the rate of SUD among subjects with refractory epilepsy is needed to provide a comparison.

The Risk of Myocardial Infarction Associated with Antihypertensive Drug Treatment in Persons with Uncomplicated Essential Hypertension

We conducted a case‐control study based on computer‐recorded information accrued in the United Kingdom General Practice Research Database to assess and compare the relation between different antihypertensive drug therapies and myocardial infarction in patients with no known clinical or laboratory risk factors for myocardial infarction other than hypertension. Cases were treated hypertensive patients with no other known risk factors who developed a first acute myocardial infarction between January 1, 1993, and October 31, 1994. They were ascertained from a review of the clinical record together with a questionnaire filled out by the attending general practitioner. Controls were matched to each case for age, sex, general practice, and index date. Antihypertensive therapy was derived from the computerized patient record. The study consisted of 210 cases and 793 controls. Compared with users of β‐blockers alone, the adjusted relative risk (RR) estimates for all other treatment regimens were close to 1.0. A comparison of users of calcium channel blockers alone with users of β‐blockers alone yielded a RR estimate of 0.9 (95% CI 0.5, 1.7). We conclude that the risk of acute myocardial infarction in otherwise healthy, treated hypertensive patients is not materially associated with the particular drug they receive.

The risk of seizures associated with tramadol

We conducted a study of the risk of idiopathic incident seizures among users of tramadol derived from data present in the General Practice Research Database based in the United Kingdom for 1994–1996. We used a nested case‐control study design, comparing risks of idiopathic incident seizures during exposed and unexposed times among patients who had ever taken tramadol using a 90‐day follow‐up. Among the 10,916 subjects, we identified 17 cases of idiopathic seizures, 11 of which were definite and 6 possible. None of the patients was exposed to tramadol alone in the prior 90 days. Eight patients were exposed to opiates, five to both tramadol and opiates, three to other analgesics, and one to no analgesics. We found no increased risk of idiopathic incident seizures associated with exposure to tramadol alone. Thus seizures seem rarely attributable to the agent.

A large population-based follow-up study of trimethoprim-sulfamethoxazole, trimethoprim, and cephalexin for uncommon serious drug toxicity.

We conducted a population‐based 45‐day follow‐up study of 232,390 people who were prescribed trimethoprim‐sulfamethoxazole (TMP‐SMZ), 266,951 prescribed trimethoprim alone, and 196,397 prescribed cephalexin, to estimate the risk of serious liver, blood, skin, and renal disorders resulting in referral or hospitalization associated with these drugs. The results were based on information recorded on office computers by selected general practitioners in the United Kingdom, together with a review of clinical records. The risk of clinically important idiopathic liver disease was similar for persons prescribed TMP‐SMZ (5.2/100,000) and those prescribed trimethoprim alone (3.8/100,000). The risk for those prescribed cephalexin was somewhat lower (2.0/100,000). Only five patients experienced blood disorders, one of whom was exposed to TMP‐SMZ; of seven with erythema multiforme and Stevens‐Johnson syndrome, four were exposed to TMP‐SMZ. The one case of toxic epidermal necrolysis occurred in a patient who took cephalexin. Finally, only five cases of acute parenchymal renal disease occurred, none likely to be caused by a study drug. We conclude that the risk of the serious diseases studied is small for the three agents, and compares reasonably with the risk for many other antibiotics.

The incidence of breast cancer in the General Practice Research Database compared with national cancer registration data.

Breast cancer incidence rates in the UK from 1990 to 1996 among women aged 35–69 estimated from the General Practice Research Database (GPRD) were closely similar to those reported by the Office for National Statistics from cancer registration data (ONS). The GPRD is a valuable and up-to-date resource for further study of the incidence of breast cancer in the UK as well as changes in cancer treatment and their relation to survival trends.