Catherine Vasilakis

Risk of idiopathic cardiovascular death and rionfatal venous thromboembolism in women using oral contraceptives with differing progestagen components

Concern about the risks of cardiovascular illness in women using combined oral contraceptives (OC) containing the progestagens desogestrel and gestodene prompted two studies of data from the UK General Practice Research Database. We compared the risks of certain cardiovascular illnesses in otherwise healthy women exposed to one of three OCs containing < 35 micrograms oestrogen plus levonorgestrel, desogestrel, or gestodene. In the first study, based on some 470 general practices, there were 15 cases of unexpected idiopathic cardiovascular death among 303,470 women who were current users of one of the study OCs. The estimated incidence rates were 8/184,536 (4.3 per 100,000) woman-years at risk for users of combined OCs containing levonorgestrel, 2/135,567 (1.5 per 100,000) for desogestrel users, and 5/105,201 (4.8 per 100,000) for gestodene users. The relative risk (RR) estimates were 0.4 (95% CI 0.1-2.1) and 1.4 (CI 0.5-4.5) for desogestrel and gestodene, respectively, compared with levonorgestrel. In the second study, derived from some 370 general practices, there were 80 cases of nonfatal venous thromboembolism (VTE) in a cohort of 238,130 otherwise healthy women. The incidence rates of VTE per 100,000 woman-years at risk were 16.1 for levonorgestrel users, 29.3 for desogestrel, and 28.1 for gestodene. The adjusted RR estimates from the cohort analysis were 1.9 (1.1-3.2) and 1.8 (1.0-3.2) for desogestrel and gestodene users, respectively, compared with users of levonorgestrel. In a nested case-control analysis the adjusted matched RR estimates were 2.2 (1.1-4.4) and 2.1 (1.0-4.4) for desogestrel and gestodene users, respectively, compared with users of levonorgestrel. The excess risk for nonfatal VTE associated with the new generation of combined OCs containing low-dose oestrogen and the progestagens desogestrel or gestodene compared with levonorgestrel is estimated to be 16 per 100,000 woman-years.

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.

Risk of acute myocardial infarction and low-dose combined oral contraceptives

Researchers from Boston University Medical Center assessed 303470 women who had used combined low estrogen oral contraceptives (OCs) containing levonorgestrel desogestrel or gestodene between January 1991 and October 1994 to investigate the risk of myocardial infarction. 11 women had experienced an acute myocardial infarction or sudden death. Each myocardial infarction case was matched to four controls by age index date of the case and general practice. The relative risk for desogestrel gestodene and past use compared with levonorgestrel stood at 0.7 0.6 and 0.9 respectively (95% confidence interval: 0.1-8.2 0.1-6.4 and 0.2-4.5 respectively). 6 of the 11 cases were either current smokers or past smokers. Based on these findings the researchers concluded that users of low-dose OCs were at low risk of myocardial infarction and any risk was limited to smokers. Further these findings support the findings of earlier studies that also found the risk of acute myocardial infarction to be very low in otherwise healthy users of low-dose OCs.

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.

Antihypertensive drugs and fatal myocardial infarction in persons with uncomplicated hypertension

We conducted a case‐control study to evaluate the risk of fatal myocardial infarction in otherwise healthy treated hypertensive subjects according to the type of the antihypertensive drug used. The study encompassed 207 cases and 409 controls matched to cases on age, sex, and general practice. Compared with beta‐blocker users, the matched relative risk estimates for fatal myocardial infarction, adjusted for recent blood pressure, body mass index, smoking, duration of hypertension, and prior use of other antihypertensive drugs, were 0.7 [95% confidence interval (CI) = 0.4–1.2] for angiotensin‐converting enzyme inhibitor users, 0.9 (95% CI = 0.5–1.5) for calcium channel blocker users, and 0.7 (95% CI = 0.4–1.2) for diuretic users.

Pregnancies and terminations after 1995 warning about third-generation oral contraceptives.

On Oct 18, 1995, the Medicines Control Agency sent a warning letter based on in-press studies that reported that women who used third-generation oral contraceptives containing gestodene or desogestrel were at increased risk for venous thromboembolism compared with women using oral contraceptives containing levonorgestrel (“other” users). The warning letter raised concerns that the number of pregnancies and terminations of pregnancy (TOP) would increase. With data from the General Practice Research Database, we identified women who had received a thirdgeneration or “other” oral contraceptive prescription in the months before October, 1994, and compared their subsequent use of oral contraceptives as well as the frequency of pregnancy and TOP in the subsequent 12 months with that of women who received oral contraceptives in the months prior to October, 1995, just before the Committee on Safety of Medicines warning. The study encompassed over 31 000 users of oral contraceptives in each of the study years of which over 17 000 were users of third-generation pills. In the 1994 cohort, 77% of other users and 74% of third-generation users continued the same pill after October; 8% and 4%, respectively, switched to another oral contraceptive, and 15% and 22%, respectively, stopped taking pills. By contrast, in the 1995 cohort 79% of other users but only 14% of third-generation users continued the same pill after Oct 18, 1995. 5% of other users and 68% of third-generation users switched to an alternative oral contraceptive. The percentage of women who stopped taking oral contraceptives in the 1995 cohort was similar for both other and thirdgeneration users—16% and 18%, respectively. The 12-month frequency of pregnancies did not materially differ in the 1995 cohort compared with the 1994 cohort, nor did the frequencies differ in other users compared with third-generation users. The age-adjusted frequency of TOP in each of the 3-month periods after October 1, 1994, was similar for the two types of oral contraceptive (table). Although the frequencies of termination after Oct 1, 1995, were similar to those in the 1994 cohort, when the comparison was between types of pill users, the frequency of termination was slightly higher in the fourth quarter in thirdgeneration users (3·0 per 1000 compared with 1·8 per 1000, p<0·05, table), reflecting a low TOP frequency among other users rather than an increased frequency in third-generation users. The main findings of this study are first that, by contrast to the previous year’s experience, most third-generation users switched to another oral contraceptive shortly after the warning letter of Oct 18, 1995, but there was little change in the proportion of women who stopped using the pill. Second, the frequency of unterminated pregnancies and TOP was similar for both 12-month follow-up periods and between the different types of oral contraceptive, except possibly for the period July–September in the 1995 cohort. When we reviewed the experience of all women (oral contraceptive users and non-users) in the General Practice Research Database population, we found little differences in the frequencies of non-terminated pregnancies or pregnancy terminations between the 2-year periods. The pregnancy frequencies in the entire General Practice Research Database population less than age 50 were 30·7 and 31·4 per thousand women for the 12 months following October, 1994, and Increased risk of cerebral venous sinus thrombosis with thirdgeneration oral contraceptives