To achieve absolute risk estimates of venous thromboembolism (VTE) among women on cyproterone acetate plus ethinylestradiol (CPA/EE), and among women on combined oral contraceptives (COCs).
From the Danish National Register of Patients (NRP), 1996 to 1998, the records of 1.1 million Danish women, ages 15 to 44 years, were searched for evidence of VTE. COC use was ascertained through mailed questionnaires. Sales statistics of COCs and CPA/EE were provided through Danish Drug Statistics.
During the time frame of the study, 330 women were found to have had VTE while on COCs. Of these women, 67 were on levonorgestrel-containing COCs. Eleven were on CPA/EE. The corresponding absolute risk of VTE was 3.4 (range, 3.1-3.8) per 10 000 women years among the women on COCs, 4.2 (range, 3.2-5.2) per 10 000 women years among women on levonorgestrel-containing COCs, and 3.1 (range, 1.3-4.9) per 10 000 women years among the women on CPA/EE.
Our results suggest the absolute risk of VTE among Danish women on COCs is similar to that among women taking CPA/EE.
Data from the Swedish Adverse Reactions Advisory Committee suggest that use of clozapine is associated with venous thromboembolic complications. We summarise 12 cases of thromboembolism during clozapine treatment. In five cases the outcome was fatal.
A number of case-control studies published in 1995/1996 have shown an apparent increase in the risk of venous thromboembolism (VTE) associated with the use of third-generation oral contraceptives (OC). However, it was discussed very early on that these studies were subject to a number of biases or residual confounding that would have increased the risk estimates for third-generation OC while lowering those for second-generation preparations. Six new studies or analyses were performed trying to take into account many of the methodological problems that were discussed for the initial studies: Two population-based database analyses in the UK and Germany, a new analysis of the General Practice Registry database (GPRD) in the UK, an analysis of a new database of the Transnational study, a re-analysis of the original Transnational study with a new technique, and a population-based study in Denmark. These studies could not confirm a higher VTE risk in users of third-generation OC compared with those using second-generation OC. Data on the risk of arterial thromboembolism (ischaemic stroke and myocardial infarction) show no such difference between generations of OC, with a statistically significant reduction in the risk of acute myocardial infarction from first- to third-generation preparations in one major study. Some of the investigators concluded that there is very likely no increased risk of arterial thromboembolism associated with the use of low-dose oestrogen OC in young women who are properly screened for cardiovascular risk factors or for such conditions. These findings should be taken into account when interpreting the results of studies on the risk of VTE in women taking combined OC.
Cyclooxygenase-2 (COX-2) inhibitors belong to a new class of drugs which have anti-inflammatory efficacy similar to that of traditional non-steroidal anti-inflammatory drugs (NSAIDs), but are associated with a reduced incidence of adverse upper gastrointestinal events. Biochemical evidence that COX-2 inhibitors could promote or exacerbate a tendency to thrombosis is supported by recent results from clinical trials and case reports. Two agents in this class, celecoxib and rofecoxib, have been listed on the Pharmaceutical Benefits Scheme (PBS) for very broad indications in chronic arthropathies, suggesting that they will move into widespread community use. It is important to canvass the possibility that use of these agents could be associated with thrombotic events.
Comment In: Med J Aust. 2002 Jan 21;176(2):88-9; author reply 8911936297
BACKGROUND: Fatal venous thromboembolism (VTE) is a rare complication of combined oral contraceptive (COC) treatment. This study aims to determine incidences of fatal VTE in relation to the type of COC and the percentage of cases reported to the Swedish Adverse Drug Reactions Advisory Committee (SADRAC). A further aim is to compare the characteristics of reported and not reported cases. METHODS: This retrospective study is a separate analysis using data from a larger study that included women aged 15-44 years between 1990 and 1999 with VTE coded as the underlying or contributory cause of death in the Swedish Cause of Death Register. COC use within 2 months of the date of symptom onset or death was identified in 28 cases. Sales data were obtained from the National Corporation of Swedish Pharmacies. Reported cases were identified in the SADRAC database. RESULTS: After excluding two cases where the type of COC was unknown, the crude incidences of fatal VTE were 5.1 (95% CI 2.3, 9.6), 8.6 (95% CI 4.3, 15.4) and 9.1 (95% CI 3.3, 19.8) cases per million women per year for levonorgestrel-, desogestrel- and norethisterone-containing COCs, respectively. Age-adjusted incidences were approximately twice as high for desogestrel- and norethisterone-containing COCs compared with levonorgestrel-containing COCs, although differences were not statistically significant. Thirty-six percent of cases were reported. Reporting was positively associated with information in medical records relevant to the VTE diagnosis that the patient was a COC user and was significantly higher in northern Sweden. CONCLUSION: Results from this study support a higher incidence of fatal VTE with desogestrel-containing COCs than with levonorgestrel-containing COCs.
BACKGROUND: We wanted to study the incidence of venous thromboembolism (VTE), acquired risk factors of VTE and preventable cases among users of combined oral contraceptives (COCs). METHODS: All women aged 15-44 years, (n = 24 373) living in the county of Jämtland, Sweden, between 1991 and 2000, constituted the study base in a retrospective case-reference study. Women with VTE were identified through hospital registers and interviewed by telephone. The utilization of COCs according to age was obtained from a prospective prescription database, and data from national health databases were used. RESULTS: Of 88 women with first-time VTE, 43 (49%) were COC users and 13 (15%) were pregnant. All women had at least one known risk factor, and 51 (58%) women had combinations of risk factors. The total incidence rate of VTE per 100,000 women-years for all women were 36 (29-44), for nonusers 19 (12-25) for women using third generation COCs 115 (67-184), for women using other COCs 60 (37-83), and for women during pregnancy and postpartum 103 (55-177). Of the total 244,000 women-years represented, COC users constituted 24%, pregnant women 5%, and women with other acquired risk factors 5%. The corresponding incidence rates after excluding VTE cases with other acquired risk factors were 10 (6-14), 1.2 (0.14-4.4), 64 (29-121), 27 (13-48), and 59 (24-121), per 100,000 women-years. In 11 (26%) of the COC-related VTE cases, there were relative contraindications for use of COCs or lack of thromboprophylaxis in relation to surgery. CONCLUSION. We found a very low incidence of idiopathic VTE among young non-OC users. The incidence of VTE during pregnancy was only slightly higher than during COC use. It was considered that a significant part of COC-related VTE might have been avoided.
In experimental systems, interference with coagulation can affect tumor biology. Furthermore, it has been suggested that low molecular weight heparin therapy may prolong survival in patients with cancer. The primary aim of this study was to assess survival at 1 year of patients with advanced cancer.
Patients with advanced malignancy (N = 385) were randomly assigned to receive either a once-daily subcutaneous injection of dalteparin (5,000 IU), a low molecular weight heparin, or placebo for 1 year.
The Kaplan-Meier survival estimates at 1, 2, and 3 years after randomization for patients receiving dalteparin were 46%, 27%, and 21%, respectively, compared with 41%, 18%, and 12%, respectively, for patients receiving placebo (P =.19). In an analysis not specified a priori, survival was examined in a subgroup of patients (dalteparin, n = 55; and placebo, n = 47) who had a better prognosis and who were alive 17 months after randomization. In these patients, Kaplan-Meier survival estimates at 2 and 3 years from randomization were significantly improved for patients receiving dalteparin versus placebo (78% v 55% and 60% v 36%, respectively, P =.03). The rates of symptomatic venous thromboembolism were 2.4% and 3.3% for dalteparin and placebo, respectively, with bleeding rates of 4.7% and 2.7%, respectively.
Dalteparin administration did not significantly improve 1-year survival rates in patients with advanced malignancy. However, the observed improved survival in a subgroup of patients with a better prognosis suggests a potential modifying effect of dalteparin on tumor biology.
BACKGROUND: Pregnancy and use of combined oral contraceptives (COCs) are major risk factors for venous thromboembolism (VTE) in young women and we wanted to obtain accurate VTE mortality data overall, by age, associated with the use of COCs and pregnancy. METHODS: From the Swedish Cause of Death Register (CDR) we identified women aged 15-44 with VTE as underlying or contributory cause of death during the period 1990-1999. We scrutinized medical records and included verified VTE cases without active cancer or terminal disease. Pregnancy statistics and COC utilization data were obtained from national databases. RESULTS: Of the 120 cases included, 9 (8%) were associated with pregnancy and 28 (23%) with current COC use. The overall refined VTE mortality rate in current COC users was 7.5[4.7; 10.3] per million user-years and the corresponding pregnancy-related rate was 8.9[4.1;17.0] per million pregnancy years, rates increasing with age. For ages 15-24, the rate was significantly higher in current COC users than in non-pregnant women not using COCs: 6.0[3.1; 10.5] per million user-years vs. 0.3[0.0; 1.2] per million woman years. Underlying cause mortality data included 82% of VTE deaths associated with COCs, and 56% of maternal deaths had a pregnancy-related code. CONCLUSION: Mortality figures from VTE associated with the use of COCs and pregnancy were similar. COC use had an important impact on the total VTE mortality in the youngest age group. Standard mortality statistics do not allow accurate monitoring of VTE mortality in young women due to missing data, misdiagnoses and coding rules.