Marian Wald Myers

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.

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 sulfasalazine- and mesalazine-associated blood disorders.

Sulfasalazine (SASP) has often been reported to cause serious blood disorders, particularly agranulocytosis; however, little quantitative information is available to estimate the risk or to identify possible modifiers of the risk. We used comprehensive clinical information recorded on office computers by selected general practitioners in Britain to conduct a follow‐up study of some 10,000 users of SASP and some 4000 users of mesalazine to estimate the risk of blood disorders associated with these drugs. Overall, the frequency of blood disorders attributable to SASP was 27/10,332 (2.6/1000 users). The risk for SASP users who were treated for arthritic disorders (6.1/1000 users) was some 10 times higher than that for users who were treated for inflammatory bowel disease (0.6/1000 users). There were no cases of blood disorders in users of mesalazine.

Acetaminophen and the risk of renal and bladder cancer in the general practice research database.

We conducted a nested, matched case-control study in the General Practice Research Database (GPRD) to assess whether acetaminophen use is associated with renal or bladder cancer. We matched 109 cases of renal cancer and 189 cases of bladder cancer with up to 4 controls each by age, sex, general practice, duration of drug history in the GPRD, and index date. We found that use of acetaminophen from 1 to 5 years before the index date was associated with an increased risk of renal cancer, with a direct relation between risk and number of prescriptions and an adjusted odds ratio of 2.3 (95% CI 1.0–5.3) for subjects with 20 or more prescriptions. There was no evidence for an increase in risk of bladder cancer with acetaminophen use. We found no association between use of non-steroidal anti-inflammatory drugs and either renal or bladder cancer. These results support previous findings from our group and are consistent with a slight increase in the risk of renal cancer, but not bladder cancer, with heavy acetaminophen use.

Risk of idiopathic cerebral haemorrhage in women on oral contraceptives with differing progestagen components

The risk of idiopathic cerebral haemorrhage in users of third-generation oral contraceptives compared with that of users of second-generation oral contraceptives was evaluated using data from the General Practice Research Database. We found no increased risk for third-generation oral contraceptives, compared with second-generation oral contraceptives.